Methods of treating heart failure with preserved ejection fraction

Abstract

Described herein are neonatal cardiac mesenchymal progenitor cells (nMPCs), nMPC secretomes, nMPC exosomes, or a combination thereof for treating heart failure with preserved ejection fraction (HFpEF), dilated cardiomyopathy, or kidney disease in a subject. One or more doses of the neonatal cardiac mesenchymal progenitor cells, nMPC secretomes, nMPC exosomes, or a combination thereof can be administered to the subject. Neonatal cardiac mesenchymal progenitor cells can be allogeneic. The subject may also be administered one or more combination therapies.

Description

WSGR Docket No. 64320-711.601METHODS OF TREATING HEART FAILURE WITH PRESERVED EJECTION FRACTION CROSS-REFERENCE

[0001] This application claims the benefit of U. S. Provisional Application No. 63 / 769,528, filed March 10, 2025, U.S. Provisional Application No. 63 / 902,246, filed October 20, 2025, U.S. Provisional Application No. 63 / 769,531, filed March 10, 2025, and U.S. Provisional Application No. 63 / 890,106, filed September 29, 2025, which applications are incorporated herein by reference in their entireties.BACKGROUND

[0002] Heart failure with preserved ejection fraction (HFpEF, also known as diastolic heart failure) accounts for about half of all U. S. heart failure hospitalizations, with the majority of these patients being over 70 years of age. HFpEF may co-occur in patients who have chronic hypertension, diabetes, and / or obesity. For patients under age 65, diastolic heart failure is uncommon, except in association with longstanding severe hypertension, which is particularly prevalent in African American men. Heart failure with preserved ejection fraction (HFpEF) remains a major therapeutic challenge due to its complex pathophysiology and pronounced cellular heterogeneity. There is an unmet need for new treatment methodologies for HFpEF.

[0003] Dilated cardiomyopathy (DCM) is a heart disease characterized by ventricular dilatation and systolic dysfunction. Dilated cardiomyopathy is not only the most common cause of coronary artery disease and heart failure after hypertension, but also an important sign for heart transplantation. In the United States alone, the cost for the management of dilated cardiomyopathy was estimated to be between $4 billion and $10 billion. There is an unmet need for new treatments for dilated cardiomyopathy.

[0004] Acute kidney injury (AKI) refers to rapid onset damage to the kidney, notably the tubular epithelial cells. It may be chemically driven, for example renal damage or injury caused by a medicine, chemical, contrast dye or herbal or dietary supplements. It may also be caused by ischemia, mechanical or immune factors. AKI affects up to 10% of patients in hospital settings. There is major mortality associated with AKI and mortality in patients requiring intensive care post AKI can be up to 50%. For those surviving AKI, there are long-term risks of progressing to chronic kidney disease (CKD), end stage renal failure, renal replacement therapy or transplantation. Chronic kidney disease (CKD) is a major chronic disease that seriously endangers human health and significantly increases the morbidity and mortality of cardiovascular diseases. Many patients with chronic kidney disease are not diagnosed early, which leads to an increase in the risk of end-stage kidney diseases and cardiovascular diseases and brings a huge medical burden. There is an unmet need for compositions which can be used to treat chronic kidney disease or acute kidney injury.SUMMARY OF THE DISCLOSURE

[0005] Described herein, in certain aspects, are compositions comprising neonatal cardiac mesenchymal progenitor cells (nMPCs) and uses thereof in the treatment of various diseases such as, for example, Heart Failure with Preserved Ejection Fraction (HFpEF), dilated cardiomyopathy, and kidney diseases.WSGR Docket No. 64320-711.601

[0006] Described herein, in certain aspects, are compositions comprising neonatal cardiac mesenchymal progenitor cells (nMPCs) and uses thereof in the treatment of cardiomyopathy in subjects with heart failure with preserved ejection fraction (HFpEF). Described herein, in certain aspects, are compositions comprising an nMPC secretome (conditioned media), nMPC exosomes, an nMPC total secretome, or a combination thereof in the treatment of cardiomyopathy in subjects with heart failure with preserved ejection fraction (HFpEF). The therapeutic mechanism of action of nMPCs in HFpEF is through the upregulation of Tregs resulting in multi-modular effects, reduced systemic inflammation and immune dysregulation, inhibition of fibrosis, improved ventricular relaxation, restoration of microvascular function, enhanced metabolism, and reduced oxidative stress. Provided herein is a method of treating heart failure with preserved ejection fraction (HFpEF), in a subject in need thereof, comprising administering to the subject neonatal cardiac mesenchymal progenitor cells (nMPCs), an nMPC secretome (conditioned medium), nMPC exosomes, an nMPC total secretome, or a combination thereof, whereby the HFpEF is treated.

[0007] Described herein, in certain aspects, are compositions comprising neonatal cardiac mesenchymal progenitor cells (nMPCs) and uses thereof in the treatment of cardiomyopathy in subjects with dilated cardiomyopathy (DCM). Described herein, in certain aspects, are compositions comprising secretomes (conditioned media) and / or exosomes produced by the nMPCs in the treatment of cardiomyopathy in subjects with dilated cardiomyopathy (DCM). Provided herein is a method of treating dilated cardiomyopathy (DCM) in a subject in need thereof, comprising administering to the subject neonatal cardiac mesenchymal progenitor cells (nMPCs), a secretome (conditioned medium) produced by the nMPCs, exosomes produced by the nMPCs, or any combination thereof, whereby DCM is treated.

[0008] Described herein, in certain aspects, are compositions comprising neonatal cardiac mesenchymal progenitor cells (nMPCs) and uses thereof in the treatment of acute kidney injury, acute kidney disease, or chronic kidney disease. Described herein, in certain aspects, are compositions comprising nMPC secretome (conditioned media) and / or nMPC exosomes in the treatment of acute kidney injury, acute kidney disease, or chronic kidney disease.

[0009] In one embodiment of any of such methods, the nMPCs are (a) positive for protein expression of Ki67 orNkx2.5, (b) positive for cell surface protein expression of c-Kit (CD117), CD44, CD73, CD47, CD105, and / or CD90, (c) positive for miRNA expression of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and / or miR-374b-5p, and (d) negative for protein expression of CD34, CD45, CD31, PECAM-1, tryptase, GATA4, ISL1, SSEA3, SSEA4, and / or pl6INK4a. In one embodiment, the nMPCs are (a) positive for protein expression of Ki67 or Nkx2.5, (b) positive for cell surface protein expression ofc-Kit (CD117), CD44, CD73, CD47, CD105, or CD90, (c) positive for miRNA expression of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, or miR-374b-5p, and (d) negative for protein expression of CD34, CD45, CD31, PECAM-1, tryptase, GATA4, ISL1, SSEA3, SSEA4, or p!6INK4aIn another embodiment, the nMPCs are (a) positive for protein expression of Ki67 and Nkx2.5, (b) positive for cell surface protein expression of c-Kit (CD117), CD44, CD73, CD47, CD105, and CD90, (c) positive for miRNA expression of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, andWSGR Docket No. 64320-711.601miR-374b-5p, and (d) negative for protein expression of CD34, CD45, CD31, PECAM-1, tryptase, GATA4, ISL1, SSEA3, SSEA4, and pl6INK4a. In certain embodiments, the nMPCs are further positive for protein expression of PDL1, OCT3 / 4, NANOG, KLF4, HSF1, or SOX2. In some embodiments, the nMPCs are further positive for protein expression of PDL1, OCT3 / 4, NANOG, KLF4, HSF1, and SOX2. Alternatively, or in addition, the nMPCs are further negative for protein expression of p!6INK4aup to at least passage 8. In some embodiments, the nMPCs are (a) positive for protein expression of Ki67, Nkx2.5, OCT3 / 4, NANOG, KLF4, HSF1, and / or SOX2, (b) positive for cell surface protein expression of c-kit (CD117), CD44, CD73, CD47, CD105, CD90, and / or PDL1, (c) positive for miRNA expression ofmiR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and / or miR-374b-5p, and (d) negative for protein expression of CD34, CD45, CD31, PECAM-1, tryptase, GATA4, ISL1, SSEA3, SSEA4, and / or p!6INK4a. In certain embodiments, the nMPCs are (a) positive for protein expression of Ki67, Nkx2.5, OCT3 / 4, NANOG, KLF4, HSF1, or SOX2, (b) positive for cell surface protein expression of c-kit (CD117), CD44, CD73, CD47, CD105, CD90, or PDL1, (c) positive for miRNA expression of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, or miR-374b-5p, and (d) negative for protein expression of CD34, CD45, CD31, PECAM-1, tryptase, GATA4, ISL1, SSEA3, SSEA4, or p!6INK4aIn yet other embodiments, the nMPCs are (a) positive for protein expression of Ki67, Nkx2.5, OCT3 / 4, NANOG, KLF4, HSF1, and SOX2, (b) positive for cell surface protein expression of c-kit (CD117), CD44, CD73, CD47, CD105, CD90, andPDLl, (c) positive for miRNA expression of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and miR-374b-5p, and (d) negative for protein expression of CD34, CD45, CD31, PECAM-1, tryptase, GATA4, ISL1, SSEA3, SSEA4, and pl6INK4a.

[0010] In some embodiments, the nMPCs are genetically engineered. In other embodiments, the nMPCs are genetically engineered to overexpress one or more paracrine factors. In some embodiments, the nMPCs are genetically engineered to overexpress HGF, SCF, SDF-la, ANG1, VEGFA, PDGFB, bFGF, HSP20, Akt, miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and / or miR-374b-5p. In some embodiments, the nMPCs are genetically engineered to overexpress 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 of HGF, SCF, SDF-la, ANG1, VEGFA, PDGFB, bFGF, HSP20, Akt, miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and miR-374b-5p. In certain embodiments, the nMPCs are (a) positive for protein expression of Ki67, Nkx2.5, OCT3 / 4, NANOG, KLF4, HSF1, and / or SOX2, (b) positive for cell surface protein expression of c-Kit (CD117), CD44, CD73, CD47, CD105, CD90, and / or PDL1, (c) positive for miRNA expression of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and / or miR-374b-5p, (d) negative for protein expression of CD34, CD45, CD31, PECAM-1, tryptase, GATA4, ISL1, SSEA3, SSEA4, and / or pl6INK4a, and (e) genetically engineered to overexpress HGF, SCF, SDF-la, ANG1, VEGFA, PDGFB, bFGF, HSP20, Akt, miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and / or miR-374b-5p. In one embodiment, the nMPCs are (a) positive for protein expression of Ki67, Nkx2.5, OCT3 / 4, NANOG, KLF4, HSF1, and SOX2, (b) positive for cell surface protein expression of c-Kit (CD117), CD44, CD73, CD47, CD105, CD90, and PDL1, (c) positive for miRNA expression of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and miR-374b-5p, (d) negative for protein expression of CD34, CD45, CD31, PECAM-1, tryptase,WSGR Docket No. 64320-711.601GATA4, ISL1, SSEA3, SSEA4, and p!6INK4a, and (e) genetically engineered to overexpress HGF, SCF, SDF-la, ANG1, VEGFA, PDGFB, bFGF, HSP20, Akt, miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and miR-374b-5p. In some embodiments, the nMPCs are allogeneic or autologous. In certain embodiments, the nMPCs are non-naturally occurring. In other embodiments, the nMPCs are not xenogenic. In some embodiments, the nMPCs are obtained from a subject who is biologically a female. In certain other embodiments, the nMPCs are obtained from a subject who is biologically a male.

[0011] In some embodiments, the nMPCs are: (a) positive for protein expression of 1, 2, 3, 4, 5, 6, or 7 of Ki67, Nkx2.5, OCT3 / 4, NANOG, KLF4, HSF1, and SOX2; (b) positive for cell surface protein expression of 1, 2, 3, 4, 5, 6, or 7 ofc-Kit (CD117), CD44, CD73, CD47, CD105, CD90, and PDL1; (c) positive for miRNA expression of 1, 2, 3, 4, 5, or 6 of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and miR-374b-5p, (d) negative for protein expression of 1, 2, 3, 4, 5, 6, 7, 8, or 9 of CD34, CD45, CD31, PECAM-1, tryptase, GATA4, ISL1, SSEA3, and SSEA4; and / or (e) negative for protein expression of p!6INK4aup to at least passage 8. In one embodiment, the nMPCs are: (a) positive for protein expression of 1, 2, 3, 4, 5, 6, or 7 of Ki67, Nkx2.5, OCT3 / 4, NANOG, KLF4, HSF1, and SOX2; (b) positive for cell surface protein expression of 1, 2, 3, 4, 5, 6, or 7 of c-Kit (CD117), CD44, CD73, CD47, CD105, CD90, and PDL1; (c) positive for miRNA expression of 1, 2, 3, 4, 5, or 6 of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and miR- 374b- 5p; and (d) negative for protein expression of 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 of CD34, CD45, CD31, PECAM-1, tryptase, GATA4, ISL1, SSEA3, SSEA4, and p!6INK4a. In some embodiments, the nMPCs express HSF1 at levels higher than adult mesenchymal progenitor cells (aMPCs). In some embodiments, the nMPCs are further negative for protein expression of IGF 1. In some instances, the nMPCs do not express 42254.

[0012] In one aspect, compositions comprise an nMPC secretome. In another aspect, the subject is administered a composition comprising the nMPC secretome. In some embodiments, the nMPC secretome comprises cytokines, chemokines, hormones, digestive enzymes, antibodies, extracellular proteinases, morphogens, antimicrobial peptides, chaperone proteins, growth factors, miRNAs, extracellular vesicles (e.g., exosomes), or a combination thereof. In certain embodiments, the nMPC secretome is (a) positive for protein expression of HGF, SCF, SDF-la, ANG1, VEGFA, PDGFB, bFGF, HSP20, HSF1, and / or Akt, and (b) positive for miRNA expression of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and / or miR-374b-5p. In one embodiment, the nMPC secretome is (a) positive for protein expression of HGF, SCF, SDF-la, ANG1, VEGFA, PDGFB, bFGF, HSP20, HSF1, or Akt, and (b) positive for miRNA expression of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, or miR-374b-5p. In another embodiment, the nMPC secretome is (a) positive for protein expression of HGF, SCF, SDF-la, ANG1, VEGFA, PDGFB, bFGF, HSP20, HSF1, and Akt, and (b) positive for miRNA expression of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and miR-374b-5p. In certain embodiments, the nMPC secretome is positive for miRNA expression of one, two, three, four, five, or six of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, or miR-374b-5p.WSGR Docket No. 64320-711.601

[0013] Alternatively, or in addition, in certain embodiments, the nMPC secretome is positive for protein expression of one, two, three, four, five, six, seven, eight, nine, ten, or more of FUS, TAF15, CAP2, SNX9, PSMB7, SUMO1, EIF3A, ECHI, HNRNPL, NTM, ANG, ERP44, NAA38, RRM2B, RAB1A, RAB1B, PGRMC1, ERH, TIGAR, ITGA2, SGTA, AR1C1, AKR1C2, DNASE2, HSP90AB4P, ANGPTL2, SF3B2, GREM1, ARF3, ARF1, ARF5, LSM5, PSMD9, SUGT1, ALDH1A3, PDGFRB, HIST1H1C, SP100, G6PD, PPIL1, SNRPD1, FDPS, RAB6B, RAB6A, DCTD, GLB1, ARIH1, IST1, HNRNPU, ULBP2, RAET1G, ERAP2, CDC42, EDF1, LIPG, FKBP4, RBMX, RBMXL1, RPL30, THY1, AP2M1, RPS16, FHL3, BZW1, BZW2, EIF4G1, PFDN4, CLTB, PIR, MVP, ECU, DCI, ALYREF, RPS10, PPP3CA, TAX1BP3, PPA1, DDX39B, DDX39A, GNPNAT1, LIMA1, SNRPD3, ADH5, ENAH, DYNLL1, DYNLL2, HUWE1, HMGB2, PTMS, UCHL3, PFDN2, DYNLRB1, HDGFRP2, INF2, HPRT1, EIF2S2, ADAMT7, EIF3C, EIF3CL, RPS5, VPS35, CS, ECHS1, UBQLN1, GBP2, GBP1, SF3B1, RANBP1, GNS, HLA-B, UBXN1, GNPDA1, IGF2, EIF3B, TCEB1, VASP, GSR, HLA-A, HLA-HIGF2, NUDT5, COPE, HNRNPA3, SRI, HNRNPC, MMP10, EWSR1, IPO7, YARS, TMPO, HNRNPH1, HLA-A, PDGFC, IL1B, S100A10, TXNDC2, DPY30, LAMP1, LYPLA1, CBR1, ARHGAP1, TPR, NAMPT, NAMPTL, CXCL2, EIF4A2, RPS4X, PABPN1, PHLDB1, NAP1L4, DDX6, PSMC3, MAP7D1, OSCAR, TES, NMT1, NMT2, MAT2A, PRMT1, COX17, SELM, CARS, PPP2CA, PPP2CB, VEGFC, VPS26A, PXN, PAWR, STRAP, RABI 1 A, RABI IB, EIF5, COPZ1, C0PS3, CHMP4B, PDXK, RALA, RALB, SEC13, FHL2, TOMI, PYCARD, PDLIM4, RBBP4, RBBP7, RPS20, SRSF1, DLD, SNRPE, EIF4EBP1, RPLPO, RPLP0P6, LSM3, SLC16A3, CSE1L, NUCKS1, TSNAX, RPSA, RPSAP58, AP1B1, EIF2S1, LCP1, PSMD4, AARS, SRSF2, SFRS2, TRIP10, CLTA, USO1, VBP1, UBE2K, MRPL12, UAP1, HIST1H1B, YBX3, RPL10A, IDH1, SNRPN, SNRPB, PCK2, EIF6, MMP3, DHX9, MATR3, UBE2D2, UBE2D3, PTRF, ACTR1A, LAMA1, PDCD6IP, QARS, HN1L, PLBD2, OS9, ILF3, ISOCI, PPP1R7, MAPK1, PDCD1LG2, GOLGB1, HSPA9, ACBD3, BTF3, UBE2I, SRRT, EIF4H, FERMT2, EIF3G, PARVA, DBNL, BOLA2, MAPRE1, PRDX5, STX12, EIF1, SMS, GRPEL1, OAF, SYNCRIP, ECE1, VAPA, PCNP, PSME1, EIF3J, C14orfl66, DDX1, AKR1B1, SRP9, PCMT1, XPO1, MMP9, RPS7, NRCAM, FKBP3, SSB, DSC3, XRCC5, CCT6A, LIF, SERPINA9, SND1, ANP32B, G3BP1, GPC6, GLOD4, RRBP1, TGFB1, USP14, PLAUR, CXCL3, FASN, COPB2, TARDBP, TNFAIP6, RPS3, NDUFAB1, LMNB1, COL16A1, PSMF1, PHGDH, PRKCDBP, CXCL5, YAP1, TROVE2, MACF1, EIF5B, STX7, PFDNS, APOA1, PDAP1, STX12, EIF3K,FH, RBM8A, EIF1, RPS2, PTGR1, EEA1, CAB39, DCTN2, GDF15, MYL9, TCP1, RPS12, RAD23A, SKP1, PDLIM1, HSPH1, PSMB3, SUB1, API5, TWF2, KTN1, DYNC1H1, SNRNP70, MCFD2, PPP1R18, PTGES3, APEX1, TNKS1BP1, FUBP1, VAT1, PAFAH1B1, CBX1, PTK7, HNRPDL, ZNF185, DYNC1I2, KHDRBS1, SFPQ, PDCD5, TRIM28, PPIC, NARS, PCBP2, CD2AP, PSMA1, CAPRIN1, KHSRP, NSFL1C, PPP1R12A, NUDC, MFAP2, IGF2R, RGMB, PABPC1, MANI Al, DDB1, PTBP1, FBN2, CNBP, OTUB1, NASP,HSPD1, EEF1D, RNPEP, CRKL, HNRNPAB, EIF3F, PAICS,ILF2, COPB1, PA2G4, COP A, NT5E, HMGA1, SF1, XRCC6, GNB2L1, MEI, MTAP, CCT2, ARCN1, PEPD, and EPB41L3. Alternatively, or in addition, in certain embodiments, the nMPC secretome is positive for protein expression of one, two, three, four, five, six,WSGR Docket No. 64320-711.601seven, eight, nine, ten, or more of PPP1CA, PPP1CC, ST13, ST13P5, ST13P4, HMGB1, HMGB1P1, HNRNPA1, HNRNPA1L2, NEDD8, N EDD8-MDP1, YBX1, YBX2, CCT7, HNRNPH3, LTBP1, UBE2N, IL8, CYCS, LGALS1, IL6, PGAM1, YWHAH, TXN, ARHGDIB, PSMA3, RAN, TPM3, BASP1, HSPA8, ITGAV, PPIA, NACA, HSP90AB1, PCBP1, CAP1, NUTF2, PSMA5, CAPZA1, RPLP1, GLO1, ACTG1, ICAM1, SDC4, SOD2, PSMB4, TFPI2, C1QBP, NAP1L1, HSP90AA1, SET, EN01, CCT3, GOT2, HSPE1, PGM3, PLIN3, CNDP2, PGD, SH3BGRL, TLN1, HSP90AB2P, GOT1, HNRNPAO, FTH1, TPD52L2, UGP2, AHNAK, CCT8, PSMA7, CCT4, SRPX2, CLIC4, KPNB1, AP2B1, and PAFAH1B2.

[0014] In some embodiments, the nMPC secretome comprises a final protein concentration of from about 0.1 mg / ml to about 50.0 mg / ml, or from about 0.5 mg / ml to about 20.0 mg / ml. In some embodiments, the nMPC secretome comprises a final protein concentration of (a) at least about 0.1 mg / ml, 0.5 mg / ml, 1.0 mg / ml, about 2.0 mg / ml, about 3.0 mg / ml, about 4.0 mg / ml, about 5.0 mg / ml, about 6.0 mg / ml, about 7.0 mg / ml, about 8.0 mg / ml, about 9.0 mg / ml, about 10.0 mg / ml, about 11.0 mg / ml, about 12.0 mg / ml, about 13.0 mg / ml, about 14.0 mg / ml, about 15.0 mg / ml, about 16.0 mg / ml, about 17.0 mg / ml, about 18.0 mg / ml, about 19.0 mg / ml, about 20.0 mg / ml, about 22.0 mg / ml, about 24.0 mg / ml, about 26.0 mg / ml, about 28.0 mg / ml, about 30.0 mg / ml, about 35.0 mg / ml, about 40.0 mg / ml, about 45.0 mg / ml, or about 50.0 mg / ml, or (b) at most about 250.0 mg / ml, about 225.0 mg / ml, about 200.0 mg / ml, about 175 mg / ml, about 150 mg / ml, about 125 mg / ml, about 100 mg / ml, about 75 mg / ml, about 50 mg / ml, about 45.0 mg / ml, about 40.0 mg / ml, about 35.0 mg / ml, about 30.0 mg / ml, about 25 mg / ml, about 20 mg / ml, about 15 mg / ml, about 10 mg / ml, about 5 mg / ml, about 1 mg / ml, about 0.5 mg / ml, or about 0.1 mg / ml. In some embodiments, the nMPC secretome comprises a final protein concentration of at least about 1.0 mg / ml±0.5. In other embodiments, the nMPC secretome comprises a final protein concentration of at least about 4.0 mg / ml±1.0. In some embodiments, the nMPC secretome comprises a final protein concentration of at least about 8.0 mg / ml±2.0. In yet other embodiments, the nMPC secretome comprises a final protein concentration of at least about 16.0 mg / ml±3.0. In some instances, the composition is concentrated. In some instances, the composition is diluted prior to the administration. In some instances, the nMPC secretome is administered at a concentration of at least about 10 pg / ml to at least about 1000 pg / ml.

[0015] In one aspect, compositions comprise nMPC exosomes. In another aspect, the subject is administered a composition comprising the nMPC exosomes. In some embodiments, the nMPC exosomes comprise a transmembrane protein, tetraspanin, antigen presenting molecule, glycoprotein, adhesion molecule, heat shock protein (Hsp), cytoskeletal protein, ESCRT component, membrane transport protein, fusion protein, growth factor, cytokine, lipid, Fas ligand (FasL), mRNA, miRNA, noncoding RNA, DNA, TNF receptor, or transferrin receptor (TfR), or a combination thereof. In some embodiments, the lipid comprises cholesterol, ceramides, sphingomyelin, phosphatidylinositol (PI), phosphatidylserine (PS), phosphatidylcholine (PC), phosphatidylethanolamine (PE), gangliosides (GM), or a combination thereof. In some embodiments, the nMPC exosomes are (a) positive for protein expression of HGF, SCF, SDF-la, ANG1, VEGFA, PDGFB, bFGF, HSP20, HSF1, and / or Akt, and (b)WSGR Docket No. 64320-711.601positive for miRNA expression of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and / or miR-374b-5p. In one embodiment, the nMPC exosomes are (a) positive for protein expression of HGF, SCF, SDF-la, ANG1, VEGFA, PDGFB, bFGF, HSP20, HSF1, or Akt, and (b) positive for miRNA expression of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, or miR-374b-5p. In another embodiment, the nMPC exosomes are (a) positive for protein expression of HGF, SCF, SDF-la, ANG1, VEGFA, PDGFB, bFGF, HSP20, HSF1, and Akt, and (b) positive formiRNA expression of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and miR-374b-5p. In some embodiments, the nMPC exosomes are positive for miRNA expression of one, two, three, four, five, or six of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and miR-374b-5p. In some embodiments, the nMPC exosomes are positive for protein expression of CD81 and / or CD63. In some embodiments, the nMPC exosomes are positive for protein expression of CD81 and CD63.

[0016] Alternatively, or in addition, in some embodiments, nMPC exosomes are positive for protein expression of one, two, three, four, five, six, seven, eight, nine, ten, or more of FUS, TAF15, CAP2, SNX9, PSMB7, SUMO1, EIF3A, ECHI, HNRNPL, NTM, ANG, ERP44, NAA38, RRM2B, RAB1A, RAB1B, PGRMC1, ERH, TIGAR, ITGA2, SGTA, AR1C1, AKR1C2, DNASE2, HSP90AB4P, ANGPTL2, SF3B2, GREM1, ARF3, ARF1, ARF5, LSM5, PSMD9, SUGT1, ALDH1A3, PDGFRB, HIST1H1C, SP100, G6PD, PPIL1, SNRPD1, FDPS, RAB6B, RAB6A, DCTD, GLB1, ARIH1, IST1, HNRNPU, ULBP2, RAET1G, ERAP2, CDC42, EDF1, LIPG, FKBP4, RBMX, RBMXL1, RPL30, THY1, AP2M1, RPS16, FHL3, BZW1, BZW2, EIF4G1, PFDN4, CLTB, PIR, MVP, ECU, DCI, ALYREF, RPS10, PPP3CA, TAX1BP3, PPA1, DDX39B, DDX39A, GNPNAT1, LIMA1, SNRPD3, ADH5, ENAH, DYNLL1, DYNLL2, HUWE1, HMGB2, PTMS, UCHL3, PFDN2, DYNLRB1, HDGFRP2, INF2, HPRT1, EIF2S2, ADAMT7, EIF3C, EIF3CL, RPS5, VPS35, CS, ECHS1, UBQLN1, GBP2, GBP1, SF3B1, RANBP1, GNS, HLA-B, UBXN1, GNPDA1, IGF2, EIF3B, TCEB1, VASP, GSR, HLA-A, HLA-HIGF2, NUDT5, COPE, HNRNPA3, SRI, HNRNPC, MMP10, EWSR1, IPO7, YARS, TMPO, HNRNPH1, HLA-A, PDGFC, IL1B, S100A10, TXNDC2, DPY30, LAMP1, LYPLA1, CBR1, ARHGAP1, TPR, NAMPT, NAMPTL, CXCL2, EIF4A2, RPS4X, PABPN1, PHLDB1, NAP1L4, DDX6, PSMC3, MAP7D1, OSCAR, TES, NMT1, NMT2, MAT2A, PRMT1, COX17, SELM, CARS, PPP2CA, PPP2CB, VEGFC, VPS26A, PXN, PAWR, STRAP, RABI 1 A, RABI IB, EIF5, COPZ1, COPS3, CHMP4B, PDXK, RALA, RALB, SEC13, FHL2, TOMI, PYCARD, PDLIM4, RBBP4, RBBP7, RPS20, SRSF1, DLD, SNRPE, EIF4EBP1, RPLPO, RPLP0P6, LSM3, SLC16A3, CSE1L, NUCKS1, TSNAX, RPSA, RPSAP58, AP1B1, EIF2S1, LCP1, PSMD4, AARS, SRSF2, SFRS2, TRIP10, CLTA, USO1, VBP1, UBE2K, MRPL12, UAP1, HIST1H1B, YBX3, RPL10A, IDH1, SNRPN, SNRPB, PCK2, EIF6, MMP3, DHX9, MATR3, UBE2D2, UBE2D3, PTRF, ACTR1A, LAMA1, PDCD6IP, QARS, HN1L, PLBD2, OS9, ILF3, ISOCI, PPP1R7, MAPK1, PDCD1LG2, GOLGB1, HSPA9, ACBD3, BTF3, UBE2I, SRRT, EIF4H, FERMT2, EIF3G, PARVA, DBNL, BOLA2, MAPRE1, PRDX5, STX12, EIF1, SMS, GRPEL1, OAF, SYNCRIP, ECE1, VAPA, PCNP, PSME1, EIF3J, C14orfl66, DDX1, AKR1B1, SRP9, PCMT1, XPO1, MMP9, RPS7, NRCAM, FKBP3, SSB, DSC3, XRCC5, CCT6A, LIF, SERPINA9, SND1, ANP32B, G3BP1, GPC6, GLOD4, RRBP1, TGFB1, USP14,WSGR Docket No. 64320-711.601PLAUR, CXCL3, FASN, C0PB2, TARDBP, TNFAIP6, RPS3, NDUFAB1, LMNB1, C0L16A1, PSMF1, PHGDH, PRKCDBP, CXCL5, YAP1, TR0VE2, MACF1, EIF5B, STX7, PFDNS, AP0A1, PDAP1, STX12, EIF3K, FH, RBM8A, EIF1, RPS2, PTGR1, EEA1, CAB39, DCTN2, GDF15, MYL9, TCP1, RPS12, RAD23A, SKP1, PDLIM1, HSPH1, PSMB3, SUB1, API5, TWF2, KTN1, DYNC1H1, SNRNP70, MCFD2, PPP1R18, PTGES3, APEX1, TNKS1BP1, FUBP1, VAT1, PAFAH1B1, CBX1, PTK7, HNRPDL, ZNF185, DYNC1I2, KHDRBS1, SFPQ, PDCD5, TRIM28, PPIC, NARS, PCBP2, CD2AP, PSMA1, CAPRIN1, KHSRP, NSFL1C, PPP1R12A, NUDC, MFAP2, IGF2R, RGMB, PABPC1, MANI Al, DDB1, PTBP1, FBN2, CNBP, OTUB1, NASP,HSPD1, EEF1D, RNPEP, CRKL, HNRNPAB, EIF3F, PAICS, ILF2, COPB1, PA2G4, COP A, NT5E, HMGA1, SF1, XRCC6, GNB2L1, MEI, MTAP, CCT2, ARCN1, PEPD, or EPB41L3. Alternatively, or in addition, in some embodiments, the nMPC exosomes are positive for protein expression of one, two, three, four, five, six, seven, eight, nine, ten, or more of PPP1CA, PPP1CC, STI 3. ST13P5, ST13P4, HMGB1, HMGB1P1, HNRNPA1, HNRNPA1L2, NEDD8, N EDD8-MDP1, YBX1, YBX2, CCT7, HNRNPH3, LTBP1, UBE2N, IL8, CYCS, LGALS1, IL6, PGAM1, YWHAH, TXN, ARHGDIB, PSMA3, RAN, TPM3, BASP1, HSPA8, ITGAV, PPIA, NACA, HSP90AB1, PCBP1, CAP1, NUTF2, PSMA5, CAPZA1, RPLP1, GLO1, ACTG1, ICAM1, SDC4, SOD2, PSMB4, TFPI2, C1QBP, NAP1L1, HSP90AA1, SET, EN01, CCT3, GOT2, HSPE1, PGM3, PLIN3, CNDP2, PGD, SH3BGRL, TLN1, HSP90AB2P, GOT1, HNRNPAO, FTH1, TPD52L2, UGP2, AHNAK, CCT8, PSMA7, CCT4, SRPX2, CLIC4, KPNB1, AP2B1, and PAFAH1B2.

[0017] In some embodiments, the nMPC exosomes comprise particles in a range of from about 50 nm to about 1000 nm, about 100 nm to about 1000 nm, about 500 nm to about 1000 nm, about 600 nm to about 900 nm, about 700 nm to about 800 nm, about 300 nm to about 600 nm, about 300 nm to about 500 nm, 300 nm to about 400 nm, about 200 nm to about 500 nm, 200 nm to about 400 nm, about 100 nm to about 500 nm, about 100nmto about 300nm, 100 nm to about 200 nm, 100 nm to about 150 nm, about 50 nm to about 200 nm, about 50 nm to about 150 nm, about 50 nm to about 110 nm, about 50 nm to about 100 nm, about 75 nm to about 250 nm, about 75 nm to about 200 nm, about 75 nm to about 150 nm, about 75 nm to about 100 nm, about 90 nm to about 150 nm, about 90 nm to about 125 nm, about 90 nm to about 110 nm, or about 90 nm to about 100 nm in diameter. In one embodiment, the nMPC exosomes comprise particles in a range of from about 90 nm to about 110 nm in diameter. In another embodiment, the nMPC exosomes comprise particles in a range of from about 100 nm to about 120 nm in diameter. In some embodiments, the nMPC exosomes comprise particles about 50 nm, 60 nm, 70 nm, 80 nm, 90 nm, 100 nm, HO nm, 120 nm, 130 nm, 140 nm, 150 nm, 160 nm, 170 nm, 180 nm, 190 nm, 200 nm, 250 nm, 300 nm, 350 nm, 400 nm, 450 nm, 500 nm, 550 nm, 600 nm, 650 nm, 700 nm, 750 nm, 800 nm, 850 nm, 900 nm, 950 nm, or 1000 nm in diameter. In some embodiments, the nMPC exosomes comprise particles about 90 nm in diameter. In certain embodiments, the nMPC exosomes comprise particles about 100 nm in diameter. In other embodiments, the nMPC exosomes comprise particles about 110 nm in diameter. In yet other embodiments, the nMPC exosomes have a density of about 1.13 g / ml to about 1.19 g / ml.WSGR Docket No. 64320-711.601

[0018] In some embodiments, the nMPC exosomes comprise a final protein concentration of from about 0.1 mg / ml to about 50.0 mg / ml, or from about 0.5 mg / ml to about 20.0 mg / ml. In some embodiments, the nMPC exosomes comprise a final protein concentration of (a) at least about 0.1 mg / ml, 0.5 mg / ml, 1.0 mg / ml, about 2.0 mg / ml, about 3.0 mg / ml, about 4.0 mg / ml, about 5.0 mg / ml, about 6.0 mg / ml, about 7.0 mg / ml, about 8.0 mg / ml, about 9.0 mg / ml, about 10.0 mg / ml, about 11.0 mg / ml, about 12.0 mg / ml, about 13.0 mg / ml, about 14.0 mg / ml, about 15.0 mg / ml, about 16.0 mg / ml, about 17.0 mg / ml, about 18.0 mg / ml, about 19.0 mg / ml, about 20.0 mg / ml, about 22.0 mg / ml, about 24.0 mg / ml, about 26.0 mg / ml, about 28.0 mg / ml, about 30.0 mg / ml, about 35.0 mg / ml, about 40.0 mg / ml, about 45.0 mg / ml, or about 50.0 mg / ml, or (b) at most about 250.0 mg / ml, about 225.0 mg / ml, about 200.0mg / ml, about 175 mg / ml, about 150 mg / ml, about 125 mg / ml, about 100 mg / ml, about 75 mg / ml, about 50 mg / ml, about 45.0 mg / ml, about 40.0 mg / ml, about 35.0 mg / ml, about 30.0 mg / ml, about 25 mg / ml, about 20 mg / ml, about 15 mg / ml, about 10 mg / ml, about 5 mg / ml, about 1 mg / ml, about 0.5 mg / ml, or about 0.1 mg / ml. In some embodiments, the nMPC exosomes comprise a final protein concentration of at least about 1.0 mg / ml±0.5. In other embodiments, the nMPC exosomes comprise a final protein concentration of at least about 4.0 mg / ml±1.0. In some embodiments, the nMPC exosomes comprise a final protein concentration of at least about 8.0 mg / ml±2.0. In certain embodiments, the nMPC exosomes comprise a final protein concentration of at least about 16.0 mg / ml±3.0. In some instances, the composition is concentrated. In some instances, the composition is diluted prior to the administration. In some instances, the nMPC exosomes are administered at a concentration of at least about 10 pg / ml to at least about 1000 pg / ml. Alternatively, or in addition, in certain embodiments, the nMPC secretome and / or the nMPC exosomes are positive for protein expression of one or more of the proteins in Table 5.

[0019] In one aspect, the composition comprises an nMPC Total Secretome comprising the nMPC secretome and the nMPC exosomes. In another aspect, the subject is administered a composition comprising the nMPC Total Secretome comprising the nMPC secretome and the nMPC exosomes. In some embodiments, the nMPC secretome and the nMPC exosomes collectively comprise a final protein concentration of from about 0.10 mg / ml to about 50.0 mg / ml, or from about 0.50 mg / ml to about 20.0 mg / ml. In some embodiments, the nMPC secretome and the nMPC exosomes collectively comprise a final protein concentration of (a) at least about 0.1 mg / ml, 0.5 mg / ml, 1.0 mg / ml, about 2.0 mg / ml, about 3.0 mg / ml, about 4.0 mg / ml, about 5.0 mg / ml, about 6.0 mg / ml, about 7.0 mg / ml, about 8.0 mg / ml, about 9.0 mg / ml, about 10.0 mg / ml, about 11.0 mg / ml, about 12.0 mg / ml, about 13.0 mg / ml, about 14.0 mg / ml, about 15.0 mg / ml, about 16.0 mg / ml, about 17.0 mg / ml, about 18.0 mg / ml, about 19.0 mg / ml, about 20.0 mg / ml, about 22.0 mg / ml, about 24.0 mg / ml, about 26.0 mg / ml, about 28.0 mg / ml, about 30.0 mg / ml, about 35.0 mg / ml, about 40.0 mg / ml, about 45.0 mg / ml, or about 50.0 mg / ml, or(b) at most about 250.0 mg / ml, about 225.0 mg / ml, about 200.0 mg / ml, about 175 mg / ml, about 150 mg / ml, about 125 mg / ml, about 100 mg / ml, about 75 mg / ml, about 50 mg / ml, about 45.0 mg / ml, about 40.0 mg / ml, about 35.0 mg / ml, about 30.0 mg / ml, about 25 mg / ml, about 20 mg / ml, about 15 mg / ml, about 10 mg / ml, about 5 mg / ml, about 1 mg / ml, about 0.5 mg / ml, or about 0.1 mg / ml. In some embodiments, the nMPC secretome and the nMPC exosomes collectively comprise a final protein concentration of at least aboutWSGR Docket No. 64320-711.6011.0 mg / ml±0.5. In some embodiments, the nMPC secretome and the nMPC exosomes collectively comprise a final protein concentration of at least about 4.0 mg / ml±1.0. In some embodiments, the nMPC secretome and the nMPC exosomes collectively comprise a final protein concentration of at least about 8.0 mg / ml±2.0. In some embodiments, the nMPC secretome and the nMPC exosomes collectively comprise a final protein concentration of at least about 16.0 mg / ml±3.0. In some instances, the nMPC secretome and the nMPC exosomes collectively are administered at a concentration of at least about 10 pg / ml to at least about 1000 pg / ml. Alternatively, or in addition, in certain embodiments, the nMPC secretome and / or the nMPC exosomes are positive for protein expression of one or more of the proteins in Table 5. In some embodiments, the composition is acellular.

[0020] In some embodiments, any such compositions described herein are cryopreserved. In some embodiments, any such compositions described herein are lyophilized. In certain embodiments, the lyophilized composition is reconstituted in a diluent. In certain embodiments, the diluent comprises a pharmaceutically acceptable diluent. In other embodiments, the lyophilized composition is incubated for an amount of time and / or at a suitable temperature for reconstitution. Provided herein, in one aspect, is a kit comprising any such lyophilized compositions in a sterile pouch and instructions for reconstitution and application of the composition.

[0021] In one aspect, a symptom of HFpEF, DCM, or kidney disease is improved following treatment compared to treatment with a placebo or compared to the subject prior to administration of the nMPCs, nMPC secretome (e.g., exosomes, peptides, proteins, nucleic acids, etc.), nMPC exosomes, an nMPC total secretome, or a combination thereof. In some embodiments, the one or more symptoms is improved (e.g., decreased) by about 2%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or more compared to treatment with a placebo or compared to the subject prior to administration of the nMPCs, nMPC secretome, nMPC exosomes, an nMPC total secretome, or a combination thereof. In other embodiments, the one or more symptoms is improved (e.g, decreased) by about 2-fold, 5-fold, 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, or more compared to treatment with a placebo or compared to the subject prior to administration of the nMPCs, nMPC secretome, nMPC exosomes, an nMPC total secretome, or a combination thereof. In one instance, the method treats a symptom of HFpEF. Alternatively, or in addition, in one instance, the method treats a symptom of DCM. Alternatively, or in addition, in one instance, the method treats a symptom of a kidney disease, optionally, wherein the kidney disease comprises an acute kidney injury, an acute kidney disease, or a chronic kidney disease.

[0022] In some embodiments, a symptom of HFpEF, DCM, or kidney disease is improved following treatment with the nMPC secretome compared to treatment with a placebo or compared to the subject prior to administration of the nMPC secretome. In some embodiments, the one or more symptoms is improved (e.g, decreased) by about 2%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or more compared to treatment with a placebo or compared to the subject prior to administration of the nMPC secretome. In other embodiments, the one or more symptoms is improved (e.g, decreased) by about 2-fold, 5-fold, 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, orWSGR Docket No. 64320-711.601more compared to treatment with a placebo or compared to the subject prior to administration of the nMPC secretome.

[0023] Symptoms of HFpEF include, but are not limited to, shortness of breath (e.g, difficulty breathing, especially during physical activity), fatigue (e.g, feeling tired, even after resting), swelling (e.g., swelling in the ankles, legs, feet, abdomen, and / or neck veins, etc. ), chest pain (e.g, pain occurring after physical activity and / or eating a large meal, etc.), irregular heartbeat (e.g, a rapid, pounding, or fluttering heartbeat), fainting (e.g., syncope), dizziness, coughing (e.g, while lying down), and / or difficulty sleeping. In some instances, the symptom is an elevated level of C-reactive protein, soluble interleukin-1 (IL-1) receptor-like 1, growth differentiation factor 15 (GDF15), tumor necrosis factor alpha (TNFa), or a combination thereof. In some embodiments, the symptom further comprises coronary artery disease, hypertension, valvular heart disease, cardiomyopathy, infiltrative disorders (e.g, amyloidosis), diabetes mellitus, congenital heart disease, pericardial disease, atrial fibrillation, cardiac toxins, myocardial dysfunction, metabolic dysfunction, vascular dysfunction, renal dysfunction, inflammatory dysfunction, or a combination thereof.

[0024] Symptoms of DCM to be treated include, but are not limited to, shortness of breath (e.g., difficulty breathing, especially during physical activity), fatigue (e.g., feeling tired, even after resting), swelling (e.g., swelling in the ankles, legs, feet, abdomen, and / or neck veins, etc.), chest pain (e.g., pain occurring after physical activity and / or eating a large meal, etc.), irregular heartbeat (e.g, a rapid, pounding, or fluttering heartbeat), fainting (e.g, syncope), dizziness, coughing (e.g, while lying down), and / or difficulty sleeping. In certain instances, one symptom is improved following treatment. In certain instances, two symptoms are improved following treatment. In certain instances, three (3) symptoms are improved following treatment. In certain instances, four (4) symptoms are improved following treatment. In certain instances, five (5) symptoms are improved following treatment. In certain instances, six (6) or more symptoms are improved following treatment. Treatment may, in some instances, increase the subject’s quality of life compared to treatment with a placebo or compared to the subject prior to treatment. Alternatively, or in addition, treatment may increase the subject’s lifespan (e.g, quantity) compared to treatment with a placebo or compared to the subject prior to treatment. In certain embodiments, treatment results in stasis of one or more symptoms (e.g., improving less than 2% or not getting worse). In some embodiments, the subject exhibits an improvement in shortness of breath (e.g, difficulty breathing), fatigue, muscle weakness (e.g., feeling tired, even after resting), swelling (e.g., swelling in the ankles, legs, feet, abdomen, and / or neck veins, etc.), chest pain (e.g, pain occurring after physical activity and / or eating a large meal, etc. ), irregular heartbeat (e.g. , a rapid, pounding, or fluttering heartbeat), fainting (e.g., syncope), dizziness, coughing (e.g, while lying down), and / or difficulty sleeping, or a combination thereof, or a combination thereof following administration of allogeneic, human, neonatal cardiac mesenchymal progenitor cells (nMPCs), a secretome (conditioned medium) produced by the nMPCs, exosomes produced by the nMPCs, or any combination thereof. In certain embodiments, the symptom further comprises inflammation, oxidative stress, or a combination thereof. In one instance, treatment reduces inflammation by at least 2% or by at least 2 -fold as compared toWSGR Docket No. 64320-711.601treatment with a placebo or compared to the subject prior to treatment. In another instance, treatment reduces oxidative stress by at least 2% or by at least 2-fold as compared to treatment with a placebo or compared to the subject prior to treatment. In other embodiments, treatment improves cardiac performance. In certain embodiments, treatment improves one or more of LVEF, NT-proBNP levels, 6MWT scores, Modified Ross scores, LV end-diastolic volume (EDV), LV end-systolic volume (ESV), systolic dysfunction, and / or left ventricular dilation. In certain embodiments, treatment reduces one or more symptoms, improves quality of life, prevents disease progression, reduces hospitalizations, and / or effectively manages underlying comorbidities. In some embodiments, one or more symptoms are assessed prior to treatment to establish a baseline. In some embodiments, one or more symptoms are assessed three (3) months following the last dose. In some embodiments, one or more symptoms are assessed six (6) months following the last dose. In some embodiments, one or more symptoms are assessed one (1) year following the last dose.

[0025] Symptoms of kidney disease include, but are not limited to, shortness of breath (e.g, difficulty breathing, especially during physical activity), fatigue (e.g, feeling tired, even after resting), swelling (e.g., swelling in the ankles, legs, feet, abdomen, and / or neck veins, etc. ), chest pain (e.g, pain occurring after physical activity and / or eating a large meal, etc.), irregular heartbeat (e.g, a rapid, pounding, or fluttering heartbeat), fainting (e.g., syncope), dizziness, coughing (e.g, while lying down), and / or difficulty sleeping. In some instances, the symptom is an elevated level of C-reactive protein, soluble interleukin-1 (IL-1) receptor-like 1, growth differentiation factor 15 (GDF15), tumor necrosis factor alpha (TNFa), or a combination thereof. In some embodiments, the symptom further comprises coronary artery disease, hypertension, valvular heart disease, cardiomyopathy, infiltrative disorders (e.g, amyloidosis), diabetes mellitus, congenital heart disease, pericardial disease, atrial fibrillation, cardiac toxins, metabolic dysfunction, vascular dysfunction, renal dysfunction, inflammatory dysfunction, or a combination thereof. Treatment may, in some instances, increase the subject’s quality of life compared to treatment with a placebo or compared to compared to the subject prior to administration of the nMPCs, nMPC secretome, nMPC exosomes, or a combination thereof. Alternatively, or in addition, treatment may increase the subject’s lifespan compared to treatment with a placebo or compared to the subject prior to administration of the nMPCs, nMPC secretome, nMPC exosomes, or a combination thereof. In some embodiments, treatment improves ventricular relaxation. In some embodiments, the treatment improves ventricular relaxation by about 2% or more compared to treatment with a placebo or compared to the subject prior to administration of the nMPCs. In other embodiments, treatment improves cardiac performance. In some embodiments, the improvement in cardiac performance comprises a reduction in Tau (r) and / or end-diastolic pressure volume relationship. In certain embodiments, the treatment improves cardiac performance by about 2% or more compared to treatment with a placebo or compared to the subject prior to administration of the nMPCs. In certain embodiments, treatment improves one or more of the early -to-late ventricular filling (E / A) ratio, left ventricle (LV) relaxation, LV end-diastolic pressure, and / or lung congestion. In certain embodiments, treatment reduces one or more symptoms, improves the subject’s quality of life, prevents disease progression, reduces hospitalizations, and / orWSGR Docket No. 64320-711.601effectively manages underlying comorbidities. In certain instances, one symptom is improved following treatment. In certain instances, two symptoms are improved following treatment. In certain instances, three (3) symptoms are improved following treatment. In certain instances, four (4) symptoms are improved following treatment. In certain instances, five (5) symptoms are improved following treatment. In certain instances, six (6) or more symptoms are improved following treatment. In some embodiments, treatment reduces one or more symptoms, improves quality of life, prevents disease progression, reduces hospitalizations, and / or effectively manages underlying comorbidities. Treatment may, in some instance^ increase the subject’s quality of life compared to treatment with a placebo or compared to the subject prior to treatment. Alternatively, or in addition, treatment may increase the subject’s lifespan (e.g, quantity) compared to treatment with a placebo or compared to the subject prior to treatment. In certain embodiments, treatment results in stasis of one or more symptoms (e.g., improving less than 2% or not getting worse).

[0026] Treatment may, in some instances, increase the subject’s quality of life compared to treatment with a placebo or compared to compared to the subject prior to administration of the nMPCs, nMPC secretome, nMPC exosomes, an nMPC total secretome, or a combination thereof. Alternatively, or in addition, treatment may increase the subject’s lifespan compared to treatment with a placebo or compared to the subject prior to administration of the nMPCs, nMPC secretome, nMPC exosomes, an nMPC total secretome, or a combination thereof. In some embodiments, treatment improves ventricular relaxation. In some embodiments, the treatment improves ventricular relaxation by about 2% or more compared to treatment with a placebo or compared to the subject prior to administration of the nMPCs. In other embodiments, treatment improves cardiac performance. In some embodiments, the improvement in cardiac performance comprises a reduction in Tau (r) and / or end-diastolic pressure volume relationship. In certain embodiments, the treatment improves cardiac performance by about 2% or more compared to treatment with a placebo or compared to the subject prior to administration of the nMPCs. In certain embodiments, treatment improves one or more of the early-to-late ventricular filling (E / A) ratio, left ventricle (LV) relaxation, LV end-diastolic pressure, and / or lung congestion. In certain embodiments, treatment reduces one or more symptoms, improves the subject’s quality of life, prevents disease progression, reduces hospitalizations, and / or effectively manages underlying comorbidities. In certain instances, one symptom is improved following treatment. In certain instances, two symptoms are improved following treatment. In certain instances, three (3) symptoms are improved following treatment. In certain instances, four (4) symptoms are improved following treatment. In certain instances, five (5) symptoms are improved following treatment. In certain instances, six (6) or more symptoms are improved following treatment. In some embodiments, treatment reduces one or more symptoms, improves quality of life, prevents disease progression, reduces hospitalizations, and / or effectively manages underlying comorbidities. Treatment may, in some instances, increase the subject’s quality of life compared to treatment with a placebo or compared to the subject prior to treatment. Alternatively, or in addition, treatment may increase the subject’s lifespan (e.g., quantity) compared to treatment with aWSGR Docket No. 64320-711.601placebo or compared to the subject prior to treatment. In certain embodiments, treatment results in stasis of one or more symptoms (e.g, improving less than 2% or not getting worse).

[0027] In one aspect, provided herein is a method of improving a stroke volume index (S VI) in a subject diagnosed with a HFpEF or DCM, comprising intravenously administering to the subject a composition comprising about 50*106, about lOOxlO6, about 150xl06, or about 200xl06nMPCs, wherein the subject exhibits an improvement in SVI following treatment. In some embodiments, the subject exhibits at least about a 2% improvement in the SVI following treatment compared to baseline or compared to a placebo. In some embodiments, the SVI increases by at least about 2 mL / m2, at least about 2.5 mL / m2, at least about 3 mL / m2, about 3.5 mL / m2, at least about 4 mL / m2, at least about 4.5 mL / m2, at least about 5 mL / m2, at least about 5.5 mL / m2, at least about 6 mL / m2, at least about 6.5 mL / m2, at least about 7 mL / m2, at least about 7.5 mL / m2, at least about 8 mL / m2, at least about 8.5 mL / m2, at least about 9 mL / m2, at least about 9.5 mL / m2, or at least about 10 mL / m2following treatment compared to baseline. In some embodiments, the SVI increases by at least about 2 mL / m2following treatment compared to baseline. In some embodiments, the SVI increases by at least about 4 mL / m2following treatment compared to baseline. In some embodiments, the SVI increases by at least about 5 mL / m2following treatment compared to baseline. In some embodiments, the SVI increases by at least about 6 mL / m2following treatment compared to baseline. In some embodiments, the SVI increases by at least about 9 mL / m2following treatment compared to baseline.

[0028] In one aspect, provided herein is a method of treating a subject diagnosed with a HFpEF, or DCM, comprising intravenously administering to the subject a composition comprising about 50 / IO6, about 100 / 106, about 150xl06, or about 200xl06nMPCs, wherein the subject exhibits an improvement in a 6-minute walk test (6MWT) following treatment. In some embodiments, the subject exhibits at least about a 2% improvement in the 6MWT following treatment compared to baseline or compared to a placebo. In some embodiments, the 6MWT increases by at least about 2 meters, at least about 4 meters, at least about 6 meters, at least about 8 meters, at least about 9 meters, at least about 10 meters, at least about 12 meters, at least about 14 meters, at least about 16 meters, at least about 18 meters, at least about 20 meters, at least about 22 meters, at least about 24 meters, at least about 25 meters, at least about 26 meters, at least about 28 meters, at least about 30 meters, at least about 40 meters, or at least about 50 meters following treatment compared to baseline. In some embodiments, the 6MWT increases by at least about 2 meters following treatment compared to baseline. In some embodiments, the 6MWT increases by at least about 9 meters following treatment compared to baseline. In some embodiments, the 6MWT increases by at least about 16 meters following treatment compared to baseline. In some embodiments, the 6MWT increases by at least about 22 meters following treatment compared to baseline. In some embodiments, the 6MWT increases by at least about 25 meters following treatment compared to baseline. In some embodiments, the 6MWT increases by at least about 50 meters following treatment compared to baseline.

[0029] In one aspect, provided herein is a method of treating a subject diagnosed with a HFpEF or DCM, comprising intravenously administering to the subject a composition comprising about 50xl06,WSGR Docket No. 64320-711.601about 100*106, about 150*106, or about 200*106nMPCs, wherein the subject exhibits an improvement as determined by a Kansas City Cardiomyopathy Questionnaire (KCCQ) following treatment. In some embodiments, the subject exhibits at least a 2% improvement in the KCCQ following treatment compared to baseline or compared to a placebo. In some embodiments, the KCCQ increases by at least about 3, at least about 4, at least about 5, at least about 6, at least about 7, at least about 8, at least about 9, at least about 10, at least about 11, at least about 12, at least about 13, at least about 14, at least about 15, at least about 16, at least about 17, at least about 18, at least about 19, at least about 20, at least about 21, at least about 22, at least about 23, at least about 24, at least about 25, or at least about 30 points following treatment compared to baseline. In some embodiments, the KCCQ increases by at least about 9 points following treatment compared to baseline. In some embodiments, the KCCQ increases by at least about 17 points following treatment compared to baseline. In some embodiments, the KCCQ increases by at least about 18 points following treatment compared to baseline. In some embodiments, the KCCQ increases by at least about 20 points following treatment compared to baseline. In some embodiments, the KCCQ increases by at least about 21 points following treatment compared to baseline. In some embodiments, the subject improves from a “good to fair health status” to a “good to excellent health status” as determined by the KCCQ following treatment compared to baseline.

[0030] In one aspect, provided herein is a method of improving a left ventricular filling pressure or a diastolic dysfunction in a subject diagnosed with aHFpEF or DCM, comprising intravenously administering to the subject a composition comprising about 50 / IO6, about lOOxlO6, about 150 / IO6, or about 200 x 106nMPCs, wherein the subj ect exhibits an improvement in left ventricular filling pressure or diastolic dysfunction following treatment. In some embodiments, the subject exhibits at least about a 2% improvement in the left ventricular filling pressure following treatment compared to baseline or compared to a placebo. In some embodiments, the subject exhibits at least about a 2% improvement in the left ventricular filling pressure following treatment compared to baseline or compared to a placebo. In some embodiments, the subject exhibits at least about a 2% improvement in the diastolic dysfunction following treatment compared to baseline or compared to a placebo. In some embodiments, an E / e’ mean of the subject improves from a diseased level (>13) to anon-diseased level (<I3) following treatment compared to baseline. In some embodiments, an E / e’ mean of the subject decreases by a score of at least about 0.5, at least about 0.75, at least about 1, at least about 1.25, at least about 1.5, at least about 1.75, at least about 2, at least about 2.25, at least about 2.5, at least about 2.75, at least about 3, at least about 3.25, at least about 3.5, at least about 3.75, at least about 4, at least about 4.5, or at least about 5 following treatment compared to baseline. In some embodiments, an E / e’ mean of the subject decreases by a score of at least about 0.5 following treatment compared to baseline. In some embodiments, an E / e’ mean of the subject decreases by a score of at least about 1 following treatment compared to baseline. In some embodiments, an E / e’ mean of the subject decreases by a score of at least about 1.5 following treatment compared to baseline. In some embodiments, an E / e’ mean of the subject decreases by a score of at least about 2 following treatment compared to baseline. In some embodiments, an E / e’ mean of the subject decreases by a score of at least about 2.25 following treatment compared to baseline. In someWSGR Docket No. 64320-711.601embodiments, an E / e’ mean of the subject decreases by at least about 2% following treatment compared to baseline.

[0031] In one aspect, provided herein is a method of decreasing a level of aN-terminal pro-B-type natriuretic peptide (NT-proBNP) in a subject diagnosed with a HFpEF, DCM, or kidney disease, comprising intravenously administering to the subject a composition comprising about 50 / IO6, about lOOxlO6, about 150 / 106, or about 200* 106nMPCs, wherein the subject exhibits a decreased level of the NT-proBNP following treatment. In some embodiments, the subject to be treated has an elevated level of NT-proBNP prior to treatment. In some embodiments, the subject to be treated has a level of NT-proBNP of >240 pg / mL prior to treatment. In some embodiments, the subject to be treated has a level of NT-proBNP of <240 pg / mL following treatment. In some embodiments, NT-proBNP levels vary depending on age and other factors. In certain embodiments, a level of NT-proBNP of less than about 125 pg / mL is associated with a lower likelihood to have heart failure. In one embodiment, a level of NT-proBNP of between about 125 and about 900 pg / mL is associated with possible heart failure. In another embodiment, a level of NT-proBNP greater than about 900 pg / mL is highly associated with heart failure. In some embodiments, the subject exhibits at least about a 2% decrease in the level of NT-proBNP of <240 pg / mL following treatment compared to baseline. In some embodiments, the subject exhibits a decrease in the level of NT-proBNP of at least about 2 pg / mL, 4 pg / mL, 6 pg / mL, 8 pg / mL, 10 pg / mL, about 20 pg / mL, about 30 pg / mL, about 40 pg / mL, about 50 pg / mL, about 60 pg / mL, about 70 pg / mL, about 80 pg / mL, about 90 pg / mL, about 100 pg / mL, about 110 pg / mL, about 120 pg / mL, about 130 pg / mL, about 140 pg / mL, about 150 pg / mL, about 160 pg / mL, about 170 pg / mL, about 180 pg / mL, about 190 pg / mL, about 200 pg / mL, about 210 pg / mL, about 220 pg / mL, about 230 pg / mL, about 240 pg / mL, about 250 pg / mL, about 260 pg / mL, about 270 pg / mL, about 280 pg / mL, about 290 pg / mL, about 300 pg / mL, or more, following treatment compared to baseline. In some embodiments, the subject exhibits a decrease in the level of NT-proBNP of at least about 2 pg / mL following treatment compared to baseline. In some embodiments, the subject exhibits a decrease in the level of NT-proBNP of at least about 10 pg / mL following treatment compared to baseline. In some embodiments, the subject exhibits a decrease in the level of NT-proBNP of at least about 12 pg / mL following treatment compared to baseline. In some embodiments, the subject exhibits a decrease in the level of NT-proBNP of at least about 20 pg / mL following treatment compared to baseline. In some embodiments, the subject exhibits a decrease in the level of NT-proBNP of at least about 30 pg / mL following treatment compared to baseline. In some embodiments, the subject exhibits a decrease in the level of NT-proBNP of at least about 40 pg / mL following treatment compared to baseline. In some embodiments, the subject exhibits a decrease in the level of NT-proBNP of at least about 50 pg / mL following treatment compared to baseline. In some embodiments, the subject exhibits a blood level of NT-proBNP of over about 125 pg / mL, about 150 pg / mL, about 175 pg / mL, about 200 mg / mL, about 225 pg / mL, about 250 pg / mL, or about 275 pg / mL prior to treatment. In some embodiments, the subject exhibits a blood level of NT-proBNP of at least about 10 pg / mL, about 20 pg / mL, about 30 pg / mL, about 40 pg / mL, about 50 pg / mL, about 60 pg / mL, about 70 pg / mL, about 80 pg / mL, about 90 pg / mL, about 100 pg / mL, about 110 pg / mL, about 120WSGR Docket No. 64320-711.601pg / mL, about 130 pg / mL, about 140 pg / mL, about 150 pg / mL, about 160 pg / mL, about 170 pg / mL, about 180 pg / mL, about 190 pg / mL, about 200 pg / mL, about 210 pg / mL, about 220 pg / mL, about 230 pg / mL, about 240 pg / mL, about 250 pg / mL, about 260 pg / mL, about 270 pg / mL, about 280 pg / mL, about 290 pg / mL, about 300 pg / mL prior to treatment. In some embodiments, the subject exhibits a blood level of NT-proBNP of over about 250 pg / mL, about 300 pg / mL, about 400 pg / mL, about 500 pg / mL, about 600 pg / mL, about 700 pg / mL, about 800 pg / mL, about 900 pg / mL, or more prior to treatment.

[0032] Described herein, in one aspect, is a method of increasing an estimated glomerular filtration rate (eGFR) (mL / min / 1.73 m2) in a subject diagnosed with a HFpEF, DCM, or kidney disease, comprising intravenously administering to the subject Described herein, in an aspect, is a composition comprising about 50*106, about 100*106, about 150*106, or about 200*106nMPCs, wherein the subject exhibits an increased eGFR following treatment. In some embodiments, the subject to be treated has a reduced eGFR prior to treatment. In some embodiments, the subject to be treated has an eGFR lower than about 89 mL / min / 1.73 m2, about 85 mL / min / 1.73 m2, about 80 mL / min / 1.73 m2, about 75 mL / min / 1.73 m2, about 70 mL / min / 1.73 m2, about 65 mL / min / 1.73 m2, about 60 mL / min / 1.73 m2, about 55 mL / min / 1.73 m2, about 50 mL / min / 1.73 m2, or about 45 mL / min / 1.73 m2prior to treatment. In some embodiments, the subject to be treated has an eGFR lower than about 80 mL / min / 1.73 m2prior to treatment. In some embodiments, the subject to be treated has an eGFR lower than about 70 mL / min / 1.73 m2prior to treatment. In some embodiments, the subj ect to be treated has an eGFR lower than about 60 mL / min / 1.73 m2prior to treatment. In some embodiments, the subject exhibits at least about a 2% increase in an eGFR of at least about 0.5 mL / min / 1.73 m2, about 1 mL / min / 1.73 m2, about 1.5 mL / min / 1.73 m2, about 2 mL / min / 1.73 m2, about 2.5 mL / min / 1.73 m2, about 3 mL / min / 1.73 m2, about 3.5 mL / min / 1.73 m2, about 4 mL / min / 1.73 m2, about 4.5 mL / min / 1.73 m2, about 5 mL / min / 1.73 m2, about 5.5 mL / min / 1.73 m2, about 6 mL / min / 1.73 m2, about 6.5 mL / min / 1.73 m2, about 7 mL / min / 1.73 m2, about 7.5 mL / min / 1.73 m2, about 8 mL / min / 1.73 m2, about 8.5 mL / min / 1.73 m2, about 9 mL / min / 1.73 m2, about 9.5 mL / min / 1.73 m2, about 10 mL / min / 1.73 m2, about 11 mL / min / 1.73 m2, about 12 mL / min / 1.73 m2, about 13 mL / min / 1.73 m2, about 14 mL / min / 1.73 m2, about 15 mL / min / 1.73 m2, about 17.5 mL / min / 1.73 m2, or about 20 mL / min / 1.73 m2following treatment compared to baseline. In some embodiments, the subject exhibits an increase in an eGFR of at least about 0.5 mL / min / 1.73 m2following treatment compared to baseline. In some embodiments, the subject exhibits an increase in an eGFR of at least about 1 mL / min / 1.73 m2following treatment compared to baseline. In some embodiments, the subject exhibits an increase in an eGFR of at least about 4 mL / min / 1.73 m2following treatment compared to baseline. In some embodiments, the subject exhibits an increase in an eGFR of at least about 6 mL / min / 1.73 m2following treatment compared to baseline. In some embodiments, the subject exhibits an increase in an eGFR of at least about 8 mL / min / 1.73 m2following treatment compared to baseline. In some embodiments, the subject exhibits an increase in an eGFR of at least about 9 mL / min / 1.73 m2following treatment compared to baseline. In some embodiments, the subject exhibits an increase in an eGFR of at least about 10 mL / min / 1.73 m2following treatment compared to baseline. In some embodiments, the subject exhibits an increase in an eGFR of at least about 11 mL / min / 1.73 m2following treatmentWSGR Docket No. 64320-711.601compared to baseline. In some embodiments, the subject exhibits an increase in an eGFR of at least about 12 mL / min / 1.73 m2following treatment compared to baseline. In some embodiments, the subj ect exhibits an increase in an eGFR of at least about 13 mL / min / 1.73 m2following treatment compared to baseline.

[0033] Described herein, in one aspect, is a method of reducing a level of C -reactive protein (CRP) (mg / L) in a subject diagnosed with aHFpEF, or DCM, comprising intravenously administering to the subject Described herein, in an aspect, is a composition comprising about 50 / IO6, about lOOxlO6, about 150* 106, or about 200 / 106nMPCs, wherein the subject exhibits a decreased level of CRP as assessed by a high-sensitivity C-Reactive Protein (hs-CRP) blood test following treatment. In some embodiments, the subj ect to be treated has an elevated level of CRP prior to treatment as assessed by a high-sensitivity C-Reactive Protein (hs-CRP) blood test. In some embodiments, the subject to be treated has a CRP level greater than about 1.0 mg / L, about 1.5 mg / L, about 3.0 mg / L, about 5.0 mg / L, or about 10.0 mg / L prior to treatment. In some embodiments, the subject to be treated has a CRP level greater than about 1.0 mg / L prior to treatment. In some embodiments, the subject to be treated has a CRP level greater than about 1.5 mg / L prior to treatment. In some embodiments, the subject to be treated has a CRP level greater than about 2.0 mg / L prior to treatment. In some embodiments, the subject to be treated has a CRP level greater than about 2.5 mg / L prior to treatment. In some embodiments, the subject to be treated has a CRP level greater than about 3.0 mg / L prior to treatment. In some embodiments, the subject exhibits at least about a 2% decrease in CRP level of at least about 0.1 mg / L, about 0.2 mg / L, about 0.3 mg / L, about 0.4 mg / L, about 0.5 mg / L, about 0.75 mg / L, about 1.0 mg / L, about 1.5 mg / L, about 2.0 mg / L, about 2.5 mg / L, or about 3.0 mg / L following treatment compared to baseline. In some embodiments, the subject exhibits a decrease in CRP level of at least about 0.1 mg / L following treatment compared to baseline. In some embodiments, the subject exhibits a decrease in CRP level of at least about 0.2 mg / L following treatment compared to baseline. In some embodiments, the subject exhibits a decrease in CRP level of at least about 0.5 mg / L following treatment compared to baseline. In some embodiments, the subject exhibits a decrease in CRP level of at least about 1.0 mg / L following treatment compared to baseline. In some embodiments, the subject exhibits a decrease in CRP level of at least about 2.0 mg / L following treatment compared to baseline.

[0034] Described herein, in one aspect, is a method of increasing an end-diastolic volume index (EDVI) in a subject diagnosed with a HFpEF, or DCM, comprising intravenously administering to the subject a composition comprising about 50*106, about 100*106, about 150*106, or about 200*106nMPCs, wherein the subject exhibits an increased EDVI following treatment. In some embodiments, the subject to be treated has a low EDVI prior to treatment. In some embodiments, the subject to be treated has an EDVI less about 60 mL / m2, about 55 mL / m2, about 50 mL / m2, about 45 mL / m2, about 40 mL / m2, about 35 mL / m2, or about 30 mL / m2prior to treatment. In some embodiments, the subject to be treated has an EDVI less than about 60 mL / m2prior to treatment. In some embodiments, the subject to be treated has an EDVI less than about 50 mL / m2prior to treatment. In some embodiments, the subject to be treated has an EDVI less than about 40 mL / m2prior to treatment. In some embodiments, the subject to be treated has an EDVI less than about 30 mL / m2prior to treatment. In some embodiments, the subject exhibits at leastWSGR Docket No. 64320-711.601about a 2% increase in EDVI of at least about 0.5 mL / m2, about 0.75 mL / m2, about 1.0 mL / m2, about 1.25 mL / m2, about 1.5 mL / m2, about 1.75 mL / m2, about 2.0 mL / m2, about 2.25 mL / m2, about 2.5 mL / m2, about 2.75 mL / m2, about 3.0 mL / m2, about 3.25 mL / m2, about 3.5 mL / m2, about 3.75 mL / m2, about 4.0 mL / m2, about 4.25 mL / m2, about 4.5 mL / m2, about 4.75 mL / m2, about 5.0 mL / m2, about 5.25 mL / m2, about 5.5 mL / m2, about 5.75 mL / m2, about 6.0 mL / m2, about 6.25 mL / m2, about 6.5 mL / m2, about 6.75 mL / m2, about 7.0 mL / m2, about 7.25 mL / m2, about 7.5 mL / m2, about 7.75 mL / m2, about 8.0 mL / m2, about 8.25 mL / m2, about 8.5 mL / m2, about 8.75 mL / m2, about 9.0 mL / m2, about 9.25 mL / m2, about 9.5 mL / m2, about 9.75 mL / m2, or about 10.0 mL / m2following treatment compared to baseline. In some embodiments, the subject exhibits an increase in EDVI of at least about 2.0 mL / m2following treatment compared to baseline. In some embodiments, the subject exhibits an increase in EDVI of at least about 3.0 mL / m2following treatment compared to baseline. In some embodiments, the subject exhibits an increase in EDVI of at least about 4.0 mL / m2following treatment compared to baseline. In some embodiments, the subject exhibits an increase in EDVI of at least about 5.0 mL / m2following treatment compared to baseline.

[0035] In some embodiments, a dose of the nMPCs comprises from about 15 million to about 250 million nMPCs. In some embodiments, a dose of the nMPCs comprises from about 35 million to about 65 million nMPCs. In some embodiments, a dose of the nMPCs comprises from about 45 million to about 55 million nMPCs. In some embodiments, a dose of the nMPCs comprises about 50 million nMPCs. In some embodiments, a dose of the nMPCs comprises from about 85 million to about 115 million nMPCs. In some embodiments, a dose of the nMPCs comprises from about 95 million to about 105 million nMPCs. In some embodiments, a dose of the nMPCs comprises about 100 million nMPCs. In some embodiments, a dose of the nMPCs comprises from about 135 million to about 165 million nMPCs. In some embodiments, a dose of the nMPCs comprises from about 145 million to about 155 million nMPCs. In some embodiments, a dose of the nMPCs comprises about 150 million nMPCs. In some embodiments, a dose of the nMPCs comprises from about 185 million to about 215 million nMPCs. In some embodiments, a dose of the nMPCs comprises from about 195 million to about 205 million nMPCs. In some embodiments, a dose of the nMPCs comprises about 200 million nMPCs. In some embodiments, a dose of the nMPCs comprises from about 235 million to about 265 million nMPCs. In some embodiments, a dose of the nMPCs comprises from about 245 million to about 255 million nMPCs. In some embodiments, a dose of the nMPCs comprises about 250 million nMPCs.

[0036] In some embodiments, administration of any composition comprising nMPCs, nMPC secretome, nMPC exosomes, an nMPC total secretome, or a combination thereof, as described herein comprises intravenous (IV) injection, or intravenous (IV) catheter (e.g, intravenous (IV) infusion). In some embodiments, the nMPCs, nMPC secretome, nMPC exosomes, an nMPC total secretome, or a combination thereof, are administered into the heart of the subject via intramyocardial transplantation. In some embodiments, the method comprises treating a subject diagnosed with HFpEF, DCM, or kidney disease with nMPCs, nMPC secretome, nMPC exosomes, an nMPC total secretome, or a combination thereof, described herein. In some embodiments, the method comprises treating a subject diagnosed withWSGR Docket No. 64320-711.601HFpEF, DCM, or kidney disease with a secretome described herein. In some embodiments, the method comprises treating a subject diagnosed with HFpEF, DCM, or kidney disease by intravenous delivery of nMPCs, nMPC secretome, nMPC exosomes, an nMPC total secretome, or a combination thereof, described herein.

[0037] In some embodiments, the nMPCs, nMPC secretome, nMPC exosomes, an nMPC total secretome, or a combination thereof, are administered to the subject once every twenty-eight (28) days. In some embodiments, the nMPCs, nMPC secretome, nMPC exosomes, an nMPC total secretome, or a combination thereof, are administered to the subject once every 29, 30, 31, 32, 33, 34, 35, or 36 days. In some embodiments, the nMPCs, nMPC secretome, nMPC exosomes, an nMPC total secretome, or a combination thereof, are administered to the subject for from about 1 month to about 10 years, or from about 1 year to about 50 years. In certain embodiments, the nMPCs, nMPC secretome, nMPC exosomes, an nMPC total secretome, or a combination thereof, are administered to the subject for from about 1 to about 100 years. In one embodiment, a dose of the nMPCs, nMPC secretome, nMPC exosomes, an nMPC total secretome, or a combination thereof, is administered to the subject about every twenty-eight (28) days or about every thirty (30) days. In some embodiments, the subject is administered a first dose of the nMPCs, nMPC secretome, nMPC exosomes, an nMPC total secretome, or a combination thereof, at day 0 and a second dose of the nMPCs, nMPC secretome, nMPC exosomes, an nMPC total secretome, or a combination thereof, at day 28. In some embodiments, the subject is assessed at day 7 following treatment.

[0038] In some embodiments, the subject is administered the nMPCs once about every 28±3 days. In some embodiments, the subject is administered the nMPCs once about every 28±2 days. In some embodiments, the subject is administered the nMPCs once about every 28±1 days. In some embodiment^ the subject is administered the nMPCs once about every 28 days.

[0039] Alternatively, in some embodiments, the subject is administered the nMPCs once about every 30±3 days. In some embodiments, the subject is administered the nMPCs once about every 30±2 days. In some embodiments, the subject is administered the nMPCs once about every 30±l days. In some embodiments, the subject is administered the nMPCs once about every 30 days.

[0040] Alternatively, in some embodiments, the subject is administered the nMPCs once about every 45±3 days. In some embodiments, the subject is administered the nMPCs once about every 45±2 days. In some embodiments, the subject is administered the nMPCs once about every 45±1 days. In some embodiments, the subject is administered the nMPCs once about every 45 days.

[0041] In some embodiments, the subject is administered the nMPCs once about every 28±3 days. In some embodiments, the subject is administered the nMPCs once about every 28±2 days. In some embodiments, the subject is administered the nMPCs once about every 28±1 days. In some embodiment^ the subject is administered the nMPCs once about every 28 days.

[0042] In some embodiments, the subject is administered the nMPCs at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 times. In some embodiments, the subject is administered about 50x106nMPCs per dose. In some embodiments, the subject is administered aboutWSGR Docket No. 64320-711.601100* 106nMPCs per dose. In some embodiments, the subject is administered about 150* 106nMPCs per dose. In some embodiments, the subject is administered about 200 *106nMPCs per dose. In some embodiments, the subject exhibits an improvement for at least about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, or about 24 months (or more) following treatment. In some embodiments, the subject exhibits an improvement for at least about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, about 30, about 31, about 32, about 33, about 34, about 35, about 36, about 37, about 38, about 39, or about 40 years (or more) following treatment. In some embodiments, when the subject exhibits a reduction in improvement, a slowing of improvement, or a worsening of at least a symptom of HFpEF following treatment, the subject is administered at least one more doses of the nMPCs. Alternatively, or in addition, in some embodiments, when the subject exhibits a reduction in improvement, a slowing of improvement, or a worsening of at least a symptom of DCM following treatment, the subject is administered at least one more doses of the nMPCs. Alternatively, or in addition, in some embodiments, when the subject exhibits a reduction in improvement, a slowing of improvement, or a worsening of at least a symptom of a kidney disease following treatment, the subject is administered at least one more doses of the nMPCs, optionally, wherein the kidney disease comprises an acute kidney injury, an acute kidney disease, or a chronic kidney disease.

[0043] In some embodiments, the method further comprises administering to the subject one or more additional therapeutic agent(s). In some embodiments, the one or more additional therapeutic agent(s) help manage one or more symptoms of HFpEF, DCM, or kidney disease. In some embodiments, the method further comprises administering the nMPCs, nMPC secretome, nMPC exosomes, an nMPC total secretome, or a combination thereof, concomitantly with other standard of care treatment. In some embodiments, the one or more additional therapeutic agent(s) comprise(s) an aldosterone antagonist, an angiotensin-converting enzyme inhibitor (ACEi), an angiotensin receptor blocker (ARB), a beta blocker, a blood thinner, a calcium channel blocker, digoxin, a diuretic, metformin, a statin, a sodium-glucose cotransporter-2 (SGLT2) inhibitor, a glucagon-1 receptor agonist, or any combination thereof. In some embodiments, the one or more additional therapeutic agent(s) comprise(s) an aldosterone antagonist, and the aldosterone antagonist comprises CAROSPIR®, Eplenenone, Spironolactone, etc. In other embodiments, the one or more additional therapeutic agent(s) comprise(s) the angiotensin-converting enzyme inhibitor (ACEi) comprises Benazepril, Captopril, Enalapril, Fosinopril, Lisinopril, Moexipril, Perindopril, Quinapril, Ramipril, Trandolapril, etc. In yet other embodiments, the one or more additional therapeutic agent(s) comprise(s) the angiotensin receptor blockers (ARB), and the ARB comprises Candesartan, Eprosartan, Irbesartan, Losartan, Olmesartan, Telmisartan, Valsartan, etc. In some embodiments, the one or more additional therapeutic agent(s) comprise(s) the beta blocker, and the beta blocker comprise Acebutolol, Atenolol, Betaxolol, Bisoprolol, Carteolol, Carvedilol, Labetalol, Metoprolol, Nadolol, Nebivolol, Penbutolol, Pindolol, Propanolol, Sotalol, Timolol, etc. In someWSGR Docket No. 64320-711.601embodiments, the one or more additional therapeutic agent(s) comprise(s) the blood thinner, and the blood thinner comprises Apixaban, Dabigatran, Dalteparin, Edoxaban, Enoxaparin, Fondaparinux, Heparin, Rivaroxaban, Warfarin, etc. In some embodiments, the one or more additional therapeutic agent(s) comprise(s) the calcium channel blocker, and the calcium channel blocker comprises Amlodipine, Diltiazem, Felodipine, Isradipine, Nicardipine, Nifedipine, Nisoldipine, Verapamil, etc. In some embodiments, the one or more additional therapeutic agent(s) comprise(s) the diuretic, and the diuretic comprise(s) Bumetanide, Chlorthalidone, Chlorothiazide, Ethacrynate, Furosemide, Hydrochlorothiazide HCTZ, Indapamide, Methyclothiazide, Metolazone, Torsemide, etc. In some embodiments, the one or more additional therapeutic agent(s) comprise(s) the statin, and the statin comprises Atorvastatin, Fluvastatin, Pravastatin, Rosuvastatin, Simvastatin, etc. In some embodiments, the one or more additional therapeutic agent(s) comprise(s) the sodium-glucose Cotransporter-2 (SGLI2) inhibitor, and the SGLT2 inhibitor comprises Canagliflozin, Dapagliflozin, Empagliflozin, Ertugliflozin, etc. In some embodiments, the one or more additional therapeutic agent(s) comprise(s) the glucagon -1 receptor agonist, and the glucagon- 1 receptor agonist comprises Dulaglutide, Exenatide, Exenatide Extended Release, Liraglutide, Lixisenatide, Semaglutide (subcutaneous, tablet), Tirzepatide, etc.

[0044] In some embodiments, the subject is a mammal. In some embodiments, the mammal is a human. In certain embodiments, the subject to be treated is from birth to 18 years of age. In some embodiments, the subject to be treated is an adult of 18 years of age or older. In some embodiments, the subject to be treated is a child from about 1 to about 4 years of age, or from about 5 to about 14 years of age. In some embodiments, the subject to be treated is from about 15 to about 40 years of age, or 41 years of age or older. In certain embodiments, the subject to be treated is from about 4 to about 18 years of age. In certain embodiments, the subject to be treated is from about 19 to about 25 years of age. In certain embodiments, the subject to be treated is 26 years of age or older. In some embodiments, the subject is from about 1 to about 10 years of age, from about 11 to about 20 years of age, from about 21 to about 30 years of age, from about 31 to about 40 years of age, from about 51 to about 60 years of age, from about 71 to about 80 years of age, from about 81 to about 90 years of age, or about 91+ years of age.

[0045] In any of such methods, the nMPCs are allogeneic. In any of such methods, the subject to be treated can be a mammal such as, for example, a human. In some embodiments, the nMPCs are infused via IV catheter for about 60 minutes to about 180 minutes. In some embodiments, the subject is screened one or more times prior to treatment, during treatment, and / or after treatment. In some embodiments, screening comprises a physical evaluation. In some embodiments, screening comprises assessment of blood pressure, heart rate, respiratory rate, temperature, and / or oxygen saturation. In some embodiments, screening comprises analysis of: urinalysis / microscopy, urine protein to creatinine ratio, measurement of N-terminal Pro-Brain Natriuretic Peptide (NT-proBNP), high-sensitivity cardiac troponin test (hs-cTnT), high sensitivity C-reactive protein (hs-CRP) measurement, cytokine analysis (e.g, IL-6, IL-8, IL-10, transforming growth factor, beta receptor II (TGF -f> RII), interleukin 1 a (IL- la), interferon gamma (IFN-y), transforming growth factor alpha (TGF-a), and / or tumor necrosis factor receptor 1 (TNF-RI)), virus serology (e.g, hepatitis A, B, and C viruses, and / or anti-HIV type 1), exosome biomarker analysis (e.g,WSGR Docket No. 64320-711.601human leukocyte antigen (HLA)), human leukocyte antigen (HLA) phenotyping, peripheral blood mononuclear cell (PBMC) inflammatory biomarker analysis (e.g, inflammatory cells such as, for example, CD4+, CD17+, CD25+, CD68+, CD163+) and serum levels of cytokines (e.g, IL-6, IL-8, TNF-a), a 6-Minute Walk Test (MWT), a Borg Dyspnea Score, a Kansas City Cardiomyopathy Questionnaire (KCCQ), a New York Heart Association (NYHA) Functional Classification, a hematology assessment, a clinical chemistry assessment, an echocardiogram, and / or an electrocardiogram. In some embodiments, the subject is pre-treated with Hydrocortisone and / or a Hl blocker (e.g, Diphenhydramine (Benadryl), azelastine, brompheniramine, buclizine, carbinoxamine, cetrizine, chlorpheniramine, clemastine, cyclizine, cyproheptadine, desloratidine, dimenhydrinate, emedastine, fexofenadine, hydroxyzine, ketotifen, levocabastine, loratadine, meclizine, olopatadine, phenindamine, promethazine, etc.). In some embodiments, the subject is administered a first dose of the nMPCs at day 0 and a second dose of the nMPCs at day 28±3. In some embodiments, the subject is administered a first dose of the nMPCs at day 0 and a second dose of the nMPCs at day 30±3. In some embodiments, the subject is administered a first dose of the nMPCs at day 0 and a second dose of the nMPCs at 6 weeks±3. In some embodiments, the subject is assessed at day 7 following treatment. In some embodiments, N-terminal pro-brain natriuretic peptide (NT-proBNP) in the subject is reduced by about 2%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or more compared to treatment with a placebo or compared to the subject prior to treatment. In some embodiments, a proinflammatory cytokine in the subject is reduced by about 2%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or more compared to treatment with a placebo or compared to the subject prior to treatment. In some embodiments, a high-sensitivity troponin-I is reduced by about 2%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or more compared to treatment with a placebo or compared to the subject prior to treatment. In some embodiments, a two-dimensional transthoracic echocardiography (2D- TIE) parameter (e’ velocity and E / e’ ratio) screening result of the subject is improved by 2%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or more compared to treatment with a placebo or compared to the subject prior to treatment.

[0046] In some embodiments, the subject has a left ventricular ejection fraction (LVEF) of about 50% or more prior to administration of the nMPCs. In some embodiments, the subject does not have an LVEF of between about 41% and about 49% prior to administration of the nMPCs. In some embodiments, the subject does not have an LVEF of less than about 40% prior to administration of the nMPCs. In some embodiments, the subject is biologically a male. In some embodiments, the subject is biologically a female. In certain embodiments, the subject has one or more risk factors comprising a positive smoker identity; weight in excess (overweight); obesity; diabetes; hypertension; a valvular disease; sleep apnea; pulmonary hypertension; a chronic obstructive pulmonary disease; an iron deficiency with or without anemia; coronary artery disease; atrial fibrillation; a dysrhythmia; a tachyarrhythmia; atrial fibrillation; an acute kidney injury or worsening chronic kidney disease; an infection; ischemia; increased salt intake or water retention; a medication noncompliance; antihypertensive medication noncompliance; diuretics medication noncompliance; racial identification as black, white, Latino, or Hispanic; racial nonidentification as Latino or Hispanic; hyponatremia; hypochloremia; dysregulation of lipid metabolism;WSGR Docket No. 64320-711.601hypertriglyceridemia; metabolic dysfunction-associated steatotic liver disease (MASLD; nonalcoholic fatty liver disease or NAFLD); hypothyroidism; hyperthyroidism; low triiodothyronine syndrome; or an elevated natriuretic peptide level.

[0047] In some embodiments, one or more proinflammatory cytokines in the subject are reduced by at least 2% compared to treatment with a placebo or compared to the subject prior to treatment. In certain embodiments, the one or more proinflammatory cytokines comprise IL-1 , IL-6, IL-8, IL-12, IL-17a, IL-18, MCP-1, TNF-a, IFN-y, or a combination thereof. In one embodiment, the one or more proinflammatory cytokines comprise IL-10, IL-6, IL-8, IL-12, IL-17a, IL-18, MCP-1, TNF-a, and IFN-y. In another embodiment, the one or more proinflammatory cytokines comprise IL-8, IL-17a, MCP-1, TNF-a, and IFN-y. In yet another embodiment, the one or more proinflammatory cytokines comprise IL-8, MCP-1, and TNF-a. In one embodiment, the one or more proinflammatory cytokines comprise IL-17a and IFN-y. In some embodiments, the administration of the allogeneic, human, neonatal cardiac mesenchymal progenitor cells (nMPCs), an nMPC secretome (conditioned medium), nMPC exosomes, or any combination thereof, inhibits IL-10, IL-6, IL-8, IL-12, IL-17a, IL-18, monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor (TNF)-a, interferon gamma (IFN-y), or a combination thereof by at least 2% or by at least 2-fold as compared to treatment with a placebo or compared to the subject prior to treatment.

[0048] In any of such methods, the nMPCs are stable in storage at a temperature for a period of time. In some embodiments, the temperature is about 4 °C, 1 °C, 0 °C, -10 °C, -20 °C, or -80 °C. In some embodiments, the period of time is at least about 1, 2, 3, 4, 5, 6, or 7 days; at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks; or at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months. In some embodiments, the nMPCs are stored in cell cryopreservation media-CS10 (CRYOSTOR®; Sigma- Aldrich, Israel). In some embodiments, the nMPCs are thawed in a 37 °C water bath until a single ice crystal remained prior to administration to the subject. In some embodiments, the nMPCs are further washed with a volume of Complete Medium (CM). In some embodiments, the nMPCs are washed twice with a volume of Complete Medium (CM). In some embodiments, the volume is at least about 10 ml.

[0049] In some aspects, the administering the nMPCs is at a dose of about 5. Ox 107nMPCs per kilogram (kg) of weight of the subject. In some aspects, the administering the nMPCs is at a dose of about 2. Ox 108nMPCs per kilogram (kg) of weight of the subject. In some aspects, the administering the nMPCs is at a dose of about 2.5xl08nMPCs per kilogram (kg) of weight of the subject. In some aspects, the administering the nMPCs is at a dose of about 0.7 x 106nMPCs per kilogram (kg) of weight of the subj ect. In some aspects, the administering the nMPCs is at a dose of about 1.43x 106nMPCs per kilogram (kg) of weight of the subject. In some aspects, the administering the nMPCs is at a dose of about 2.85xl06nMPCs per kilogram (kg) of weight of the subject.WSGR Docket No. 64320-711.601INCORPORATION BY REFERENCE

[0050] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. To the extent publications and patents or patent applications incorporated by reference contradict the disclosure contained in the specification, the specification is intended to supersede and / or take precedence over any such contradictory material.BRIEF DESCRIPTION OF THE DRAWINGS

[0051] Various features of the present disclosure are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the disclosure are utilized, and the accompanying drawings of which:

[0052] FIGS. 1A-1G are data showing improvements in various aspects of cardiac symptoms associated with dystrophinopathies after intravenous administration of 100*106nMPCs at Day 0 (first dose) and Day 28 (second dose), and assessed at Day 0 (baseline) and Day 56 (end of study). Line charts show Stroke Volume Index (SVI) data (FIG. 1A), walking distance from a 6-Minute Walk Test (6MWT) (FIG. IB), scores from a Kansas City Cardiomyopathy Questionnaire (KCCQ) (FIG. 1C), data for Left Ventricular Filling Pressure or a Diastolic Dysfunction (E / e’ mean) (FIG. ID), data for N-terminal pro-B-type natriuretic peptide (NT-proBNP) (FIG. IE), data for mean end-diastolic volume index (EDVI) (FIG. IF), and data for Estimated Glomerular Filtration Rate (eGFR) (FIG. 1G).

[0053] FIG. 2 illustrates different phases of AKI development and progression and associated diagnostic tests. AKI: acute kidney injury, TIMP: tissue inhibitor of metalloproteinases, IGFBP: insulinlike growth factor-binding protein, NGAL: neutrophil gelatinase-associated lipocalin, UO: urine output. Pickkers et al. Intensive Care Med., 2021 Aug;47(8):835-850. doi: 10.1007 / s00134-021-06454-7.

[0054] FIG. 3 illustrates the progression of AKI to ADK and CKD. Pickkers et al. Intensive Care Med. , 2021 Aug;47(8):835-850.

[0055] FIG. 4 is an illustrative schematic of dose escalation. DLT - dose limiting toxicities; MTD -maximum tolerated dose. Adult patients are between about 18 and 30 years of age. Pediatric patients are older than about 4 years old and younger than 18 years old.DETAILED DESCRIPTION

[0056] The details of one or more inventive embodiments are set forth in the accompanying drawings, the claims, and the description herein. Other features, objects, and advantages of the inventive embodiments disclosed and contemplated herein can be combined with any other embodiment unless explicitly excluded. It is to be understood that the embodiments of the disclosures herein are illustrative of the principles of the present disclosure. Accordingly, this disclosure includes all modifications and equivalents of the subject matter recited in the claims appended hereto. Any combination of the abovedescribed elements in all possible variations thereof is encompassed by the disclosure unless otherwise indicated herein or otherwise clearly contradicted by context. Other modifications that may be employedWSGR Docket No. 64320-711.601are within the scope of the disclosure. Thus, by way of example, but not of limitation, alternative configurations of the present disclosure may be utilized in accordance with the teachings herein.Accordingly, the present disclosure is not limited to that precisely as shown and described.

[0057] The present disclosure provides, among other things, methods and compositions for treating Heart failure with preserved ejection fraction (HFpEF, also known as diastolic heart failure), dilated cardiomyopathy (DCM), or a kidney disease, based on neonatal cardiac mesenchymal progenitor cells (nMPCs), nMPC secretome, nMPC exosomes, an nMPC total secretome, or a combination thereof, as therapeutics. In particular embodiments, an nMPC secretome can comprise, for example, nMPC exosomes, growth factors, cytokines, macromolecules, such as peptides, proteins, and nucleic acids (e.g, miRNAs), or a combination thereof. In some embodiments, the present disclosure provides methods of treating a symptom of HFpEF, including, for example, administering to an individual who is suffering from or susceptible to HFpEF an effective amount of nMPCs, nMPC secretome, nMPC exosomes, an nMPC total secretome, or a combination thereof, such that at least one symptom or feature of HFpEF is reduced by at least 2% or by at least 2-fold in intensity, severity, or frequency, or has delayed onset compared to treatment with a placebo. In some embodiments, the present disclosure provides methods of treating a symptom of DCM, including, for example, administering to an individual who is suffering from or susceptible to DCM an effective amount of nMPCs, nMPC secretome, nMPC exosomes, an nMPC total secretome, or a combination thereof, such that at least one symptom or feature of DCM is reduced by at least 2% or by at least 2-fold in intensity, severity, or frequency, or has delayed onset compared to treatment with a placebo. In some embodiments, the present disclosure provides methods of treating a symptom of a kidney disease, including, for example, administering to an individual who is suffering from or susceptible to a kidney disease an effective amount of nMPCs, nMPC secretome, nMPC exosomes, an nMPC total secretome, or a combination thereof, such that at least one symptom or feature of a kidney disease is reduced by at least 2% or by at least 2-fold in intensity, severity, or frequency, or has delayed onset compared to treatment with a placebo. In some cases, the kidney disease comprises an acute kidney injury, an acute kidney disease, or a chronic kidney disease.Heart Failure with Preserved Ejection Fraction (HFpEF)

[0058] HFpEF is a complex syndrome characterized by signs and symptoms of heart failure (HF) and a normal or near-normal left ventricular ejection fraction (LVEF). Signs and symptoms of heart failure include but are not limited to, a decrease in left ventricular compliance, increased pressure at end-diastole in the left ventricle, and increased left atrial pressure, but with an ejection fraction greater than 50%. Increased left atrial size is often seen with HFpEF as a result of slow or incomplete left ventricular relaxation. Arrhythmias, including those affecting the atrium (atrial fibrillation, AF), are coincident with HFpEF. Frequencies of preexisting and incident AF were 43.2% and 9.5%, respectively, in those with HFpEF. Ventricular dysfunction in HFpEF increases the risk of imminently life-threatening ventricular fibrillation.

[0059] The American Heart Association (AHA) staging system for HF can be applied to patients with HFpEF, to classify disease severity and to track the progression of the disease. Stage A are at high risk ofWSGR Docket No. 64320-711.601developing HF; and stage B includes patients with known structural disease, such as a history of myocardial infarction or systolic or diastolic dysfunction, but no overt symptoms of HF. Patients at Stage C have evidence of structural disease and symptoms of HF, such as fatigue, shortness of breath, or reduced exercise tolerance, with Stage D including refractory HF, with marked symptoms even at rest despite medical therapy.

[0060] In the absence of endocardial or pericardial disease, diastolic LV dysfunction results from increased myocardial stiffness. Myocardial diastolic stiffness of the extracellular matrix is determined by collagen through regulation of its total amount, relative abundance of collagen type I, and degree of cross-linking. In HFpEF patients, all three mechanisms appear to be involved, including excessive collagen type I deposition resulting from an imbalance between an exaggerated synthesis and a depressed degradation. In hypertensive patients with HFpEF, there is decreased matrix degradation because of downregulation of matrix metalloproteinases (MMPs) and upregulation of tissue inhibitors of matrix metalloproteinases (TIMPs). As a result, a characteristic feature of HFpEF is slow LV relaxation, which may reduce LV stroke volume, especially at high heart rates, whereas normal heart function, accelerates LV relaxation at high heart rates.

[0061] HFpEF etiology and pathophysiology are complex and not fully understood. The diverse etiology includes coronary artery disease, hypertension, valvular heart disease, cardiomyopathy, infdtrative disorders (e.g, amyloidosis), diabetes mellitus, congenital heart disease, pericardial disease, atrial fibrillation, cardiac toxins (e.g., chemotherapy), myocardial dysfunction, metabolic dysfunction, vascular dysfunction, renal dysfunction, and inflammatory dysfunction. The prevalence of HFpEF is estimated to be 1.1-5.5% in the general population and accounts for approximately 50% of heart failure cases, and the 5-year survival rate among participants with HFpEF is 35-40% after hospitalization. Indeed, HFpEF diagnosis is easily missed; up to 76% of the unrecognized cases of heart failure are participants with HFpEF. HFpEF constitutes a distinct clinical syndrome refractory to routine medical approaches. Randomized clinical trials (RCTs), epidemiologic studies, and mechanistic studies in patients with chronic heart failure (HF) have generally divided HF into two clinical syndromes: HFrEF (EF<50%) and HFpEF (EF>50%).

[0062] Accumulating evidence implicates systemic inflammation as a major driver of HFpEF pathophysiology and disease progression. Circulating inflammatory biomarkers that are significantly elevated in HFpEF participants include C-reactive protein, soluble interleukin- 1 (IL-1) receptor-like 1, growth differentiation factor 15 (GDF15), and tumor necrosis factor alpha (TNFa) among others. Systemic inflammation is strongly correlated with vascular remodeling and myocardial fibrosis in HFpEF participants. Indeed, clinical studies in HFpEF participants have demonstrated a strong association between increased cardiac fibrosis and risk of mortality, as well as strong correlations between inflammation and HFpEF disease progression.

[0063] Because the heart has limited regenerative capacity, stem cell-derived therapies with the cells, secretomes, and / or exosomes described herein, can reverse model ventricular anatomy and reduce systemic inflammation, and represent a promising therapeutic approach for treating HFpEF. nMPCs,WSGR Docket No. 64320-711.601nMPC secretome, nMPC exosomes, an nMPC total secretome, or a combination thereof, described heron can reduce levels of inflammation, reduce levels of pro-inflammatory factors, and / or reduce levels of oxidative stress. In some embodiments, reduction is at least 2% or more compared to a placebo or compared to a subject prior to treatment. In other embodiments, reduction is at least 2-fold or more compared to a placebo or compared to a subject prior to treatment. The goal of using the compositions comprising nMPCs, nMPC secretomes, and / or nMPC exosomes described herein is to offset pathophysiological consequences of degeneration of a subject by partially or treating a symptom of HFpEF.

[0064] Disclosed herein are compositions and formulations of neonatal cardiac mesenchymal progenitor cells (nMPCs), nMPC secretome, nMPC exosomes, an nMPC total secretome, or a combination thereof, which reverse or inhibit (completely or partially) pathophysiological hallmarks and symptoms of HFpEF. Alternatively, or in addition, disclosed herein are compositions and formulations of nMPC secretomes which reverse or inhibit (completely or partially) pathophysiological hallmarks and symptoms of HFpEF. Alternatively, or in addition, disclosed herein are compositions and formulations of nMPC exosomes which reverse or inhibit (completely or partially) pathophysiological hallmarks and symptoms of HFpEF.

[0065] nMPCs disclosed herein comprise allogeneic nMPCs with potent immunomodulatory effects for treating HFpEF. These nMPCs are isolated from the right atrial appendage of neonatal (<30 days old) donors with normal myocardium undergoing congenital heart surgery. In certain instances, therapeutic benefits of nMPCs can be exerted through the nMPC secretome, which is comprised of, for example, independently secreted growth factors, cytokines, chemokines, and / or miRNA-enriched exosomes. Robust analyses, including deep proteomic analysis and RNA sequencing of the nMPC secretome coupled with Ingenuity Pathway Analysis, have shown the presence of unique proteins and miRNA within the nMPC secretome may be responsible for downregulating fibrotic, inflammatory, and oxidative stress pathways (ERK / MAPK Signaling pathway) while promoting cellular growth, survival, and proliferation pathways. Thus, nMPCs, nMPC secretome, and nMPC exosomes operate through a multimodal mechanism of action, enhancing pathways related to angiogenesis, immunomodulation, energy production, and cardiomyocyte proliferation while reducing oxidative stress, inflammation, and / or fibrosis.

[0066] Provided herein is a method of treating HFpEF in a subject in need thereof, comprising administering neonatal cardiac mesenchymal progenitor cells (nMPCs) to the subject, wherein the nMPCs are (a) positive for protein expression of Ki67 or Nkx2.5, (b) positive for cell surface protein expression of c-Kit (CD117), CD44, CD73, CD47, CD105, and / or CD90, (c) positive for miRNA expression of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and / or miR-374b-5p, and (d) negative for protein expression of CD34, CD45, CD31, PECAM-1, tryptase, GATA4, ISL1, SSEA3, SSEA4, and / or p!6INK4a. In one embodiment, the nMPCs are (a) positive for protein expression of Ki67 or Nkx2.5, (b) positive for cell surface protein expression of c-Kit (CD117), CD44, CD73, CD47, CD105, or CD90, (c) positive for miRNA expression of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, or miR-374b-5p, and (d) negative for protein expression of CD34, CD45, CD31, PECAM-WSGR Docket No. 64320-711.6011, tryptase, GATA4, ISL1, SSEA3, SSEA4, or pl6INK4a. In another embodiment, the nMPCs are (a) positive for protein expression of Ki67 andNkx2.5, (b) positive for cell surface protein expression of c-Kit (CD117), CD44, CD73, CD47, CD105, and CD90, (c) positive for miRNA expression of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and miR-374b-5p, and (d) negative for protein expression of CD34, CD45, CD31, PECAM-1, tryptase, GATA4, ISL1, SSEA3, SSEA4, and pl6INK4a. In certain embodiments, the nMPCs are further positive for protein expression of PDL1, OCT3 / 4, NANOG, KLF4, HSF1, or SOX2. In some embodiments, the nMPCs are further positive for protein expression of PDL1, OCT3 / 4, NANOG, KLF4, HSF1, and SOX2. Alternatively, or in addition, the nMPCs are further negative for protein expression of p!6INK4aup to at least passage 8. In some embodiments, the nMPCs are (a) positive for protein expression of Ki67, Nkx2.5, OCT3 / 4, NANOG, KLF4, HSF1, and / or SOX2, (b) positive for cell surface protein expression of c-kit (CD117), CD44, CD73, CD47, CD105, CD90, and / or PDL1, (c) positive for miRNA expression of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and / or miR-374b-5p, and (d) negative for protein expression of CD34, CD45, CD31, PECAM-1, tryptase, GATA4, ISL1, SSEA3, SSEA4, and / or p!6INK4a. In certain embodiments, the nMPCs are (a) positive for protein expression of Ki67, Nkx2.5, OCT3 / 4, NANOG, KLF4, HSF1, or SOX2, (b) positive for cell surface protein expression of c-kit (CD117), CD44, CD73, CD47, CD105, CD90, or PDL1, (c) positive for miRNA expression of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, or miR-374b-5p, and (d) negative for protein expression of CD34, CD45, CD31, PECAM-1, tryptase, GATA4, ISL1, SSEA3, SSEA4, or p!6INK4a. In yet other embodiments, the nMPCs are (a) positive for protein expression of Ki67, Nkx2.5, OCT3 / 4, NANOG, KLF4, HSF1, and SOX2, (b) positive for cell surface protein expression of c-kit (CD117), CD44, CD73, CD47, CD105, CD90, and PDL1, (c) positive for miRNA expression of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and miR-374b-5p, and (d) negative for protein expression of CD34, CD45, CD31, PECAM-1, tryptase, GATA4, ISL1, SSEA3, SSEA4, and pl6INK4a. In one aspect, the subject treated by the method exhibits an improvement of one or more symptoms of cardiomyopathy by about 2% or more compared to treatment with a placebo or compared to the subject prior to administration of the nMPCs, nMPC secretome, nMPC exosomes, an nMPC total secretome, or a combination thereof. In any of such methods, the nMPCs are allogeneic. In any of such methods, the subject to be treated can be a mammal such as, for example, a human. The human can be a child (from birth to 18 years of age) or an adult (over 18 years of age). In one embodiment, treating HFpEF includes an improvement in cardiac performance. Alternatively, or in addition, the improvement in cardiac performance includes an improvement in early -to-late ventricular filling (E / A) ratio, left ventricle (LV) relaxation, LV end-diastolic pressure and / or lung congestion. Alternatively, or in addition, the improvement in cardiac performance includes a reduction in Tau and / or end-diastolic pressure-volume relationship. Alternatively, or in addition, treating HFpEF includes a reduction in fibrosis. Alternatively, or in addition, treating HFpEF includes a reduction in inflammation. Treating HFpEF comprises an improvement in cardiac performance, wherein improvement in cardiac performance comprises an improvement in the early-to-late ventricular filling (E / A) ratio, left ventricle (LV) relaxation, LV end-diastolic pressure, and / or lung congestion. Alternatively, or in addition,WSGR Docket No. 64320-711.601improvement in cardiac performance comprises a reduction in Tau and / or end-diastolic pressure- volume relationship (EDPVR). As used herein, “Tau” refers to the time constant of left ventricular relaxation, which is a measure of how quickly the ventricle relaxes during diastole. In some embodiments, prolonged Tau is a symptom of HFpEF to be treated by the disclosed methods. End-diastolic pressurevolume relationship (EDPVR) describes the amount of pressure built up in the ventricle as it fills with blood. In some embodiments, a EDPVR that is shifted upwards is a symptom of HFpEF to be treated by the disclosed methods. In an embodiment, an EDPVR that has been shifted upwards indicates increased stiffness and impaired diastolic function in a subject with HFpEF to be treated by the disclosed methods. In any of such methods, a biological sample of the subject can be assessed on day 7 following treatment. Treating HFpEF can further comprise a reduction in NT-proBNP, a reduction in one or more proinflammatory cytokine(s), a reduction in troponin levels in a high- sensitivity troponin (hs-cTn) test, an improvement in wherein a two-dimensional transthoracic echocardiography (2D- 1 IE) parameter (e’ velocity and E / e’ ratio) screening result, and / or an improved quality of life following treatment compared to treatment with a placebo or compared to the subject prior to treatment.Cardiomyopathy

[0067] Cardiomyopathy is a condition that affects the heart muscle, changing its shape and function. Cardiomyopathy causes the heart to lose its ability to pump blood well. In some cases, the heart rhythm also becomes disturbed. This leads to arrhythmias (irregular heartbeats). In some cases, cardiomyopathy includes DCM.

[0068] Symptoms of cardiomyopathy in patients diagnosed with HFpEF or DCM include, but are not limited to, shortness of breath, chest pain, rapid heartbeats, and swelling in the legs, ankles, feet, stomach, and neck veins. One or more of the following tests may be recommended to diagnose HFpEF, DCM and / or efficacy of treatment with the methods described herein: blood tests, chest X-ray, e.g, assess whether the subject’s heart is enlarged or if fluid is building up in the lungs), electrocardiogram (EKG or ECG; which may reveal changes from cardiomyopathy as well as other problems, including heart attacks, arrhythmias (abnormal heartbeats), and / or heart failure), Holter and event monitors, echocardiogram (Echo), or Stress test.

[0069] Ejection fraction is a measurement of the percentage of blood leaving the heart each time it squeezes (contracts). Ejection fraction is one of many tests a health care provider may use to see how a subject’s heart works. When the heart contracts, it pumps out (ejects) blood from the two lower heart chambers, called ventricles. When the heart relaxes, the ventricles refill with blood. No matter how forceful the contraction, the heart can never pump all the blood out of a ventricle. The term “ejection fraction” is the amount of blood (as a percentage) that is pumped out of a filled ventricle with each heartbeat. The ejection fraction is usually measured only in the left ventricle. The left ventricle is the heart’s main pumping chamber. It pumps oxygen-rich blood up into the body’s main artery, called the aorta, and this oxygen-rich blood then goes to the rest of the body. A left ventricle (LV) ejection fraction of about 50% to 70% is categorized as normal. A mildly reduced LV ejection fraction is usually between 41% and 49%. A reduced LV ejection fraction is usually 40% or less. Some things that may cause aWSGR Docket No. 64320-711.601reduced ejection fraction comprise weakness of the heart muscle, such as cardiomyopathy; heart attack that damaged the heart muscle; heart valve problems; and / or long-term, uncontrolled high blood pressure. Ejection fraction can be measured with imaging tests, including, but not limited to: Echocardiogram, Cardiac catheterization to measure the ejection fraction of a subject’s heart, Magnetic resonance imaging (MRI) to create cross-sectional images of specific parts of the heart, computerized tomography (CT) to create cross-sectional images of specific parts of the heart, or a nuclear medicine scan,

[0070] Confirming a diagnosis may involve one or more medical procedures. If surgery is planned, a diagnostic procedure may be performed in preparation for surgery. Such diagnostic procedures may include the following: Cardiac catheterization, Coronary angiography, Myocardial biopsy, or Genetic testing.Kidney Disease

[0071] The present disclosure provides, among other things, methods and compositions for treating a kidney disease, based on neonatal cardiac mesenchymal progenitor cells (nMPCs), nMPC secretome, nMPC exosomes, or a combination thereof, as therapeutics. A kidney disease can be an acute kidney injury, an acute kidney disease, or a chronic kidney disease. In particular embodiments, an nMPC secretome can comprise, for example, the exosomes, growth factors, cytokines, macromolecules, such as peptides, proteins, and nucleic acids (e.g, miRNAs), or a combination thereof In some embodiments, the present disclosure provides methods of treating a symptom of kidney disease, including, for example, administering to an individual who is suffering from or susceptible to kidney disease an effective amount of nMPCs, nMPC secretome, nMPC exosomes, or a combination thereof, such that at least one symptom or feature of a kidney disease is reduced by at least 2% or by at least 2-fold in intensity, severity, or frequency, or has delayed onset compared to treatment with a placebo.Acute kidney injury (AKI)

[0072] Acute kidney injury (AKI) is a heterogeneous syndrome that not only affects acute morbidity and mortality, but also a patient’s long-term prognosis. AKI affects 30-60% of critically ill patients and is associated with acute morbidity and mortality. The burden of AKI extends beyond the acute phase with progression to chronic kidney disease (CKD), increased risk of cardiovascular complications, recurrent episodes of AKI and long-term mortality. Prevention of development and / or progression is currently limited to hemodynamic and fluid status optimization and avoidance of nephrotoxins. Search for a specific pharmacologic treatment is hampered by the late diagnosis and the complex and incompletely elucidated pathophysiology. Progress in the management of AKI is to be expected from the recognition that AKI is a very heterogeneous syndrome with variable etiology, pathophysiology and clinical presentation.

[0073] AKI is mostly defined as a decrease of glomerular filtration rate (GFR). The KDIGO workgroup proposed a consensus definition and staging system for clinical practice (the KDIGO definition) that relies on the increase of serum creatinine (Scr) within 7 days and / or the presence of oliguria, both surrogate markers of GFR.WSGR Docket No. 64320-711.601

[0074] Acute kidney disease (AKD) defined as an AKI episode that lasts longer than 7 days but less than 90 days. It bridges the gap between AKI and CKD (which requires 3 months to be diagnosed). AKD uses the creatinine criteria of the KDIGO definition. The diagnosis of AKD (severity) or apparent recovery may be affected by the decrease of Scr related to muscle mass loss associated with chronic critical illness.

[0075] Following the development of AKI, several scenarios are possible that may lead to recovery of renal function or to more prolonged dysfunction. Acute kidney disease (AKD) is assessed between 7 and 90 days after AKI. In patients that do not improve, chronic kidney disease (CKD) is established after day 90. Biomarkers of renal injury and function may be able to refine the prediction of rapid recovery (i.e., transient AKI) or transition to more persistent impairment of renal function and several therapeutic interventions may be able to modulate the progression of the disease course.

[0076] Chronic kidney disease (CKD) is a progressive disease with no cure and high morbidity and mortality. CKD is a condition where the kidneys gradually lose their ability to filter waste products from the blood and maintain fluid balance. Early stages are often asymptomatic. Symptoms in later stages include, but are not limited to, fatigue, swelling in the legs, feet, and hands, shortness of breath, nausea, loss of appetite, bone pain, or a combination thereof.

[0077] CKD may be caused by, or associated with, diabetes, high blood pressure, heart disease, glomerulonephritis (inflammation of the kidneys), autoimmune disorders, and may be associated with genetic factors. CKD most commonly occurs in the general adult population but is increased in people with diabetes and hypertension. Preservation of kidney function can improve outcomes and can be achieved through non-pharmacological strategies (e.g, dietary and lifestyle adjustments) and chronic kidney disease-targeted and kidney disease-specific pharmacological interventions.

[0078] CKD affects a significant proportion of the population and is growing rapidly owing to an increased aging population and prevalence of type 2 diabetes mellitus, obesity, hypertension and cardiovascular disease that contribute towards CKD.

[0079] CKD stratification is based upon the estimated glomerular filtration rate (eGFR) and albuminuria. There are six eGFR categories. An eGFR ofless than 60 mL / min per 1.73 m2for more than 3 months is indicative of impaired renal function and the severity of kidney damage increases with decreasing eGFR measurements. Patients with early onset of the disease, stage 1-2, have normal to mild decreased levels of eGFR (60 to > 90 mL / min per 1.73 m2). Patients with stage 3a-3b have mild to moderate decreased levels of eGFR (45-59 mL / min per 1.73 m2, respectively). Severely decreased levels of eGFR, stage 4-5 (15-29 to < 15 mL / min per 1.73 m2, respectively), are indicative of advanced stages of the disease and kidney failure.

[0080] Stratification also comprises three categories of albuminuria. Patients with an albumin to creatinine ratio (ACR) of 3 to at most 30 mg / mmol are classified as having microalbuminuria and at moderate risk of adverse outcomes. Those with ACR of greater than 30 mg / mmol are classified as having macroalbuminuria and being severely at risk of developing adverse events. The eGFR and albuminuria categories independently predict adverse outcomes for patients with CKD, and the combination of bothWSGR Docket No. 64320-711.601increases this risk further. The CKD classification system aids clinicians in carrying out accurate assessments of CKD severity and other complications which helps to inform decisions associated with the management and monitoring of patients.

[0081] Complications such as CKD mineral bone disorder, anemia, hypertension and hyperkalemia may occur and advanced stages of CKD, stage 4-5, ensue. Clinical symptoms, such as fatigue, itching of the skin, bone or joint pain, muscle cramps and swollen ankles, feet or hands, are often present at this stage. Further deterioration of kidney function causes tubular and glomerular hypertrophy, sclerosis and fibrosis, leading to a significant reduction in eGFR, extreme albuminuria and kidney failure.

[0082] As the disease progresses, the risk of cardiovascular disease is markedly increased, such that 50% of patients with late-stage CKD, stage 4-5, have cardiovascular disease. The risk of atrial fibrillation (AF) and acute coronary syndrome (ACS) is doubled in patients with eGFR < 60 mL / min per 1.73 m2. AF is associated with a threefold higher risk of progression to ESKD. The incidence of heart failure (HF) is also threefold greater in patients with eGFR < 60 mL / min per 1.73 m2 compared with > 90 mL / min per 1.73 m2 and HF is associated with CKD progression, hospitalization and death.

[0083] Because the heart has limited regenerative capacity, stem cell-derived therapies with the cells, secretomes, and / or exosomes described herein, can reverse model ventricular anatomy and reduce systemic inflammation, and represent a promising therapeutic approach for treating kidney disease. nMPCs, nMPC secretome, nMPC exosomes, or a combination thereof, described herein can reduce levels of inflammation, reduce levels of pro-inflammatory factors, and / or reduce levels of oxidative stress. In some embodiments, reduction is at least 2% or more compared to a placebo or compared to a subject prior to treatment. In other embodiments, reduction is at least 2-fold or more compared to a placebo or compared to a subject prior to treatment. The goal of using the compositions comprising nMPCs, nMPC secretomes, and / or nMPC exosomes described herein is to offset pathophysiological consequences of degeneration of a subject by partially or treating a symptom of kidney disease.Cell-Derived and Secretome-Derived Therapies

[0084] Therapies with the cells described herein, secretomes, and / or exosomes described herein, which have a multimodal mechanism of action capable of targeting the critical pathological mechanisms of HFpEF, DCM, or kidney disease, represent a promising therapeutic approach for reducing the symptoms associated with HFpEF, and for facilitating healing of HFpEF DCM, or kidney disease. nMPCs, nMPC secretome, and / or nMPC exosomes can help reduce levels of inflammation, reduce levels of pro-inflammatory factors, and / or reduce levels of oxidative stress both locally and systemically. The goal of using the compositions comprising nMPCs, nMPC secretome, and / or nMPC exosomes is to offset the pathophysiological consequences of HFpEF, DCM, or kidney disease, by recruiting regenerative factors and / or targeting inflammation. nMPCs, nMPC secretome, and / or nMPC exosomes described herein can reduce the severity of symptoms of HFpEF. In some embodiments, reduction is at least about 2%, 2.5%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, or at least about 1.1-fold, 1.5-fold, 2-fold, 2.5-fold, 3-fold, 3.5-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 40-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, orWSGR Docket No. 64320-711.601100-fold as compared to a placebo or compared to a subject prior to treatment. The goal of using the compositions comprising nMPCs, nMPC secretome, and / or nMPC exosomes described herein is to offset pathophysiological consequences of HFpEF, DCM, or kidney disease of a subject by partially or treating a symptom of HFpEF, DCM, or kidney disease of the subject.

[0085] nMPCs, an nMPC secretome, and / or nMPC exosomes disclosed herein comprise an allogeneic, culture-expanded neonatal cardiac mesenchymal progenitor cell (nMPC) formulation with potent immunomodulatory effects and the potential to block cytokine storms. These nMPCs are isolated from the right atrial appendage of neonatal (<30 days old) donors with normal myocardium undergoing congenital heart surgery. In certain instances, therapeutic benefits of nMPCs can be exerted through the nMPC secretome, which is comprised of, for example, independently secreted growth factors, cytokines, chemokines, and / or miRNA-enriched exosomes. In some embodiments, an nMPC Total Secretome comprises both nMPC secretome and nMPC exosomes that provide therapeutic relief for a subject in need thereof. Robust analyses, including deep proteomic analysis and RNA sequencing of the nMPC secretome coupled with Ingenuity Pathway Analysis, have shown the presence of unique proteins and miRNA within the nMPC secretome may be responsible for downregulating fibrotic, inflammatory, and oxidative stress pathways (ERK / MAPK Signaling pathway) while promoting cellular growth, survival, and proliferation pathways. Thus, the nMPCs, nMPC secretomes, and / or nMPC exosomes operate through a multimodal mechanism of action, enhancing pathways related to angiogenesis, immunomodulation, energy production, and cardiomyocyte proliferation while reducing oxidative stress, inflammation, and / or fibrosis.

[0086] The nMPCs, nMPC secretomes, and / or nMPC exosomes disclosed herein have demonstrated superior therapeutic potential compared to other well -characterized and clinically relevant progenitor cell types in vitro and in vivo. The nMPCs, nMPC secretomes, and / or nMPC exosomes significantly inhibited secretion of pro-inflammatory cytokines TNF-a, IL-8, and MCP-1. IL-17a and IFN-y were also shown to be reduced following exposure to nMPCs.

[0087] In various embodiments, a damaged or dysfunctional tissue (e.g, skin, muscle, or connective tissue) may need repair, regeneration, or improved function due to chronic inflammation or degeneration In some embodiments, administration of a composition as described herein comprising nMPCs, nMPC secretomes, nMPC exosomes, or any combination thereof can result in a decrease in inflammatory factors or factors associated with oxidative stress. In various embodiments, the subject to be treated is a mammal. In some embodiments, the mammal is a human. The human can be a child (from birth to 18 years of age) or an adult (over 18 years of age).Neonatal Cardiac Mesenchymal Progenitor Cells (nMPCs)

[0088] In one aspect, neonatal cardiac mesenchymal progenitor cells (nMPCs) for use in the methods described herein are (a) positive for protein expression of Ki67 or Nkx2.5, (b) positive for cell surface protein expression of c-Kit (CD117), CD44, CD73, CD47, CD105, and / or CD90, (c) positive for miRNA expression of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and / or miR-374b-5p, and (d) negative for protein expression of CD34, CD45, CD31, PECAM-1, tryptase, GATA4, ISL1, SSEA3,WSGR Docket No. 64320-711.601SSEA4, and / or pl6INK4a. In one embodiment, the nMPCs are (a) positive for protein expression of Ki67 or Nkx2.5, (b) positive for cell surface protein expression of c-Kit (CD117), CD44, CD73, CD47, CD105, or CD90, (c) positive for miRNA expression of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, or miR-374b-5p, and (d) negative for protein expression of CD34, CD45, CD31, PECAM-1, tryptase, GATA4, ISL1, SSEA3, SSEA4, or pl6INK4a. In another embodiment, the nMPCs are (a) positive for protein expression of Ki67 andNkx2.5, (b) positive for cell surface protein expression of c-Kit (CD117), CD44, CD73, CD47, CD105, and CD90, (c) positive for miRNA expression of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and miR-374b-5p, and (d) negative for protein expression of CD34, CD45, CD31, PECAM-1, tryptase, GATA4, ISL1, SSEA3, SSEA4, and pl6INK4a. In certain embodiments, the nMPCs are further positive for protein expression of PDL1, OCT3 / 4, NANOG, KLF4, HSF1, or SOX2. In some embodiments, the nMPCs are further positive for protein expression of PDL1, OCT3 / 4, NANOG, KLF4, HSF1, and SOX2. Alternatively, or in addition, the nMPCs are further negative for protein expression of p!6INK4aup to at least passage 8. In some embodiments, the nMPCs are (a) positive for protein expression of Ki67, Nkx2.5, OCT3 / 4, NANOG, KLF4, HSF1, and / or SOX2, (b) positive for cell surface protein expression of c-kit (CD117), CD44, CD73, CD47, CD105, CD90, and / or PDL1, (c) positive for miRNA expression of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and / or miR-374b-5p, and (d) negative for protein expression of CD34, CD45, CD31, PECAM-1, tryptase, GATA4, ISL1, SSEA3, SSEA4, and / or p!6INK4a. In certain embodiments, the nMPCs are (a) positive for protein expression of Ki67, Nkx2.5, OCT3 / 4, NANOG, KLF4, HSF1, or SOX2, (b) positive for cell surface protein expression of c-kit (CD117), CD44, CD73, CD47, CD105, CD90, or PDL1, (c) positive for miRNA expression of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, or miR-374b-5p, and (d) negative for protein expression of CD34, CD45, CD31, PECAM-1, tryptase, GATA4, ISL1, SSEA3, SSEA4, or pl6INK4a. In yet other embodiments, the nMPCs are (a) positive for protein expression of Ki67, Nkx2.5, OCT3 / 4, NANOG, KLF4, HSF1, and SOX2, (b) positive for cell surface protein expression of c-kit (CD117), CD44, CD73, CD47, CD105, CD90, and PDL1, (c) positive for miRNA expression of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and miR-374b-5p, and (d) negative for protein expression of CD34, CD45, CD31, PECAM-1, tryptase, GATA4, ISL1, SSEA3, SSEA4, and pl6INK4a

[0089] nMPCs described herein are isolated from the right atrial appendage of neonatal (<30 days old) donors with normal myocardium undergoing congenital heart surgery. The therapeutic benefits of nMPCs described herein can, in some instances, be exerted through nMPC secretomes (conditioned media) and / or exosomes which comprise, for example, independently secreted growth factors, cytokines, chemokines, and / or miRNA. In some embodiments, the nMPCs are obtained from cardiac tissue from a neonate of less than 1 month (30 days) of age. In some embodiments, the neonatal donor is less than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 days old.

[0090] Neonatal cardiac mesenchymal progenitor cells (nMPCs) may be isolated from neonatal cardiac tissue by disaggregating tissue from the tissue of the right atrial appendage which is to serve as the sourceWSGR Docket No. 64320-711.601of the neonatal cardiac mesenchymal progenitor cells that are non-naturally occurring and subsequently cultured in vitro. For example, the tissue or organ can be disaggregated mechanically and / or treated with digestive enzymes and / or chelating agents that weaken the connections between neighboring cells making it possible to disperse the tissue into a suspension of individual cells without appreciable cell breakage. Enzymatic dissociation can be accomplished by mincing the tissue and treating the minced tissue with any of a number of digestive enzymes either alone or in combination. These include, but are not limited to, trypsin, chymotrypsin, collagenase, elastase, hyaluronidase, DNase, pronase, and / or dispase, etc. Mechanical disruption can also be accomplished by a number of methods including the use of grinders, blenders, sieves, homogenizers, pressure cells, sonicators, etc. In some embodiments, nMPCs are cultured under hypoxic conditions. In some embodiments, nMPCs may be cultured according to the disclosures in Example 1. The nMPCs as described and claimed herein are not naturally occurring as demonstrated by differences in the cell phenotype and secretome profile following the culture conditions.

[0091] Once the tissue has been reduced to a suspension, the suspension can be fractionated into subpopulations from which neonatal cardiac mesenchymal progenitor cells can be obtained. This also may be accomplished using techniques for cell separation including, but not limited to, cloning and selection of specific cell types, selective destruction of unwanted cells (negative selection), separation based upon differential cell agglutinability in the mixed population, freeze-thaw procedures, differential adherence properties of the cells in the mixed population, filtration, standard and zonal centrifugation, centrifugal elutriation (counter-streaming centrifugation), unit gravity separation, countercurrent distribution, electrophoresis and fluorescence-activated cell sorting (FACS).

[0092] In one embodiment, nMPCs can be substantially free of cells that have marker profiles other than those associated with nMPCs described herein. In certain embodiments, the nMPCs are at least 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% free of such contaminating cell types. In certain embodiments, the nMPCs are at least 80%, free of such contaminating cell types. In certain embodiments, the nMPCs are at least 85%, free of such contaminating cell types. In certain embodiments, the nMPCs are at least 90%, free of such contaminating cell types. In certain embodiments, the nMPCs are at least 95%, free of such contaminating cell types. Alternatively, or in addition, the nMPCs can also be substantially free of soluble, naturally occurring molecules. As discussed more fully below, a substantially purified progenitor cell of the disclosure can be obtained, for example, by extraction (e.g, via density gradient centrifugation and / or flow cytometry) from a culture source. Purity can be measured by any appropriate method. nMPCs described herein can be about 95%-100% purified by, for example, flow cytometry (e.g, FACS analysis), as discussed herein. Such purified nMPCs may, in certain instances, lack any retroviral DNA or retroviral RNA. In certain instances, an exemplary method of obtaining the nMPCs comprises the steps of: (a) culturing nMPCs in progenitor cell culture medium (e.g, ISTEM® from Progenitor Cells, Inc., Rooster Basal™-MSC-CC, Rooster Booster ™-MSC-CC, etc.); (b) treating the cells with a cell detachment solution (e.g, ACCUTASE® from Gibco # Al 1105-05, TrypLE™ Express Enzymes), and (c) collecting cells from the enzyme-treated culture to obtain the isolated nMPCs prior to one or moreWSGR Docket No. 64320-711.601additional culturing methods. In some embodiments, the isolated nMPCs are allogeneic to a subject to be treated by the methods described herein.

[0093] As used herein the term “exosome” refers to a small (from about 20 nm to about 300 nm in diameter, from about 50 nm to about 200 nm in diameter, or from about 50 nm to about 100 nm in diameter) nMPC vesicle comprising a membrane that encloses an internal space, and which is generated from said cell by direct plasma membrane budding or by fusion of the late endosome with the plasma membrane. The exosome is a species of extracellular vesicle. The exosome comprises lipid or fatty acid and polypeptide and optionally comprises a payload (e.g, a therapeutic agent), a receiver (e.g., a targeting moiety), a polynucleotide (e.g, a nucleic acid, miRNA, RNA, or DNA), a sugar (e.g, a simple sugar, polysaccharide, or glycan) or other molecules. The exosome is an nMPC exosome, and isolated from the nMPCs based on its size, density, biochemical parameters, or a combination thereof. Exosomes generally contain a lipid bilayer with a center containing fluid, DNA, RNA, miRNAs, peptides, and / or proteins. The bilayer comprises lipids including, but not limited to, cholesterol, a diglyceride, a ceramide, a sphingolipid (e.g., sphingomyelin, ceramide, etc.), a phospholipid, a glycerophospholipid (such as, for example, phosphatidylcholine (PC), phosphatidylserine (PS), phosphatidylethanolamine (PE), phosphatidylinositol (PI), and polyglycerophospholipids (e.g., bisphosphate)), gangliosides (GM), or a combination thereof. The nMPC exosomes can also comprise a transmembrane protein, tetraspanin, antigen presenting molecule, glycoprotein, adhesion molecule, heat shock protein (Hsp), cytoskeletal protein, ESCRT component, membrane transport protein, fusion protein, growth factor, cytokine, lipid, fas ligand (FasL), mRNA, miRNA, non-coding RNA, DNA, TNF receptor, or transferrin receptor (TfR), or a combination thereof.

[0094] In one embodiment, nMPCs are genetically engineered. Genetically engineering may encompass the introduction of a nucleic acid molecule (e.g, a plasmid) which encodes one or more paracrine factors. The paracrine factors may be exogenous or endogenous. In other embodiments, genetic engineering may encompass the introduction of an exogenous construct (e.g, a plasmid or an mRNA) that expresses a secreted growth factor, a cytokine, a chemokine, and / or a microRNA. In the case of an endogenous nucleic acid sequence, the nucleic acid molecule may contain a promoter and / or enhancer which induces expression or overexpression of a protein. In one non-limiting example, nMPCs are genetically engineered to express or overexpress HGF, SCF, SDF-la, ANG1,VEGFA, PDGFB, bFGF, HSP20, Akt, miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and / or miR-374b-5p. In some embodiments, the nMPCs are genetically engineered to overexpress 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 of HGF, SCF, SDF-la, ANG1, VEGFA, PDGFB, bFGF,HSP20, Akt, miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and miR-374b-5p. In certain embodiments, the nMPCs are (a) positive for protein expression of Ki67, Nkx2.5, OCT3 / 4, NANOG, KLF4, HSF1, and / or SOX2, (b) positive for cell surface protein expression of c-Kit (CD117), CD44, CD73, CD47, CD105, CD90, and / or PDL1, (c) positive for miRNA expression of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and / or miR-374b-5p, (d) negative for protein expression of CD34, CD45, CD31, PECAM-1, tryptase, GATA4, ISL1, SSEA3, SSEA4, and / or pl6INK4a, and (e) genetically engineered to overexpressWSGR Docket No. 64320-711.601HGF, SCF, SDF-la, ANG1, VEGFA, PDGFB, bFGF, HSP20, Akt, miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and / or miR-374b-5p. In one embodiment, the nMPCs are (a) positive for protein expression of Ki67, Nkx2.5, OCT3 / 4, NANOG, KLF4, HSF1, and SOX2, (b) positive for cell surface protein expression of c-Kit (CD117), CD44, CD73, CD47, CD105, CD90, and PDL1, (c) positive for miRNA expression of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and miR-374b-5p, (d) negative for protein expression of CD34, CD45, CD31, PECAM-1, tryptase, GATA4, ISL1, SSEA3, SSEA4, andpl6INK4a, and (e) genetically engineered to overexpress HGF, SCF, SDF-la, ANG1, VEGFA, PDGFB, bFGF, HSP20, Akt, miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and miR-374b-5p. In some embodiments, the nMPCs are: (a) positive for protein expression of 1, 2, 3, 4, 5, 6, or 7 of Ki67, Nkx2.5, OCT3 / 4, NANOG, KLF4, HSF1, and SOX2; (b) positive for cell surface protein expression of 1, 2, 3, 4, 5, 6, or 7 of c-Kit (CD117), CD44, CD73, CD47, CD105, CD90, and PDL1; (c) positive for miRNA expression of 1, 2, 3, 4, 5, or 6 of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and miR-374b-5p, (d) negative for protein expression of 1, 2, 3, 4, 5, 6, 7, 8, or 9 of CD34, CD45, CD31, PECAM-1, tryptase, GATA4, ISL1, SSEA3, and SSEA4; and / or (e) negative for protein expression of p!6INK4aup to at least passage 8. In one embodiment, the nMPCs are: (a) positive for protein expression of 1, 2, 3, 4, 5, 6, or 7 of Ki67, Nkx2.5, OCT3 / 4, NANOG, KLF4, HSF1, and SOX2; (b) positive for cell surface protein expression of 1, 2, 3, 4, 5, 6, or 7 of c-Kit (CD117), CD44, CD73, CD47, CD105, CD90, and PDL1; (c) positive for miRNA expression of 1, 2, 3, 4, 5, or 6 of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and miR- 374b- 5p; and (d) negative for protein expression of 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 of CD34, CD45, CD31, PECAM-1, tryptase, GATA4, ISL1, SSEA3, SSEA4, and pl6INK4a. In some embodiments, the nMPCs express HSF1 at levels higher than adult mesenchymal progenitor cells (aMPCs). In some embodiments, the nMPCs are further negative for protein expression of IGF 1. In some instances, the nMPCs do not express 42254. In some embodiments, the nMPCs are allogeneic or autologous. In certain embodiments, the nMPCs are non-naturally occurring. In other embodiments, the nMPCs are not xenogenic. In some embodiments, the nMPCs are obtained from a subject who is biologically a female. In certain other embodiments, the nMPCs are obtained from a subject who is biologically a male. In some embodiments, the conservative amino acid changes are made to a paracrine factor in an nMPC. In an embodiment, the conservative amino acid change improves the stability of a paracrine factor. In some embodiments, the conservative amino acid changes result in an increase in the levels of a paracrine factor. A transgene may be introduced into a neonatal cardiac mesenchymal progenitor cell via conventional techniques such as calcium phosphate or calcium chloride co-precipitation, DEAE-dextran-mediated transfection, lipofection, electroporation, or microinjection. By way of example only, a transgene may be introduced into cells using an appropriate expression vector including, but not limited to, cosmids, plasmids, or modified viruses (e.g., replication defective retroviruses, adenoviruses, and adeno-associated viruses). Transfection can be obtained by using methods including culturing the cells on a monolayer of virus-producing cells.

[0095] The disclosure also provides methods of culturing the neonatal cardiac mesenchymal progenitor cell under conditions to promote the expression of selected coding sequences. Expression includes, forWSGR Docket No. 64320-711.601example, miRNA and / or protein. In some embodiments, the coding sequence(s) can comprise a growth factor, a cytokine, a chemokine, and / or a microRNA. In one non-limiting example, the coding sequence(s) can encode HGF, SCF, SDF-la, ANG1, VEGFA, PDGFB, bFGF, HSP20, and / or Akt. In some embodiments, nMPCs can express a microRNA (or “miRNA”) or be genetically engineered to express the miRNA. MicroRNAs are from about 19 to about 25 nucleotides long noncoding RNAs that bind to the 3' UTR of nucleic acid molecules and downregulate gene expression either by reducing nucleic acid molecule stability or by inhibiting translation. A microRNA sequence includes a “seed” region, e.g, a sequence in the region of positions 2-8 of the mature microRNA, which sequence has Watson-Crick complementarity to the miRNA target sequence. In some embodiments, nMPCs have positive expression of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, miR-374b-5p, or a combination thereof. In another non-limiting example, the coding sequence(s) can encode miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and / or miR-374b-5p. In some embodiments, the cytokine may comprise an anti-inflammatory cytokine (e.g., IL-1, IL4, IL-10, IL-13, TGF- , etc.). In some embodiments, the coding sequences encoding HGF, SCF, SDF-la, ANG1, VEGFA, PDGFB, bFGF, HSP20, Akt, miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and / or miR-374b-5p are either stably or transiently transfected into nMPCs. In one embodiment, the cells are passaged at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more times. In another embodiment, the cells are cultured for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 or more days. In yet another embodiment, the cells are cultured in conditioned media comprising a complete medium, such as, for example, ISTEM® medium, or Rooster Basal ™- MS C-CC.

[0096] The disclosure also provides nMPCs obtained by the methods described herein. In another embodiment, the nMPCs are substantially free of any retroviral DNA or RNA (e.g, 80% or greater retroviral DNA-free or retroviral RNA-free). In another embodiment, the nMPCs are substantially free of lenti virus DNA or RNA (e.g., 80% or greater lentivirus DNA-free or lentivirus RNA-free).

[0097] In certain embodiments, nMPCs express peptides, proteins, miRNA, or a combination thereof, downregulate an inflammatory, and / or an oxidative stress pathway (ERK / MAPK signaling pathway), while promoting cellular growth, survival, and / or proliferation pathways. In some embodiments, nMPCs operate through a multimodal mechanism of action, enhancing pathways related to, for example, angiogenesis, immunomodulation, energy production, and cardiomyocyte proliferation while reducing oxidative stress and / or inflammation. In some embodiments, nMPCs can significantly reduce the expression of fibrosis markers assessed and with superior potency compared to the other cell types, such as, for example, adult MSCs (e.g, adult counterpart of nMPCs, derived from adult right atrial appendage), bone marrow- derived MSCs (BM-MSCs), or normal human dermal fibroblasts. In other embodiments, nMPCs can positively modulate the immune system by, for example, significantly increasing Treg cell populations. In some embodiments, nMPCs can downregulate cytokines. In some instances, nMPCs can downregulate inflammatory cytokines. In some embodiments, the downregulated cytokines comprise pro-inflammatory cytokines (e.g., Interleukin (IL)- 1 [3, IL-6, IL-8, IL-12, IL-17a, IL-WSGR Docket No. 64320-711.60118, monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor (TNF)-a, interferon gamma (IFN-y)). In one embodiment, the downregulated cytokines comprise TNF-a, IL-8, MCP-1, IL-17a, and IFN-y. In another embodiment, the downregulated cytokines comprise TNF-a, IL-8, and MCP-1. In yet another embodiment, the downregulated cytokines comprise IL-17a and IFN-y. In an embodiment, nMPCs have higher immunomodulatory potential when compared to other clinically relevant cell types such as, for example, Bone Marrow-derived Mesenchymal Stem Cells (BM-MSCs), Cardiosphere-Derived Cells (CDCs), or aMPCs, as assessed by co-culturing cluster of differentiation (CD)4+T cells, and determining the proportion of CD4+, CD25+, and FoxP3+regulatory T cells (Tregs) after about 5, 6, 7, 8, 9, or 10 days by flow cytometry.nMPC Secretomes ( Conditioned Media) and Exosomes

[0098] In one aspect, provided herein are nMPC secretomes. In another aspect, provided herein are nMPC exosomes. In another aspect, provided herein is an nMPC Total Secretome comprising an nMPC secretome and nMPC exosomes. An nMPC secretome can be an nMPC Total Secretome comprising both an nMPC secretome (comprising, for example, all peptides, proteins, and nucleic acids) and nMPC exosomes. In some embodiments, an nMPC secretome or nMPC exosome as described herein is allogeneic.

[0099] An nMPC secretome (nMPC conditioned medium) can comprise nano-vesicles, microvesicles, exosomes, macromolecules such as peptides or proteins (e.g, growth factors, cytokines, etc.) and nucleic acids (e.g, miRNA, RNA, DNA), or a combination thereof. A non-limiting example of an nMPC secretome disclosed herein can comprise a chemokine, an interleukin, a growth factor, or a combination thereof. In another non-limiting example, an nMPC secretome further comprises nMPC exosomes. In certain embodiments, an nMPC secretome is isolated or purified and is not naturally occurring in a host organism or progenitor cell, from which the nMPC secretome may be derived. In some instances, the nMPC secretome is purified or extracted from a progenitor cell (e g, an nMPC) culture or medium. In some embodiments, the nMPC secretome is non-naturally occurring or engineered. In some embodiments, an nMPC secretome can comprise a microRNA. In certain embodiments, nMPCs can be genetically modified to upregulate or downregulate a desired cellular or secretome protein or peptide. In some instances, the nMPC secretome may contain one or more proteins comprising a cytokine, a chemokine, a growth factor, a soluble molecule, or a combination thereof. In some instances, the one or more proteins can be separate from exosomes or microparticles. In some instances, the one or more proteins can be on the surface of exosomes or microparticles. In some instances, the one or more proteins can be encapsulated by exosomes or microparticles. In some instances, the exosomes have an average particle diameter of for example, from about 20 nm to about 250 nm in diameter or from about 50 nm to about 100 nm in diameter. In some cases, a pharmaceutical composition comprises one or more pharmaceutically acceptable excipients.

[0100] As used herein, the term “extracellular vesicle” or “EV” refers to a cell -derived vesicle comprising a membrane that encloses an internal space. Extracellular vesicles comprise all membranebound vesicles that have a smaller diameter than the cell from which they are derived. Generally,WSGR Docket No. 64320-711.601extracellular vesicles can range in diameter from about 20 nm to about 1000 nm and can comprise various macromolecular payload either within the internal space, displayed on the external surface of the extracellular vesicle, and / or spanning the membrane. In certain embodiments, extracellular vesicles range in diameter from about 50 nm to about 200 nm and can comprise various macromolecular payloads either within the internal space, displayed on the external surface of the extracellular vesicle, and / or spanning the membrane. Said payload can comprise nucleic acids (e.g., DNA, RNA, miRNA, etc.), peptides, proteins, carbohydrates, lipids, small molecules, and / or combinations thereof. RNA can comprise, for example, miRNAs, messenger mRNA (mRNA), circular RNA (circRNA), IncRNA (long non-coding RNA), etc. By way of example and without limitation, extracellular vesicles include apoptotic bodies, fragments of cells, vesicles derived from cells by direct or indirect manipulation (e.g, by serial extrusion or treatment with alkaline solutions), vesiculated organelles, and vesicles produced by living cells (e.g, by direct plasma membrane budding or fusion of the late endosome with the plasma membrane). Extracellular vesicles can be derived from a living or dead organism, explanted tissues or organs, and / or cultured cells. In some embodiments, an nMPC exosome, as described herein, is allogeneic.

[0101] In certain embodiments, an nMPC secretome comprises peptides, proteins, miRNA, or a combination thereof, responsible for downregulating a fibrotic, inflammatory, and / or oxidative stress pathway (ERK / MAPK signaling pathway), while promoting cellular growth, survival, and / or proliferation pathways. In some embodiments, an nMPC secretome operates through a multimodal mechanism of action, enhancing pathways related to, for example, angiogenesis, immunomodulation, energy production, and cardiomyocyte proliferation while reducing oxidative stress, inflammation, and / or fibrosis. In some embodiments, an nMPC secretome can significantly reduce the expression of fibrosis markers assessed and with superior potency compared to the other cell types, such as, for example, adult MSCs (e.g., adult counterpart of nMPCs, derived from an adult right atrial appendage), bone marrow-derived MSCs (BM-MSCs), or normal human dermal fibroblasts. In other embodiments, an nMPC secretome can positively modulate the immune system by, for example, significantly increasing Treg cell population. In some embodiments, an nMPC secretome downregulates cytokines. In some embodiments, the downregulated cytokines comprise pro-inflammatory cytokines (e.g, Interleukin (IL)- 1 [3, IL-6, IL-8, IL-12, IL-17a, IL-18, MCP-1, tumor necrosis factor (TNF)-a, interferon gamma (IFN-y)). In one embodiment, the downregulated cytokines comprise TNF-a, IL-8, MCP-1, IL-17a, and IFN-y. In another embodiment, the downregulated cytokines comprise TNF-a, IL-8, and MCP-1. In yet another embodiment, the downregulated cytokines comprise IL- 17a and IFN-y. In an embodiment, an nMPC secretome has higher immunomodulatory potential when compared to other clinically relevant cell types such as, for example, Bone Marrow-derived Mesenchymal Stem Cells (BM-MSCs), Cardiosphere-Derived Cells (CDCs), or aMPCs, as assessed by co-culturing cluster of differentiation (CD)4+T cells, and determining the proportion of CD4+, CD25+, and FoxP3+regulatory T cells (Tregs) after about 5, 6, 7, 8, 9, or 10 days by flow cytometry.

[0102] In one embodiment, the nMPC secretome or the nMPC exosome is isolated. In certain embodiments, the nMPC secretomes and / or nMPC exosomes are at least about 30%, 35%, 40%, 45%,WSGR Docket No. 64320-711.60150%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% free of cells. In one embodiment, the nMPC secretomes and / or nMPC exosomes are at least about 90% free of cells. In another embodiment, the nMPC secretomes and / or nMPC exosomes are at least about 95% free of cells. In one embodiment, the nMPC secretomes and / or nMPC exosomes are at least about 99% free of cells. In yet another embodiment, the nMPC secretomes and / or nMPC exosomes are at least about 99.5% free of cells.

[0103] Substantially purified nMPCs, nMPC secretome, and / or nMPC exosomes described herein can be obtained, for example, by extraction (e.g, via density gradient centrifugation and / or flow cytometry) and filtration (e.g. , size exclusion chromatography) from a culture source. Purity can be measured by any appropriate method.

[0104] A neonatal cardiac mesenchymal progenitor cell secretome and / or exosome of the disclosure can be about 99%-100% purified by, for example, size exclusion chromatography, as discussed herein. Such purified nMPC secretomes and / or nMPC exosomes may also lack any retroviral DNA or retroviral RNA. In certain instances, the method of obtaining the nMPC secretomes and / or exosomes comprise the steps of: (a) culturing nMPCs in progenitor cell culture medium (e.g, ISTEM® from Progenitor Cells, Inc., Rooster Basal™-MSC-CC, Rooster Booster™-MSC-CC, etc.); (b) treating the cells with a cell detachment solution (e.g., ACCUTASE® from Gibco # Al 1105-05, TrypLE™ Express Enzymes), (c) centrifuging the cultures by standard or ultracentrifugation, (d) collecting the supernatant, and optionally (e) using size exclusion chromatography. In some embodiments, an isolated or purified secretome and / or exosome as described herein is allogeneic. In some aspects, disclosed herein is a composition that comprises a secretome, e.g., a protein, an exosome, or a microvesicle secreted from a cell or cells (e.g, neonatal cardiac mesenchymal progenitor cells).

[0105] In some embodiments, an nMPC secretome and / or nMPC exosomes are (a) positive for protein expression of HGF, SCF, SDF-la, ANG1, VEGFA, PDGFB, bFGF, HSP20, HSF1, and / or Akt, and (b) positive for miRNA expression of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and / or miR-374b-5p. In one embodiment, the nMPC secretome and / or nMPC exosomes are (a) positive for protein expression of HGF, SCF, SDF-la, ANG1, VEGFA, PDGFB, bFGF, HSP20, HSF1, or Akt, and (b) positive for miRNA expression of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, or miR-374b-5p. In another embodiment, the nMPC secretome and / or nMPC exosomes are (a) positive for protein expression of HGF, SCF, SDF-la, ANG1, VEGFA, PDGFB, bFGF,HSP20, HSF1, and Akt, and (b) positive for miRNA expression of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and miR-374b-5p. In certain embodiments, the nMPC secretome is positive for miRNA expression of one, two, three, four, five, or six of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, or miR-374b-5p.

[0106] In some embodiments, the nMPC exosomes are positive for miRNA expression of one, two, three, four, five, or six of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and miR-374b-5p. In some embodiments, the nMPC exosomes are positive for protein expression of CD81 and / or CD63. In some embodiments, the nMPC exosomes are positive for protein expression of CD81 and CD63.WSGR Docket No. 64320-711.601

[0107] In some embodiments, an nMPC is genetically modified to overexpress HGF, SCF, SDF-la, ANG1, VEGFA, PDGFB, bFGF, HSP20, and / or Akt such that the level of each overexpressed factor is greater in the isolated nMPC secretome and / or nMPC exosomes as compared to the level of each factor in a secretome or exosomes isolated from nMPCs that have not been genetically modified. In some embodiments, an nMPC is genetically modified to overexpress miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and / or miR-374b-5p such that the level of each overexpressed miRNA is greater in the isolated nMPC secretome and / or nMPC exosomes as compared to the level of each miRNA in a secretome isolated from nMPCs that have not been genetically modified.

[0108] In other embodiments, the nMPC secretome and / or nMPC exosomes have a marker (e.g., protein) expression profile as provided in Table 5. In some embodiments, an nMPC secretome and / or nMPC exosomes are negative for protein expression of IGF 1. In other embodiments, nMPCs are genetically engineered to overexpress one or more paracrine factors. In other embodiments, nMPCs are genetically engineered to overexpress one or more markers (e.g, proteins) provided in Table 5. In certain embodiments, nMPCs can be genetically modified to upregulate or downregulate a desired cellular or exosomal protein or peptide that can be detected in the nMPC secretome by conventional means. In some embodiments, the nMPC secretome and / or nMPC exosomes are produced by culturing nMPCs cells for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 days and collecting the supernatant of the cultured cells. In some embodiments, the nMPC secretome and / or nMPC exosomes are concentrated.

[0109] The nMPC exosomes can be characterized by their particle size. In some embodiments, an exosome described herein can comprise a particle in a range of from about 50 nm to about 100 nm, from about 50 nmto about 190 nm, from about 50 nm to about 180 nm, from about 50 nm to about 170 nm, from about 50 nm to about 160 nm, from about 50 nm to about 150 nm, from about 50 nm to about 140 nm, from about 50 nm to about 130 nm, from about 50 nm to about 120 nm, from about 50 nm to about 110 nm, from about 50 nm to about 100 nm, from about 50 nm to about 90 nm, from about 50 nm to about 80 nm, from about 50 nm to about 70 nm, or from about 50 nm to about 60 nm in diameter. In an embodiment, an exosome described herein can comprise a particle from about 50 nm to about 90 nm in diameter. In an embodiment, an exosome described herein can comprise a particle from about 50 nm to about 100 nm in diameter. In an embodiment, an exosome described herein can comprise a particle from about 50 nmto about 110 nm in diameter. The nMPC exosomes described herein can comprise particles in a range of from about 50 nm to about 1000 nm, about 100 nm to about 1000 nm, about 500 nm to about 1000 nm, about 600 nm to about 900 nm, about 700 nm to about 800 nm, about 300 nm to about 600 nm, about 300 nm to about 500 nm, 300 nm to about 400 nm, about 200 nm to about 500 nm, 200 nm to about 400 nm, about 100 nm to about 500 nm, about 100 nm to about 300 nm, 100 nm to about 200 nm, 100 nm to about 150 nm, about 50 nm to about 200 nm, about 50 nm to about 150 nm, about 50 nm to about 110 nm, about 50 nm to about 100 nm, about 75 nm to about 250 nm, about 75 nm to about 200 nm, about 75 nm to about 150 nm, about 75 nm to about 100 nm, about 90 nm to about 150 nm, about 90 nm to about 125 nm, about 90 nm to about 110 nm, or about 90 nm to about 100 nm inWSGR Docket No. 64320-711.601diameter. In one embodiment, the nMPC exosomes comprise particles in a range of from about 90 nm to about 110 nm in diameter. In another embodiment, the nMPC exosomes comprise particles in a range of from about 100 nm to about 120 nm in diameter. In some embodiments, the nMPC exosomes comprise particles about 50 nm, 60 nm, 70 nm, 80 nm, 90 nm, 100 nm, 110 nm, 120 nm, 130 nm, 140 nm, 150 nm, 160 nm, 170 nm, 180 nm, 190 nm, 200 nm, 250 nm, 300 nm, 350 nm, 400 nm, 450 nm, 500 nm, 550 nm, 600 nm, 650 nm, 700 nm, 750 nm, 800 nm, 850 nm, 900 nm, 950 nm, or 1000 nm in diameter. In some embodiments, the nMPC exosomes comprise particles about 90 nm in diameter. In certain embodiments, the nMPC exosomes comprise particles about 100 nm in diameter. In other embodiments, the nMPC exosomes comprise particles about 110 nm in diameter. In yet other embodiments, the nMPC exosomes have a density of about 1.13 g / ml to about 1.19 g / ml.Compositions and Formulations

[0110] The terms “pharmaceutical composition” and “pharmaceutical formulation” (or “formulation”) are used interchangeably and denote a mixture or solution comprising a therapeutically effective amount of an active pharmaceutical ingredient together with one or more pharmaceutically acceptable excipients to be administered to a subject, e.g, a human in need thereof. A pharmaceutical composition used in the therapeutic methods of the invention is formulated to be compatible with its intended route of administration. In certain embodiments, the active pharmaceutical ingredient comprises, for example, neonatal cardiac mesenchymal progenitor cells (nMPCs), an nMPC secretome (an nMPC conditioned medium), nMPC exosomes, an nMPC total secretome, or a combination thereof. In some embodiments, the pharmaceutical formulation comprises nMPCs in a pharmaceutically acceptable carrier (e.g, phosphate buffered saline). In some embodiments, the pharmaceutical formulation comprises nMPCs and an nMPC secretome in a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical formulation consists of an nMPC secretome in a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical formulation consists of nMPC exosomes in a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical formulation comprises nMPCs, nMPC secretome, nMPC exosomes, an nMPC total secretome, or a combination thereof. In one embodiment, the pharmaceutical formulation comprises nMPCs, an nMPC secretome (comprising, for example, exosomes, peptides and / or proteins (e.g., growth factors, cytokines), and nucleic acids (e.g., miRNA, RNA, DNA)), nMPC exosomes, an nMPC total secretome, or a combination thereof, in a pharmaceutically acceptable carrier. In another embodiment, the pharmaceutical formulation comprises an nMPC secretome and nMPC exosomes in a pharmaceutically acceptable carrier. In some embodiments, a pharmaceutical formulation disclosed herein is administered in combination with a drug or therapeutic agent. In certain aspects, combination therapy is contemplated wherein the nMPCs, nMPC secretome, and / or nMPC exosomes are administered with a drug or a therapeutic agent. In some aspects, a composition or formulation as described herein is formulated with a pharmaceutically acceptable carrier suitable for its intended route of administration. In some embodiments, a composition formulated for intravenous injection, transdermal administration, transcutaneous administration, or subcutaneous injection comprises nMPCs, nMPC secretome, nMPC exosomes, an nMPC total secretome, or aWSGR Docket No. 64320-711.601combination thereof, and a pharmaceutically acceptable carrier (e.g, PBS). In some embodiments, a composition formulated for subcutaneous injection or topical administration comprises nMPCs, nMPC secretome, and / or nMPC exosomes in combination with a hyaluronic acid and / or a hydrophilic polymer.Protein Concentrations

[0111] The compositions described herein can comprise the nMPC secretome and / or nMPC exosomes at a final protein concentration. A final protein concentration can be adjusted to achieve therapeutic efficacy depending on measured symptoms of a subject by a clinician. In some embodiments, the nMPC secretome and / or nMPC exosomes comprise a final protein concentration of from about 0.1 mg / ml to about 50.0 mg / ml, or from about 0.5 mg / ml to about 20.0 mg / ml. In some embodiments, the nMPC secretome and / or nMPC exosomes comprise a final protein concentration of (a) at least about 0.1 mg / ml, 0.5 mg / ml, 1.0 mg / ml, about 2.0 mg / ml, about 3.0mg / ml, about 4.0 mg / ml, about 5.0 mg / ml, about 6.0 mg / ml, about 7.0 mg / ml, about 8.0 mg / ml, about 9.0 mg / ml, about 10.0 mg / ml, about 11.0 mg / ml, about 12.0 mg / ml, about 13.0 mg / ml, about 14.0 mg / ml, about 15.0 mg / ml, about 16.0 mg / ml, about 17.0 mg / ml, about 18.0 mg / ml, about 19.0 mg / ml, about 20.0 mg / ml, about 22.0 mg / ml, about 24.0 mg / ml, about 26.0 mg / ml, about 28.0 mg / ml, about 30.0 mg / ml, about 35.0 mg / ml, about 40.0 mg / ml, about 45.0 mg / ml, or about 50.0 mg / ml, or (b) at most about 250.0 mg / ml, about 225.0 mg / ml, about 200.0 mg / ml, about 175 mg / ml, about 150 mg / ml, about 125 mg / ml, about 100 mg / ml, about 75 mg / ml, about 50 mg / ml, about 45.0 mg / ml, about 40.0 mg / ml, about 35.0 mg / ml, about 30.0 mg / ml, about 25 mg / ml, about 20 mg / ml, about 15 mg / ml, about 10 mg / ml, about 5 mg / ml, about 1 mg / ml, about 0.5 mg / ml, or about 0.1 mg / ml. In some embodiments, the nMPC secretome and / or nMPC exosomes comprise a final protein concentration of at least about 1.0 mg / ml ±0.1, ±0.2, ±0.3, ±0.4, or ±0.5. In other embodiments, the nMPC secretome and / or nMPC exosomes comprise a final protein concentration of at least about 4.0 mg / ml ±0.5, ±1.0, ±1.5, ±2.0, ±2.5, or ±3.0. In some embodiments, the nMPC secretome and / or nMPC exosomes comprise a final protein concentration of at least about 8.0 mg / ml ±1.0, ±2.0, ±3.0, ±4.0, or ±5.0. In certain embodiments, the nMPC secretome and / or nMPC exosomes comprise a final protein concentration of at least about 16.0 mg / ml ±2.0, ±3.0, ±4.0, ±5.0, or ±6.0. In some instances, the nMPC secretome and / or nMPC exosomes are administered at a concentration of at least about 10 pg / ml to at least about 1000 pg / ml. Alternatively, or in addition, in certain embodiments, the nMPC secretome and / or nMPC exosomes are positive for protein expression of one or more of the proteins in Table 5.

[0112] The separate components of the compositions or formulations disclosed herein may be preblended or each component may be added separately to the same environment according to a predetermined dosage for the purpose of achieving the desired concentration level of the treatment components and so long as the components eventually come into intimate admixture with each other. Further, the compositions or formulations disclosed herein may be administered or delivered on a continuous or intermittent basis. In some embodiments, nMPC secretomes and / or nMPC exosomes may be separately produced, isolated, and concentrated, followed by the blending or titration of a specific number or concentration of nMPCs into a volume of the composition or formulation comprising nMPC secretomes and / or nMPC exosomes.WSGR Docket No. 64320-711.601PH

[0113] The maintenance of a biologically suitable pH is also contemplated for the compositions described herein. In some embodiments, the composition has an acidic pH at an average human body temperature. In some embodiments, the composition has a biologically neutral pH at an average human body temperature. In some embodiments, the composition has an alkaline pH at an average human body temperature. In certain embodiments, the composition comprises a pH of from about 5.2 to about 7.7, from about 5.5 to about 7.5, from about 7.1 to about 7.5, from about 7.2 to about 7.4, from about 6.0 to about 8.0, from about 7.0 to about 9.0, or from about 5.0 to about 9.0. In one embodiment, the composition comprises a pH of about 6.0. In one embodiment, the composition comprises a pH of about 6.2. In one embodiment, the composition comprises a pH of about 6.5. In one embodiment, the composition comprises a pH of about 7.0. In another embodiment, the composition comprises a pH of about 7.2. In one embodiment, the composition comprises a pH of 7.4. In some embodiments, the composition comprises a pH of about 7.5. In certain other embodiments, the composition comprises a pH of about 7.7. In one embodiment, the composition comprises a pH of about 8.5. In another embodiment, the composition comprises a pH of about 8.9. In some embodiments, the pH of a composition upon administration is the pH at a normal body temperature range from about 97 °F to about 99 °F (about 36.1 °C to about 37.2 °C). In certain other embodiments, the pH of a composition prior to administration and / or in storage comprises a pH of from about 5.0 to about 8.0, fromabout 6.0 to about 8.0, from about 7.0 to about 9.0, or from about 5.0 to about 9.0. In some embodiments, the pH of a composition described herein is the pH as measured at about 4 °C, 10 °C, 25 °C, or about 37 °C. In one embodiment, the pH of a composition is between about 6.8 and about 7.9 at about 25 °C. In one embodiment, the pH of a composition is about 7.4 at about 25 °C. In another embodiment, the pH of a composition is between about 6.8 and about 7.9 at about 37 °C.Lyophilization

[0114] Lyophilization, also known as freeze-drying, is a preservation technique that removes water from a material, typically by freezing and then sublimating the ice into vapor under a vacuum. This process can help stabilizing sensitive materials like pharmaceuticals, biological samples, to extend their shelf life and improve ease of transportation and storage. Lyophilization of the compositions described herein is also contemplated, and may be useful for environments or situations in which a patient may have limited access to modem medical facilities. In some embodiments, the composition is lyophilized. In certain embodiments, the lyophilized composition is reconstituted in a diluent. In certain embodiments, the diluent comprises a pharmaceutically acceptable diluent. In other embodiments, the lyophilized composition is incubated for an amount of time and / or at a suitable temperature comprising, for example, a temperature of about 4 °C, 10 °C, 25 °C, or about 37 °C.Pharmaceutically Acceptable Excipients

[0115] In any such compositions, a pharmaceutically acceptable carrier may comprise, for example, buffers, surfactants, stabilizers, preservatives, suspending agents, thickening agents, viscosity regulators, dispersion media, coatings, antibacterial agents, antifungal agents, cryoprotectants isotonic andWSGR Docket No. 64320-711.601absorption delaying agents, and osmoregulators. In some instances, a pharmaceutically acceptable carrier may comprise PBS.Considerations for Intravenous Administration

[0116] Formulations for intravenous injection are also contemplated. Compositions can comprise the nMPCs, and in such cases, dosage units may comprise the number of cells to be administered in each dose. In some embodiments, a dose of the nMPCs comprises from about 15 million to about 250 million nMPCs. In some embodiments, a dose of the nMPCs comprises from about 35 million to about 65 million nMPCs. In some embodiments, a dose of the nMPCs comprises from about 45 million to about 55 million nMPCs. In some embodiments, a dose of the nMPCs comprises about 50 million nMPCs. In some embodiments, a dose of the nMPCs comprises from about 85 million to about 115 million nMPCs. In some embodiments, a dose of the nMPCs comprises from about 95 million to about 105 million nMPCs. In some embodiments, a dose of the nMPCs comprises about 100 million nMPCs. In some embodiments, a dose of the nMPCs comprises from about 135 million to about 165 million nMPCs. In some embodiments, a dose of the nMPCs comprises from about 145 million to about 155 million nMPCs. In some embodiments, a dose of the nMPCs comprises about 150 million nMPCs. In some embodiments, a dose of the nMPCs comprises from about 185 million to about 215 million nMPCs. In some embodiments, a dose of the nMPCs comprises from about 195 million to about 205 million nMPCs. In some embodiments, a dose of the nMPCs comprises about 200 million nMPCs. In some embodiments, a dose of the nMPCs comprises from about 235 million to about 265 million nMPCs. In some embodiments, a dose of the nMPCs comprises from about 245 million to about 255 million nMPCs. In some embodiments, a dose of the nMPCs comprises about 250 million nMPCs.

[0117] Compositions for intravenous administration can also comprise nMPC secretomes and / or nMPC exosomes. In such cases, a dosage unit may comprise the final protein concentration in a dose, as calculated from the total weight of protein in the nMPC secretomes and / or nMPC exosomes per volume (for example, in milliliters) administered to the subject. A final protein concentration can be adjusted to achieve therapeutic efficacy depending on measured symptoms of a subject by a clinician. In some embodiments, the nMPC secretome and / or nMPC exosomes comprise a final protein concentration of from about 0.1 mg / ml to about 50.0 mg / ml, or from about 0.5 mg / ml to about 20.0 mg / ml. In some embodiments, the nMPC secretome and / or nMPC exosomes comprise a final protein concentration of (a) at least about 0.1 mg / ml, 0.5 mg / ml, 1.0 mg / ml, about 2.0 mg / ml, about 3.0 mg / ml, about 4.0 mg / ml, about 5.0 mg / ml, about 6.0 mg / ml, about 7.0 mg / ml, about 8.0 mg / ml, about 9.0 mg / ml, about 10.0 mg / ml, about 11.0 mg / ml, about 12.0 mg / ml, about 13.0 mg / ml, about 14.0 mg / ml, about 15.0 mg / ml, about 16.0 mg / ml, about 17.0 mg / ml, about 18.0 mg / ml, about 19.0 mg / ml, about 20.0 mg / ml, about 22.0 mg / ml, about 24.0 mg / ml, about 26.0 mg / ml, about 28.0 mg / ml, about 30.0 mg / ml, about 35.0 mg / ml, about 40.0 mg / ml, about 45.0 mg / ml, or about 50.0 mg / ml, or (b) at most about 250.0 mg / ml, about 225.0 mg / ml, about 200.0 mg / ml, about 175 mg / ml, about 150 mg / ml, about 125 mg / ml, about 100 mg / ml, about 75 mg / ml, about 50 mg / ml, about 45.0 mg / ml, about 40.0 mg / ml, about 35.0 mg / ml, about 30.0 mg / ml, about 25 mg / ml, about 20 mg / ml, about 15 mg / ml, about 10 mg / ml, about 5 mg / ml, about 1WSGR Docket No. 64320-711.601mg / ml, about 0.5 mg / ml, or about 0.1 mg / ml. In some embodiments, the nMPC secretome and / or nMPC exosomes comprise a final protein concentration of at least about 1.0 mg / ml ±0.1, ±0.2, ±0.3, ±0.4, or ±0.5. In other embodiments, the nMPC secretome and / or nMPC exosomes comprise a final protein concentration of at least about 4.0 mg / ml ±0.5, ±1.0, ±1.5, ±2.0, ±2.5, or ±3.0. In some embodiments, the nMPC secretome and / or nMPC exosomes comprise a final protein concentration of at least about 8.0 mg / ml ±1.0, ±2.0, ±3.0, ±4.0, or ±5.0. In certain embodiments, the nMPC secretome and / or nMPC exosomes comprise a final protein concentration of at least about 16.0 mg / ml ±2.0, ±3.0, ±4.0, ±5.0, or ±6.0. In some embodiments, a dosage may be calculated by the total protein concentration of the composition to be administered per kilogram of body weight of the subject. In some embodiments, the subject is administered the nMPC secretome, nMPC exosomes, an nMPC total secretome, or a combination thereof at a dosage of at least about 0.25 mg / kg, 0.5 mg / kg, 0.75 mg / kg, 1 mg / kg, 1.25 mg / kg, 1.5 mg / kg, 1.75 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 11 mg / kg, 12 mg / kg, 13 mg / kg, 14 mg / kg, 15 mg / kg, 16 mg / kg, 17 mg / kg, 18 mg / kg, 19 mg / kg, 20 mg / kg, 22.5 mg / kg, 25 mg / kg, 27.5 mg / kg, 30 mg / kg, 32.5 mg / kg, 35 mg / kg, 37.5 mg / kg, 40 mg / kg, 42.5 mg / kg, 45 mg / kg, 47.5 mg / kg, or 50 mg / kg, where mg / kg is the nMPC secretome or nMPC exosome protein weight per kilogram of subject body weight.

[0118] In some embodiments, provided herein are pharmaceutical compositions and methods of producing the pharmaceutical formulations. In any of such embodiments, nMPCs, an nMPC secretome, nMPC exosomes, an nMPC total secretome, or a combination thereof, may be introduced into a volume appropriate for intravenous infusion; for example, in an amount of about 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 300, 400, 500, 600, 700, 800, 900, 1000 ml, etc. In the compositions disclosed herein, each dose comprising nMPCs, an nMPC secretome, nMPC exosomes, an nMPC total secretome, or a combination thereof, comprises a volume of about a liter or less, about 500 ml or less, about 250 ml or less, or about 100 ml or less. In some embodiments, compositions or formulations comprising nMPCs, an nMPC secretome, nMPC exosomes, an nMPC total secretome, or a combination thereof, the compositions or formulations comprise a volume of a liter or less, about 500 ml or less, about 250 ml or less, or about 100 ml or less for each dose. In certain embodiments, a composition or formulation as disclosed herein is manufactured in accordance with Good Manufacturing Practices (GMP), a set of quality assurance standards for the production of medicinal products.Storage Conditions

[0119] In any of such methods, the nMPCs are stable in storage at a temperature for a period of time. In some embodiments, the temperature is about 4 °C, 1 °C, 0 °C, -10 °C, -20 °C, or -80 °C. In some embodiments, the period of time is at least about 1, 2, 3, 4, 5, 6, or 7 days; at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks; or at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months. In some embodiments, the nMPCs are stored in cell cryopreservation media-CS10 (CRYOSTOR®; Sigma- Aldrich, Israel). In some embodiments, the nMPCs are thawed in a 37 °C water bath until a single ice crystal remained prior to administration to the subject. In some embodiments,WSGR Docket No. 64320-711.601the nMPCs are further washed with a volume of Complete Medium (CM). In some embodiments, the nMPCs are washed twice with a volume of Complete Medium (CM). In some embodiments, the volume is at least about 10 ml.Protein Expression Detection

[0120] Assessment of the presence or levels of protein expression of the one or more factors (e.g, c-Kit (CD117), HSF1, Ki67, CD44, CD73, CD47, CD105, CD90, Nkx2.5, CD34, CD45, CD31, PECAM-1, tryptase, GATA4, ISL1, SSEA3, and / or SSEA4, etc.) can be performed by, for example, detection of a signal (e.g, signal produced by a fluorescent protein) using FACS, or selection by another marker such as an antibiotic resistance marker. In some cases, the signal used to assess presence or levels of protein expression was produced by a fluorescently labeled antibody (e.g., an antibody labeled with FITC, phycoerythrin (PE), Peridinin-Chlorophyll-protein (PerCP), or Allophycocyanin (APC)) that could bind to a factor. In some cases, the presence or levels of protein expression of the one or more factors was measured by antibody staining, fluorescence microscopy, flow cytometry as discussed above, protein labeling, an enzyme-linked immunosorbent assay (ELISA), mass spectroscopy, western blotting, or Bradford protein assays. Such assays can be used to evaluate the level of expression of a factor: for example, higher protein expression levels may be correlated with stronger signals (e.g, fluorescent signals), and lower expression levels may be correlated with weaker signals. The cells may be separated based on the level of staining for a particular antigen or lack thereof. Expression levels are compared to a positive control and / or a negative control.RNA Sequencing

[0121] High-throughput RNA sequencing (RNA-Seq) technology, enabled by the developments in nextgeneration sequencing, represents a powerful tool in analyzing gene expression profdes, detecting transcript variants, and understanding the function of the non-coding regulatory RNAs. An RNA-Seq library can be generated from ligating sequencing adapters to double-stranded DNA. A first RNA-Seq library method of generating a comprises ligating different adapters to the 3' and 5' ends of the RNA molecules (see, e.g, Ion Total RNA-Seq Kit v2 from Life Technologies). A second method comprises incorporating dUTP in addition to dNTPs in the second strand DNA synthesis. Following adapter ligation, the second strand DNA can be specifically digested by an Uracil -N-glycosylase (UNG) enzyme so that only the library strand containing the first strand cDNA will be sequenced and information on the direction of the transcripts can therefore be obtained (see, M. Sultan et al. , Biochemical and Biophysical Research Communications, 422 (2012) 643-646). A third method uses the techniques described in, for example, U.S. Pat. No. 11248262B2 in which a method of RNA sequencing comprises: (i) providing RNA; (ii) generating (a) single-stranded first DNA strand(s) (cDNA), which is / are complementary to the RNA, by subjecting the RNA to reverse transcription by using a reverse transcriptase, a first set of oligonucleotide primers, and the RNA of step (i), and (iii) generating a second DNA strand by using a DNA polymerase, a second set of oligonucleotide primers, and the single-stranded cDNA of (ii), wherein a) the first set of oligonucleotide primers comprises a covalently coupled moiety at its / their 5' terminal nucleotide, which blocks ligation at the 5' terminus of the generated first DNA strand; or b) the secondWSGR Docket No. 64320-711.601set of oligonucleotide primers comprises a covalently coupled moiety at its / their 5' terminal nucleotide, which blocks ligation at the 5' terminus of the generated second DNA strand. In certain instances, the method further comprises the subsequent steps of: (iv) optionally end-repairing the double-stranded DNA strands using a polynucleotide kinase and an enzyme with polymerase and exonuclease activities to obtain end-repaired DNA strands; (v) optionally adding a terminal adenine to the 3' termini of the DNA strands using a deoxynucleotidyl transferase enzyme; and (vi) ligation of adapters, which optionally comprise terminal thymines, to the DNA strands, which optionally comprise 3' terminal adenines. The methods may further comprise sequence analysis of the generated DNA.

[0122] In some embodiments, said method comprises: (i) providing RNA; (ii) generating (a) singlestranded first DNA strand(s) (cDNA), which is / are complementary to the RNA, by subjecting the RNA to reverse transcription by using a reverse transcriptase, a first set of oligonucleotide primers, and the RNA of step (i); (iii) generating a second DNA strand by using a DNA polymerase, a second set of oligonucleotide primers, and the single-stranded cDNA of (ii); (iv) ligating adapters to the doublestranded DNA; of step (iii) and (v) sequencing the generated DNA, wherein a) the first set of oligonucleotide primers comprises a covalently coupled moiety at its / their 5' terminal nucleotide, which blocks ligation at the 5' terminus of the generated first DNA strand; or b) the second set of oligonucleotide primers comprises a covalently coupled moiety at its / their 5' terminal nucleotide, which blocks ligation at the 5' terminus of the generated second DNA strand. By generating the second DNA strand, a double-stranded DNA is generated.

[0123] In some embodiments of the above-mentioned method, prior to step (iv), the method comprises the step of: (iii)(a) end-repairing the double-stranded DNA strands using a polynucleotide kinase and an enzyme with polymerase and exonuclease activities to obtain end-repaired DNA strands.

[0124] In some embodiments, step (iii)(a) is followed by step (iii)(b) comprising adding a terminal adenine to the 3' termini of the DNA strands by using a deoxynucleotidyl transferase enzyme, wherein the adapters comprise 3' terminal thymines, which in step (iv) ligate to the DNA strands comprising 3' terminal adenines. In some embodiments, the oligonucleotide primers, which are covalently coupled to a blocking moiety and / or unmodified oligonucleotide primers, are random oligonucleotide primers.

[0125] In some embodiments, said methods comprise the initial step of extracting and optionally enriching the RNA of interest. In some embodiments, the extracted RNA is fragmented to an average size of from about 19 to about 510 bp. In some embodiments of the above methods, the molecules may be attached to a solid support for paired-end sequencing.Methods of Treatment and Mechanism of Action of nMPCs and nMPC secretome for HFpEF

[0126] The mechanism of action (MO A) of nMPCs secretome in the treatment of Heart Failure with Preserved Ejection Fraction (HFpEF) primarily involves paracrine signaling, targeting cardiac fibrosis, inflammation, and vascular remodeling. The main effects are as follows:(1) Reduction of Myocardial Fibrosis and Improved Ventricular Compliance: Paracrine secretions of nMPCs contains bioactive factors such as, for example, HGF, SDF-la, and VEGFA, which promote extracellular matrix remodeling, reducing ventricular stiffness and collagen deposition.WSGR Docket No. 64320-711.601(2) Anti-Inflammatory Effects: transplanted nMPCs modulates immune responses by reducing inflammatory cytokines (e.g, IL-6, TNF-a) and increasing regulatory T cells (e.g, Tregs), which help control chronic inflammation associated with HFpEF.(3) Enhancement of Vascular Function and Endothelial Repair: The nMPCs improve endothelial function by increasing nitric oxide bioavailability and stimulating angiogenesis via, for example, VEGFA and ANG1.(4) Cardiomyocyte Protection and Metabolic Modulation: The nMPCs activate the Akt / mTOR pathway to promote cardiomyocyte survival and mitochondrial function, reducing oxidative stress and enhancing metabolic efficiency.(5) Functional Outcomes and Clinical Benefits: Improvements in left ventricular end-diastolic pressure (LVEDP), ventricular relaxation (E / e ratio), and reduction in NT-proBNP levels, leading to better symptom management and reduced hospitalizations.

[0127] nMPCs, nMPC secretome, and nMPC exosomes thus exert their therapeutic effects through a multimodal approach, combining anti -fibrotic, anti-inflammatory, pro-angiogenic, and cardiomyocyte-protective mechanisms. Exosomal contribution to therapeutic effects for HFpEF includes, but is not limited to, the nMPCs’ mechanism is partially mediated through exosomal delivery of key paracrine factors such as HGF, VEGFA, and SDF-la, which facilitate targeted repair of myocardial tissue and endothelial cells. Effects on Diastolic Function Markers (Tau and EDPVR): The nMPC secretome has been shown to reduce the time constant of left ventricular relaxation (Tau), improving diastolic function by enhancing ventricular compliance and reducing myocardial stiffness. Additionally, EDPVR (End-Diastolic Pressure- Volume Relationship) shifts downward, signifying improved ventricular filling capacity and reduced diastolic pressure. Additionally, a composition comprising nMPC, nMPC secretome, nMPC exosomes, an nMPC total secretome, or a combination thereof as described herein improves the Stroke Volume Index (SVI), 6-minute Walk Test (6MWT), Kansas City Cardiomyopathy Questionnaire (KCCQ), Left Ventricular Filling Pressure or a Diastolic Dysfunction assessed as E / e’ mean, NT-proBNP, End- Diastolic Volume Index (ED VI), Estimated Glomerular Filtration Rate (eGFR), High- Sensitivity C-Reactive Protein (hs-CRP) results in a subject treated as compared to a subject not treated with the composition.

[0128] In one embodiment, a composition described herein, when administered to a subject, regulates fibrosis, inflammation, or metabolism. In one embodiment, a composition described herein, when administered to a subject, promotes angiogenesis, endothelial repair, or anti-inflammatory factors, including, butnot limited to, IL-10 and suppression of pro-inflammatory cytokines (e.g, TNF-a, IL-6, IL-ip, IL18, CXCL9, matrix metalloproteinase 12 (MMP12)).Compositions and Formulations

[0129] The terms “pharmaceutical composition” and “pharmaceutical formulation” (or “formulation”) are used interchangeably and denote a mixture or solution comprising a therapeutically effective amount of an active pharmaceutical ingredient together with one or more pharmaceutically acceptable excipients to be administered to a subject, e.g, a human in need thereof. A pharmaceutical composition used in theWSGR Docket No. 64320-711.601therapeutic methods of the invention is formulated to be compatible with its intended route of administration. In certain embodiments, the active pharmaceutical ingredient comprises, for example, neonatal cardiac mesenchymal progenitor cells, nMPC secretomes (nMPC conditioned media), nMPC exosomes, an nMPC total secretome, or a combination thereof. In some embodiments, the pharmaceutical formulation comprises nMPCs only in a pharmaceutically acceptable carrier (e.g, phosphate buffered saline). In some embodiments, the pharmaceutical formulation comprises nMPCs, nMPC secretomes (nMPC conditioned media), nMPC exosomes, an nMPC total secretome, or a combination thereof in a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical formulation comprises nMPC secretome (e.g., conditioned media) in a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical formulation comprises nMPC exosomes only in a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical formulation comprises nMPCs, nMPC secretome (including, for example, exosomes, peptides or proteins (e.g., cytokines, growth factors, etc.), nucleic acids (e.g, miRNA, RNA, DNA), or any combination thereof, and nMPC exosomes. In one embodiment, the pharmaceutical formulation comprises nMPCs, nMPC secretome, nMPC exosomes, an nMPC total secretome, or a combination thereof in a pharmaceutically acceptable carrier. In some embodiments, a pharmaceutical formulation disclosed herein is administered in combination with a drug or therapeutic agent. In certain aspects, combination therapy is contemplated wherein the nMPCs, nMPC secretome, nMPC exosomes, an nMPC total secretome, or a combination thereof, are administered with a drug or a therapeutic agent. For example, in some embodiments, the drug or therapeutic agent comprises Riluzole, Edaravone, Tofersen, Nuedexta®, or any combination thereof In other embodiments, the drug or therapeutic agent comprises a medication from Table 1.Table 1. Combination medications for the treatment of DCMWSGR Docket No. 64320-711.601Protein Expression Detection

[0130] Assessment of the presence or levels of protein expression of the one or more factors (e.g, c-kit (CD117), HSF1, Ki67, CD44, CD73, CD47, CD105, CD90, Nkx2.5, CD34, CD45, CD31, PECAM-1, tryptase, GATA4, ISL1, SSEA3, and / or SSEA4, etc.) can be performed by, for example, detection of a signal (e.g, signal produced by a fluorescent protein) using FACS, or selection by another marker such as an antibiotic resistance marker. In some cases, the signal used to assess presence or levels of protein expression was produced by a fluorescently labeled antibody (e.g., an antibody labeled with FITC, phycoerythrin (PE), Peridinin-Chlorophyll-protein (PerCP), or Allophycocyanin (APC)) that could bind to a factor. In some cases, the presence or levels of protein expression of the one or more factors was measured by antibody staining, fluorescence microscopy, flow cytometry as discussed above, protein labeling, an enzyme-linked immunosorbent assay (ELISA), mass spectroscopy, western blotting, or Bradford protein assays. Such assays can be used to evaluate the level of expression of a factor: for example, higher protein expression levels may be correlated with stronger signals (e.g, fluorescent signals), and lower expression levels may be correlated with weaker signals. The cells may be separated based on the level of staining for a particular antigen or lack thereof. Expression levels are compared to a positive control and / or a negative control.RNA Sequencing

[0131] High-throughput RNA sequencing (RNA-Seq) technology, enabled by the developments in nextgeneration sequencing, represents a powerful tool in analyzing gene expression profdes, detecting transcript variants, and understanding the function of the non-coding regulatory RNAs. An RNA-Seq library can be generated from ligating sequencing adapters to double-stranded DNA. A first RNA-Seq library method of generating a comprises ligating different adapters to the 3' and 5' ends of the RNA molecules (see, e.g, Ion Total RNA-Seq Kit v2 from Life Technologies). A second method comprises incorporating dUTP in addition to dNTPs in the second strand DNA synthesis. Following adapter ligation, the second strand DNA can be specifically digested by an Uracil -N-glycosylase (UNG) enzyme so that only the library strand containing the first strand cDNA are sequenced and information on the direction of the transcripts can therefore be obtained (see, M. Sultan et al. , Biochemical and Biophysical Research Communications, 422 (2012) 643-646). A third method uses the techniques described in, for example, U.S. Pat. No. 11248262B2 in which a method of RNA sequencing comprises: (i) providing RNA; (ii) generating (a) single-stranded first DNA strand(s) (cDNA), which is / are complementary to the RNA, by subjecting the RNA to reverse transcription by using a reverse transcriptase, a first set of oligonucleotide primers, and the RNA of step (i), and (iii) generating a second DNA strand by using a DNA polymerase, a second set of oligonucleotide primers, and the single-stranded cDNA of (ii), wherein a) the first set of oligonucleotide primers comprises a covalently coupled moiety at its / their 5' terminalWSGR Docket No. 64320-711.601nucleotide, which blocks ligation at the 5' terminus of the generated first DNA strand; or b) the second set of oligonucleotide primers comprises a covalently coupled moiety at its / their 5' terminal nucleotide, which blocks ligation at the 5' terminus of the generated second DNA strand. In certain instances, the method further comprises the subsequent steps of: (iv) optionally end-repairing the double-stranded DNA strands using a polynucleotide kinase and an enzyme with polymerase and exonuclease activities to obtain end-repaired DNA strands; (v) optionally adding a terminal adenine to the 3' termini of the DNA strands using a deoxynucleotidyl transferase enzyme; and (vi) ligation of adapters, which optionally comprise terminal thymines, to the DNA strands, which optionally comprise 3' terminal adenines. The methods may further comprise sequence analysis of the generated DNA.

[0132] In some embodiments, said method comprises: (i) providing RNA; (ii) generating (a) singlestranded first DNA strand(s) (cDNA), which is / are complementary to the RNA, by subjecting the RNA to reverse transcription by using a reverse transcriptase, a first set of oligonucleotide primers, and the RNA of step (i); (iii) generating a second DNA strand by using a DNA polymerase, a second set of oligonucleotide primers, and the single-stranded cDNA of (ii); (iv) ligating adapters to the doublestranded DNA; of step (iii) and (v) sequencing the generated DNA, wherein a) the first set of oligonucleotide primers comprises a covalently coupled moiety at its / their 5' terminal nucleotide, which blocks ligation at the 5' terminus of the generated first DNA strand; or b) the second set of oligonucleotide primers comprises a covalently coupled moiety at its / their 5' terminal nucleotide, which blocks ligation at the 5' terminus of the generated second DNA strand. By generating the second DNA strand, a double-stranded DNA is generated.

[0133] In some embodiments of the above-mentioned method, prior to step (iv), the method comprises the step of: (iii)(a) end-repairing the double-stranded DNA strands using a polynucleotide kinase and an enzyme with polymerase and exonuclease activities to obtain end-repaired DNA strands.

[0134] In some embodiments, step (iii)(a) is followed by step (iii)(b) comprising adding a terminal adenine to the 3' termini of the DNA strands by using a deoxynucleotidyl transferase enzyme, wherein the adapters comprise 3' terminal thymines, which in step (iv) ligate to the DNA strands comprising 3' terminal adenines. In some embodiments, the oligonucleotide primers, which are covalently coupled to a blocking moiety and / or unmodified oligonucleotide primers, are random oligonucleotide primers.

[0135] In some embodiments, said methods comprise the initial step of extracting and optionally enriching the RNA of interest. In some embodiments, the extracted RNA is fragmented to an average size of from about 19 to about 510 bp. In some embodiments of the above methods, the molecules may be attached to a solid support for paired-end sequencing.Methods of Treatment

[0136] Described herein are methods of treating a disease or an injuries with neonatal cardiac mesenchymal progenitor cells (nMPCs), nMPC secretomes, and / or nMPC exosomes. A disease or an injury to be treated includes, but is not limited to, HFpEF, dilated cardiomyopathy (DCM), or a kidney disease. In one embodiment, the disease is HFpEF. Alternatively, or in addition, the disease is DCM. Alternatively, or in addition, the disease is a kidney disease. When the disease is a kidney disease, theWSGR Docket No. 64320-711.601disease can comprise an acute kidney injury, an acute kidney disease, or a chronic kidney disease. In one instance, the disease comprises the acute kidney injury. In another instance, the disease comprises the acute kidney disease. In another instance, the disease comprises the chronic kidney disease.General methods

[0137] Subjects to be treated can be from about 4 to about 18 years of age, from about 19 to about 25 years of age, or 26 years of age or older. In one embodiment, the subject to be treated is about 4 years of age. In another embodiment, the subject to be treated is about 5 years of age. In another embodiment, the subject to be treated is about 6 years of age. In another embodiment, the subject to be treated is about 7 years of age. In another embodiment, the subject to be treated is about 8 years of age. In another embodiment, the subject to be treated is about 9 years of age. In another embodiment, the subject to be treated is about 10 years of age. In another embodiment, the subject to be treated is about 11 years of age. In another embodiment, the subject to be treated is about 12 years of age. In another embodiment, the subject to be treated is about 13 years of age. In another embodiment, the subject to be treated is about 14 years of age. In another embodiment, the subject to be treated is about 15 years of age. In another embodiment, the subject to be treated is about 16 years of age. In another embodiment, the subject to be treated is about 17 years of age. In another embodiment, the subj ect to be treated is about 18 years of age. In another embodiment, the subject to be treated is about 19 years of age. In another embodiment, the subject to be treated is about 20 years of age. In another embodiment, the subject to be treated is about 21 years of age. In another embodiment, the subject to be treated is about 22 years of age. In another embodiment, the subject to be treated is about 23 years of age. In another embodiment, the subject to be treated is about 24 years of age. In another embodiment, the subject to be treated is about 25 years of age. In another embodiment, the subject to be treated is about 26 years of age. In another embodiment, the subject to be treated is about 27 years of age. In another embodiment, the subject to be treated is about 28 years of age. In another embodiment, the subject to be treated is about 29 years of age. In another embodiment, the subject to be treated is about 30+ years of age. In any of such embodiments, the subject can be biologically male. In any of such embodiments, the subject can be biologically female. A subject to be treated with the methods described herein can exhibit an improved quality of life following treatment. Alternatively, or in addition, a subject to be treated with the methods described herein can exhibit an improved quantity of life following treatment. Administration can be via any suitable method including, but not limited to, intravenous infusion.

[0138] In one embodiment, nMPCs to be administered in the described methods are human. In one embodiment, nMPCs to be administered in the described methods are allogeneic. In one embodiment, the nMPCs are (a) positive for protein expression of Ki67 or Nkx2.5, (b) positive for cell surface protein expression of c-Kit (CD117), CD44, CD73, CD47, CD105, and / or CD90, (c) positive for miRNA expression of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and / or miR-374b-5p, and (d) negative for protein expression of CD34, CD45, CD31, PECAM-1, tryptase, GATA4, ISL1, SSEA3, SSEA4, and / or p!6INK4a. In one embodiment, the nMPCs are (a) positive for protein expression of Ki67 or Nkx2.5, (b) positive for cell surface protein expression of c-Kit (CD117), CD44, CD73, CD47,WSGR Docket No. 64320-711.601CD105, or CD90, (c) positive for miRNA expression of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, or miR-374b-5p, and (d) negative for protein expression of CD34, CD45, CD31, PECAM-1, tryptase, GATA4, ISL1, SSEA3, SSEA4, or p!6INK4a. In another embodiment, the nMPCs are (a) positive for protein expression of Ki67 andNkx2.5, (b) positive for cell surface protein expression of c-Kit (CD117), CD44, CD73, CD47, CD105, and CD90, (c) positive for miRNA expression of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and miR-374b-5p, and (d) negative for protein expression of CD34, CD45, CD31, PECAM-1, tryptase, GATA4, ISL1, SSEA3, SSEA4, and pl6INK4a. In certain embodiments, the nMPCs are further positive for protein expression of PDL1, OCT3 / 4, NANOG, KLF4, HSF1, or SOX2. In some embodiments, the nMPCs are further positive for protein expression of PDL1, OCT3 / 4, NANOG, KLF4, HSF1, and SOX2. Alternatively, or in addition, the nMPCs are further negative for protein expression of p!6INK4aup to at least passage 8. In some embodiments, the nMPCs are (a) positive for protein expression of Ki67, Nkx2.5, OCT3 / 4, NANOG, KLF4, HSF1, and / or SOX2, (b) positive for cell surface protein expression of c-kit (CD117), CD44, CD73, CD47, CD105, CD90, and / or PDL1, (c) positive for miRNA expression of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and / or miR-374b-5p, and (d) negative for protein expression of CD34, CD45, CD31, PECAM-1, tryptase, GATA4, ISL1, SSEA3, SSEA4, and / or p!6INK4a. In certain embodiments, the nMPCs are (a) positive for protein expression of Ki67, Nkx2.5, OCT3 / 4, NANOG, KLF4, HSF1, or SOX2, (b) positive for cell surface protein expression of c-kit (CD117), CD44, CD73, CD47, CD105, CD90, or PDL1, (c) positive for miRNA expression of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, or miR-374b-5p, and (d) negative for protein expression of CD34, CD45, CD31, PECAM-1, tryptase, GATA4, ISL1, SSEA3, SSEA4, or p!6INK4a. In yet other embodiments, the nMPCs are (a) positive for protein expression of Ki67, Nkx2.5, OCT3 / 4, NANOG, KLF4, HSF1, and SOX2, (b) positive for cell surface protein expression of c-kit (CD117), CD44, CD73, CD47, CD105, CD90, and PDL1, (c) positive for miRNA expression of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and miR-374b-5p, and (d) negative for protein expression of CD34, CD45, CD31, PECAM-1, tryptase, GATA4, ISL1, SSEA3, SSEA4, and pl6INK4a

[0139] In some embodiments, the nMPCs are genetically engineered. In other embodiments, the nMPCs are genetically engineered to overexpress one or more paracrine factors. In some embodiments, the nMPCs are genetically engineered to overexpress HGF, SCF, SDF-la, ANG1, VEGFA, PDGFB, bFGF, HSP20, Akt, miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and / or miR-374b-5p. In some embodiments, the nMPCs are genetically engineered to overexpress 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 of HGF, SCF, SDF-la, ANG1, VEGFA, PDGFB, bFGF, HSP20, Akt, miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and miR-374b-5p. In certain embodiments, the nMPCs are (a) positive for protein expression of Ki67, Nkx2.5, OCT3 / 4, NANOG, KLF4, HSF1, and / or SOX2, (b) positive for cell surface protein expression of c-Kit (CD117), CD44, CD73, CD47, CD105, CD90, and / or PDL1, (c) positive for miRNA expression of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and / or miR-374b-5p, (d) negative for protein expression of CD34, CD45, CD31, PECAM-1, tryptase, GATA4, ISL1, SSEA3, SSEA4, and / or pl6INK4a, and (e) genetically engineered to overexpressWSGR Docket No. 64320-711.601HGF, SCF, SDF-la, ANG1, VEGFA, PDGFB, bFGF, HSP20, Akt, miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and / or miR-374b-5p. In one embodiment, the nMPCs are (a) positive for protein expression of Ki67, Nkx2.5, OCT3 / 4, NANOG, KLF4, HSF1, and SOX2, (b) positive for cell surface protein expression of c-Kit (CD117), CD44, CD73, CD47, CD105, CD90, and PDL1, (c) positive for miRNA expression of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and miR-374b-5p, (d) negative for protein expression of CD34, CD45, CD31, PECAM-1, tryptase, GATA4, ISL1, SSEA3, SSEA4, andpl6INK4a, and (e) genetically engineered to overexpress HGF, SCF, SDF-la, ANG1, VEGFA, PDGFB, bFGF, HSP20, Akt, miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and miR-374b-5p. In some embodiments, the nMPCs are allogeneic or autologous. In certain embodiments, the nMPCs are non-naturally occurring. In other embodiments, the nMPCs are not xenogenic. In some embodiments, the nMPCs are obtained from a subject who is biologically a female. In certain other embodiments, the nMPCs are obtained from a subject who is biologically a male.

[0140] Alternatively, or in addition, in another aspect, the subject is administered an nMPC secretome (nMPC conditioned media) described herein. Alternatively, or in addition, in another aspect, the subject is administered nMPC exosomes. Alternatively, or in addition, in yet another aspect, the subject is administered an nMPC Total Secretome comprising both an nMPC secretome and nMPC exosomes. In one embodiment, the nMPC secretome and / or nMPC exosomes are (a) positive for protein expression of HGF, SCF, SDF-la, ANG1, VEGFA, PDGFB, bFGF, HSP20, HSF1, and / or Akt, and (b) positive for miRNA expression of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and / or miR-374b-5p. In one embodiment, the nMPC secretome and / or nMPC exosomes are (a) positive for protein expression of HGF, SCF, SDF-la, ANG1, VEGFA, PDGFB, bFGF, HSP20, HSF1, or Akt, and (b) positive for miRNA expression of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, or miR-374b-5p. In another embodiment, the nMPC secretome and / or nMPC exosomes are (a) positive for protein expression of HGF, SCF, SDF-la, ANG1, VEGFA, PDGFB, bFGF,HSP20, HSF1, and Akt, and (b) positive for miRNA expression of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and miR-374b-5p. In certain embodiments, the nMPC secretome and / or nMPC exosomes are positive for miRNA expression of one, two, three, four, five, or six of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, or miR-374b-5p. In some embodiments, the nMPC secretome and / or nMPC exosomes comprise HSF1 at levels higher than HSF1 in the aMPC secretome and / or aMPC exosomes. Alternatively, or in addition, in another embodiment, an nMPC secretome and / or nMPC exosomes are positive for one, two, three, four, five, six, seven, eight, nine, ten, or more of FUS, TAF15, CAP2, SNX9, PSMB7, SUMO1, EIF3A, ECH1,HNRNPL, NTM, ANG, ERP44, NAA38, RRM2B, RABI A, RAB1B, PGRMC1, ERH, TIGAR, ITGA2, SGTA, AR1C1, AKR1C2, DNASE2, HSP90AB4P, ANGPTL2, SF3B2, GREM1, ARF3, ARF1, ARF5, LSM5, PSMD9, SUGT1, ALDH1A3, PDGFRB, HIST1H1C, SP100, G6PD, PPIL1, SNRPD1, FDPS, RAB6B, RAB6A, DCTD, GLB1, ARIH1, IST1, HNRNPU, ULBP2, RAET1G, ERAP2, CDC42, EDF1, LIPG, FKBP4, RBMX, RBMXL1, RPL30, THY1, AP2M1, RPS16, FHL3, BZW1, BZW2, EIF4G1, PFDN4, CLTB, PIR, MVP, ECU, DCI, ALYREF, RPS10, PPP3CA, TAX1BP3, PPA1, DDX39B, DDX39A, GNPNAT1, LIMA1, SNRPD3, ADH5, ENAH,WSGR Docket No. 64320-711.601DYNLL1, DYNLL2, HUWE1, HMGB2, PTMS, UCHL3, PFDN2, DYNLRB1, HDGFRP2, INF2, HPRT1, EIF2S2, ADAMT7, EIF3C, EIF3CL, RPS5, VPS35, CS, ECHS1, UBQLN1, GBP2, GBP1, SF3B1, RANBP1, GNS, HLA-B, UBXN1, GNPDA1, IGF2, EIF3B, TCEB1, VASP, GSR, HLA-A, HLA-HIGF2, NUDT5, COPE, HNRNPA3, SRI, HNRNPC, MMP10, EWSR1, IPO7, YARS, TMPO, HNRNPH1, HLA-A, PDGFC, IL1B, S100A10, TXNDC2, DPY30, LAMP1, LYPLA1, CBR1, ARHGAP1, TPR, NAMPT, NAMPTL, CXCL2, EIF4A2, RPS4X, PABPN1, PHLDB1, NAP1L4, DDX6, PSMC3, MAP7D1, OSCAR, TES, NMT1, NMT2, MAT2A, PRMT1, COX17, SELM, CARS, PPP2CA, PPP2CB, VEGFC, VPS26A, PXN, PAWR, STRAP, RABI 1 A, RABI IB, EIF5, COPZ1, COPS3, CHMP4B, PDXK, RALA, RALB, SEC13, FHL2, TOMI, PYCARD, PDLIM4, RBBP4, RBBP7, RPS20, SRSF1, DLD, SNRPE, EIF4EBP1, RPLPO, RPLP0P6, LSM3, SLC16A3, CSE1L, NUCKS1, TSNAX, RPSA, RPSAP58, AP1B1, EIF2S1, LCP1, PSMD4, AARS, SRSF2, SFRS2, TRIP10, CLTA, USO1, VBP1, UBE2K, MRPL12, UAP1, HIST1H1B, YBX3, RPL10A, IDH1, SNRPN, SNRPB, PCK2, EIF6, MMP3, DHX9, MATR3, UBE2D2, UBE2D3, PTRF, ACTR1A, LAMA1, PDCD6IP, QARS, HN1L, PLBD2, OS9, ILF3, ISOCI, PPP1R7, MAPK1, PDCD1LG2, GOLGB1, HSPA9, ACBD3, BTF3, UBE2I, SRRT, EIF4H, FERMT2, EIF3G, PARVA, DBNL, BOLA2, MAPRE1, PRDX5, STX12, EIF1, SMS, GRPEL1, OAF, SYNCRIP, ECE1, VAPA, PCNP, PSME1, EIF3J, C14orfl66, DDX1, AKR1B1, SRP9, PCMT1, XPO1, MMP9, RPS7, NRCAM, FKBP3, SSB, DSC3, XRCC5, CCT6A, LIF, SERPINA9, SND1, ANP32B, G3BP1, GPC6, GLOD4, RRBP1, TGFB1, USP14, PLAUR, CXCL3, FASN, COPB2, TARDBP, TNFAIP6, RPS3, NDUFAB1, LMNB1, COL16A1, PSMF1, PHGDH, PRKCDBP, CXCL5, YAP1, TROVE2, MACF1, EIF5B, STX7, PFDNS, APOA1, PDAP1, STX12, EIF3K,FH, RBM8A, EIF1, RPS2, PTGR1, EEA1, CAB39, DCTN2, GDF15, MYL9, TCP1, RPS12, RAD23A, SKP1, PDLIM1, HSPH1, PSMB3, SUB1, API5, TWF2, KTN1, DYNC1H1, SNRNP70, MCFD2, PPP1R18, PTGES3, APEX1, TNKS1BP1, FUBP1, VAT1, PAFAH1B1, CBX1, PTK / 7, HNRPDL, ZNF185, DYNC1I2, KHDRBS1, SFPQ, PDCD5, TRIM28, PPIC, NARS, PCBP2, CD2AP, PSMA1, CAPRIN1, KHSRP, NSFL1C, PPP1R12A, NUDC, MFAP2, IGF2R, RGMB, PABPC1, MANI Al, DDB1, PTBP1, FBN2, CNBP, OTUB1, NASP,HSPD1, EEF1D, RNPEP, CRKL, HNRNPAB, EIF3F, PAICS,ILF2, COPB1, PA2G4, COP A, NT5E, HMGA1, SF1, XRCC6, GNB2L1, MEI, MTAP, CCT2, ARCN1, PEPD, and EPB41L3. Alternatively, or in addition, an nMPC secretome and / or nMPC exosomes are positive for one, two, three, four, five, six, seven, eight, nine, ten, or more of PPP1CA, PPP1CC, STI 3. ST13P5, ST13P4,HMGB1, HMGB1P1, HNRNPA1,HNRNPA1L2, NEDD8, N EDD8-MDP1, YBX1, YBX2, CCT7, HNRNPH3, LTBP1, UBE2N, IL8, CYCS, LGALS1, IL6, PGAM1, YWHAH, TXN, ARHGDIB, PSMA3, RAN, TPM3, BASP1, HSPA8, ITGAV, PPIA, NACA, HSP90AB1, PCBP1, CAP1, NUTF2, PSMA5, CAPZA1, RPLP1, GLO1, ACTG1, ICAM1, SDC4, SOD2, PSMB4, TFPI2, C1QBP, NAP1L1, HSP90AA1, SET, ENO1, CCT3, GOT2, HSPE1, PGM3, PLIN3, CNDP2, PGD, SH3BGRL, TLN1, HSP90AB2P, GOT1, HNRNPAO, FTH1, TPD52L2, UGP2, AHNAK, CCT8, PSMA7, CCT4, SRPX2, CLIC4, KPNB1, AP2B1, 42254, and PAFAH1B2. In one instance, the nMPC secretome and / or nMPC exosomes do not comprise 42254. Alternatively, or in addition, an nMPC secretome and / or nMPC exosomes are positive for one, two, three, four, five, six,WSGR Docket No. 64320-711.601seven, eight, nine, ten, or more of FUS, TAF15, CAP2, SNX9, PSMB7, SUM01, EIF3A, ECHI, HNRNPL, NTM, ANG, ERP44, NAA38, RRM2B, RAB1A, RAB1B, PGRMC1, ERH, TIGAR. ITGA2, SGTA, AR1C1, AKR1C2, DNASE2, HSP90AB4P, ANGPTL2, SF3B2, GREM1, ARF3, ARF1, ARF5, LSM5, PSMD9, SUGT1, ALDH1A3, PDGFRB, HIST1H1C, SP1OO, G6PD, PPIL1, SNRPD1, FDPS, RAB6B, RAB6A, DCTD, GLB1, ARIH1, IST1, HNRNPU, ULBP2, RAET1G, ERAP2, CDC42, EDF1, LIPG, FKBP4, RBMX, RBMXL1, RPL30, THY1, AP2M1, RPS16, FHL3, BZW1, BZW2, EIF4G1, PFDN4, CLTB, PIR, MVP, ECU, DCI, ALYREF, RPS10, PPP3CA, TAX1BP3, PPA1, DDX39B, DDX39A, GNPNAT1, LIMA1, SNRPD3, ADH5, ENAH, DYNLL1, DYNLL2, HUWE1, HMGB2, PTMS, UCHL3, PFDN2, DYNLRB1, HDGFRP2, INF2, HPRT1, EIF2S2, ADAMT7, EIF3C, EIF3CL, RPS5, VPS35, CS, ECHS1, UBQLN1, GBP2, GBP1, SF3B1, RANBP1, GNS, HLA-B, UBXN1, GNPDA1, IGF2, EIF3B, TCEB1, VASP, GSR, HLA-A, HLA-HIGF2, NUDT5, COPE, HNRNPA3, SRI, HNRNPC, MMP10, EWSR1, IPO7, YARS, TMPO, HNRNPH1, HLA-A, PDGFC, IL1B, S100A10, TXNDC2, DPY30, LAMP1, LYPLA1, CBR1, ARHGAP1, TPR, NAMPT, NAMPTL, CXCL2, EIF4A2, RPS4X, PABPN1, PHLDB1, NAP1L4, DDX6, PSMC3, MAP7D1, OSCAR, TES, NMT1,NMT2, MAT2A, PRMT1, COX17, SELM, CARS, PPP2CA, PPP2CB, VEGFC, VPS26A, PXN, PAWR, STRAP, RABI 1 A, RABI IB, EIF5, COPZ1, COPS3, CHMP4B, PDXK, RALA, RALB, SEC13, FHL2, TOMI, PYCARD, PDLIM4, RBBP4, RBBP7, RPS20, SRSF1, DLD, SNRPE, EIF4EBP1, RPLPO, RPLP0P6, LSM3, SLC16A3, CSE1L, NUCKS1, TSNAX, RPSA, RPSAP58, AP1B1, EIF2S1, LCP1, PSMD4, AARS, SRSF2, SFRS2, TRIP10, CLTA, USO1, VBP1, UBE2K, MRPL12, UAP1, HIST1H1B, YBX3, RPL10A, IDH1, SNRPN, SNRPB, PCK2, EIF6, MMP3, DHX9, MATR3, UBE2D2, UBE2D3, PTRF, ACTR1A, LAMA1, PDCD6IP, QARS, HN1L, PLBD2, OS9, ILF3, ISOCI, PPP1R7, MAPK1, PDCD1LG2, GOLGB1, HSPA9, ACBD3, BTF3, UBE2I, SRRT, EIF4H, FERMT2, EIF3G, PARVA, DBNL, BOLA2, MAPRE1, PRDX5, STX12, EIF1, SMS, GRPEL1, OAF, SYNCRIP, ECE1, VAPA, PCNP, PSME1, EIF3J, C14orfl66, DDX1, AKR1B1, SRP9, PCMT1, XPO1, MMP9, RPS7, NRCAM, FKBP3, SSB, DSC3, XRCC5, CCT6A, LIF, SERPINA9, SND1, ANP32B, G3BP1, GPC6, GLOD4, RRBP1, TGFB1, USP14, PLAUR, CXCL3, FASN, COPB2, TARDBP, TNFAIP6, RPS3, NDUFAB1, LMNB1, COL16A1, PSMF1, PHGDH, PRKCDBP, CXCL5, YAP1, TROVE2, MACF1, EIF5B, STX7, PFDNS, APOA1, PDAP1, STX12, EIF3K, FH, RBM8A, EIF1, RPS2, PTGR1, EEA1, CAB39, DCTN2, GDF15, MYL9, TCP1, RPS12, RAD23A, SKP1, PDLIM1, HSPH1, PSMB3, SUB1, API5, TWF2, KTN1, DYNC1H1, SNRNP70, MCFD2, PPP1R18, PTGES3, APEX1, TNKS1BP1, FUBP1, VAT1, PAFAH1B1, CBX1, PTK7, HNRPDL, ZNF185, DYNC1I2, KHDRBS1, SFPQ, PDCD5, TRIM28, PPIC, NARS, PCBP2, CD2AP,PSMA1, CAPRIN1, KHSRP, NSFL1C, PPP1R12A, NUDC, MFAP2, IGF2R, RGMB, PABPC1, MAN1A1, DDB1, PTBP1, FBN2, CNBP, OTUB1, NASP, HSPD1, EEF1D, RNPEP, CRKL, HNRNPAB, EIF3F, PAICS, ILF2, COPB1, PA2G4, COP A, NT5E, HMGA1, SF1, XRCC6, GNB2L1, MEI, MTAP, CCT2, ARCN1, PEPD, EPB41L3 PPP1CA, PPP1CC, STI3. ST13P5, ST13P4, HMGB1, HMGB1P1, HNRNPA1, HNRNPA1L2, NEDD8, N EDD8-MDP1, YBX1, YBX2, CCT7, HNRNPH3, LTBP1, UBE2N, IL8, CYCS, LGALS1, IL6, PGAM1, YWHAH, TXN, ARHGDIB, PSMA3, RAN, TP M3, BASP1, HSPA8, ITGAV, PPIA, NACA, HSP90AB1, PCBP1,WSGR Docket No. 64320-711.601CAP1, NUTF2, PSMA5, CAPZA1, RPLP1, GL01, ACTG1, ICAM1, SDC4, SOD2, PSMB4, TFPI2, C1QBP, NAP1L1, HSP90AA1, SET, ENO1, CCT3, GOT2, HSPE1, PGM3, PLIN3, CNDP2, PGD, SH3BGRL, TLN1, HSP90AB2P, GOT1, HNRNPAO, FTH1, TPD52L2, UGP2, AHNAK, CCT8, PSMA7, CCT4, SRPX2, CLIC4, KPNB1, AP2B1, 42254, and PAFAH1B2. In one instance, the nMPC secretome does not comprise 42254.

[0141] In any of such methods, a symptom of a disease being treated is improved by 2% or more, or by 2-fold or more, following treatment as compared to a placebo or compared to the subject prior to treatment. In some cases, a symptom is decreased about 1.1 to about 10-fold, about 1.5 to about 10-fold, about 2 to about 10-fold, about 3 to about 10-fold, about 4 to about 10-fold, about 1.1 to about 5-fold, about 1.1 to about 6-fold, about 1.1 to about 7-fold, about 1.1 to about 8-fold, about 1.1 to about 9-fold, about 2 to about 5-fold, about 2 to about 6-fold, about 2 to about 7-fold, about 2 to about 8-fold, about 2 to about 9-fold, about 3 to about 6-fold, about 3 to about 7-fold, about 3 to about 8-fold, about 3 to about 9-fold, about 4 to about 7-fold, about 4 to about 8-fold, about 4 to about 9-fold, at least about 1.1 -fold, at least about 1.5-fold, at least about 2-fold, at least about 2.5-fold, at least about 3-fold, at least about 3.5-fold, at least about 4-fold, at least about 5-fold, or at least about 10-fold, compared to a subject treated with a placebo or compared to the subject prior to treatment. In some embodiments, a symptom is improved about 1.1 to about 10-fold, about 1.5 to about 10-fold, about 2 to about 10-fold, about 3 to about 10-fold, about 4 to about 10-fold, about 1.1 to about 5-fold, about 1.1 to about 6-fold, about 1.1 to about 7-fold, about 1.1 to about 8-fold, about 1.1 to about 9-fold, about 2 to about 5-fold, about 2 to about 6-fold, about 2 to about 7-fold, about 2 to about 8-fold, about 2 to about 9-fold, about 3 to about 6-fold, about 3 to about 7-fold, about 3 to about 8-fold, about 3 to about 9-fold, about 4 to about 7-fold, about 4 to about 8-fold, about 4 to about 9-fold, at least about 1.1 -fold, at least about 1.5-fold, at least about 2-fold, at least about 2.5-fold, at least about 3-fold, at least about 3.5-fold, at least about 4-fold, at least about 5-fold, or at least about 10-fold, compared to a subject treated with a placebo or compared to the subject prior to treatment.

[0142] In some embodiments, a symptom of a disease being treated improves by at least about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% as compared to after treatment with a placebo and as compared to a symptom of the disease or condition prior to treatment with any composition described herein.

[0143] In any of such embodiments, the subject to be treated is a mammal, where the mammal is a human. In some embodiments, the human is a child of from birth to 18 years of age. In some embodiments, the human is a child about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 years of age. In some embodiments, the human is an adult of over 18 years of age. In some embodiments, the human is an adult over about 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100 years of age. In other embodiments, the subject is ambulatory. In yet other embodiments, the subject is non-ambulatory.WSGR Docket No. 64320-711.601

[0144] In some embodiments, compositions of the present disclosure are administered via intravenous infusion. In some embodiments, compositions or formulations of the present disclosure are administered to cardiac tissue via intramyocardial infusion.HFpEF

[0145] The nMPCs, secretomes, and / or exosomes as provided herein are useful for treating HFpEF. In one aspect, provided herein is a method of treating HFpEF in a subject in need thereof, comprising administering to the subject neonatal cardiac mesenchymal progenitor cells, whereby HFpEF is treated. Neonatal cardiac mesenchymal progenitor cells (nMPCs), nMPC secretomes, and / or nMPC exosomes described herein can be used to reduce the likelihood or severity of, inhibit, or treat one or more symptoms of HFpEF. Subjects to be treated by the methods described herein are diagnosed as having HFpEF. Diagnosis can be measured cardiac ejection fraction of greater than or equal to 50%. In one instance, the subject is confirmed as having an EF>50%.

[0146] Diagnosis can also comprise one or more tests to determine whether the subject has elevated levels of C-reactive protein, soluble interleukin-1 (IL- 1) receptor-like 1, growth differentiation factor 15 (GDF15), tumor necrosis factor alpha (TNFa), or a combination thereof. Diagnosis can further comprise one or more tests to determine whether the subject has at least one of coronary artery disease, hypertension, valvular heart disease, cardiomyopathy, infiltrative disorders (e.g, amyloidosis), diabetes mellitus, congenital heart disease, pericardial disease, atrial fibrillation, cardiac toxins, myocardial dysfunction, metabolic dysfunction, vascular dysfunction, renal dysfunction, inflammatory dysfunction, or a combination thereof.

[0147] In some embodiments, the symptom is an elevated level of C-reactive protein, soluble interleukin-1 (IL-1) receptor-like 1, growth differentiation factor 15 (GDF15), tumor necrosis factor alpha (TNFa), or a combination thereof. In some embodiments, the symptom is coronary artery disease, hypertension, valvular heart disease, cardiomyopathy, infiltrative disorders (e.g, amyloidosis), diabetes mellitus, congenital heart disease, pericardial disease, atrial fibrillation, cardiac toxins (e.g, chemotherapy), myocardial dysfunction, metabolic dysfunction, vascular dysfunction, renal dysfunction, inflammatory dysfunction, or a combination thereof.

[0148] In certain embodiments, the symptom of HFpEF comprises high levels of pro-inflammatory cytokines (e g, Interleukin (IL)- ip, IL-6, IL-8, IL-12, IL-17a, IL-18, MCP-1, tumor necrosis factor (TNF)-a, interferon gamma (IFN-y)). In some embodiments, the treatment reduces levels of pro-inflammatory cytokines by at least about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% as compared to a placebo or compared to the subject prior to administration of nMPCs, nMPC secretome, nMPC exosomes, an nMPC total secretome, or a combination thereof, such that the level of pro-inflammatory cytokines is considered clinically normal. In an embodiment, the treatment reduces levels of IL-ip by at least about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% as compared to a placebo or compared to the subject prior to administration of nMPCs, nMPC secretome, nMPC exosomes, anWSGR Docket No. 64320-711.601nMPC total secretome, or a combination thereof. In one embodiment, the treatment reduces levels of IL-6 by at least about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or 100% as compared to a placebo or compared to the subject prior to administration of nMPCs, nMPC secretome, nMPC exosomes, an nMPC total secretome, or a combination thereof. In another embodiment, the treatment reduces levels of IL-8 by at least about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% as compared to a placebo or compared to the subject prior to administration of nMPCs, nMPC secretome, nMPC exosomes, an nMPC total secretome, or a combination thereof. In yet another embodiment, the treatment reduces levels of IL- 12 by at least about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% as compared to a placebo or compared to the subject prior to administration of nMPCs, nMPC secretome, nMPC exosomes, an nMPC total secretome, or a combination thereof. In certain other embodiments, the treatment reduces levels of IL-17aby at least about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% as compared to a placebo or compared to the subject prior to administration of nMPCs, nMPC secretome, nMPC exosomes, an nMPC total secretome, or a combination thereof. In another embodiment, the treatment reduces levels of IL-18 by at least about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% as compared to a placebo or compared to the subject prior to administration of nMPCs, nMPC secretome, nMPC exosomes, an nMPC total secretome, or a combination thereof. In one embodiment, the treatment reduces levels of MCP-1 by at least about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% as compared to a placebo or compared to the subject prior to administration of nMPCs, nMPC secretome, nMPC exosomes, an nMPC total secretome, or a combination thereof. In another embodiment, the treatment reduces levels of TNF-aby at least about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% as compared to a placebo or compared to the subject prior to administration of nMPCs, nMPC secretome, nMPC exosomes, an nMPC total secretome, or a combination thereof. In some embodiments, the treatment reduces levels of IFN-yby at least about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% as compared to a placebo or compared to the subject prior to administration of nMPCs, nMPC secretome, nMPC exosomes, an nMPC total secretome, or a combination thereof. In another embodiment, the treatment reduces levels of TNF-a, IL-8, MCP-1, IL-17a, and IFN-y by at least about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% as compared to a placebo or compared to the subject prior to administration of nMPCs, nMPC secretome, nMPC exosomes, an nMPC total secretome, or a combination thereof. In another embodiment, the treatment reduces levels of TNF-a, IL-8, and MCP-1 by at least about 2%, 3%, 4%, 5%,WSGR Docket No. 64320-711.6016%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% as compared to a placebo or compared to the subject prior to administration of the nMPCs, nMPC secretome, nMPC exosomes, an nMPC total secretome, or a combination thereof. In another embodiment, the treatment reduces levels of IL-17a and IFN-y by at least about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% as compared to a placebo or compared to the subject prior to administration of the nMPCs, nMPC secretome, nMPC exosomes, an nMPC total secretome, or a combination thereof. In some embodiments, the treatment reduces oxidative stress in a subject by at least about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% as compared to a placebo or compared to the subject prior to administration of nMPCs, nMPC secretome, nMPC exosomes, an nMPC total secretome, or a combination thereof. In some embodiments, the treatment improves motor neuron condition in a subject by at least about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% as compared to a placebo or compared to the subject prior to administration of nMPCs, nMPC secretome, nMPC exosomes, an nMPC total secretome, or a combination thereof. In some embodiments, the treatment improves motor function or control in a subject by at least about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% as compared to a placebo or compared to the subj ect prior to administrati on of nMPCs, nMPC secretome, nMPC exosomes, an nMPC total secretome, or a combination thereof. In some embodiments, the treatment reduces muscle twitching or cramping in a subject by at least about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% as compared to a placebo or compared to the subject prior to administration of nMPCs, nMPC secretome, nMPC exosomes, an nMPC total secretome, or a combination thereof. In certain embodiments, administration of a composition described herein inhibits or reduces motor neuron loss in a subj ect by at least about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or 100% as compared to a placebo or compared to the subject prior to administration of nMPCs, nMPC secretome, nMPC exosomes, an nMPC total secretome, or a combination thereof.Stroke Volume Index (SVI)

[0149] Stroke Volume Index (SVI) is a measurement of the volume of blood ejected by a ventricle per heartbeat, normalized to a subject’s body surface area, and expressed in units of mL / m2. It is calculated by dividing the stroke volume (SV) by the body surface area (BSA): SVI = SV / BSA. SVI is used as a tool for assessing cardiac function and to diagnose and monitor conditions like aortic stenosis, where a low SVI (e. g. , < 35 mL / m2) can indicate a problem with the heart's output. In one aspect, provided herein is a method of improving a stroke volume index (SVI) in a subject diagnosed with a HFpEF, or DCM, comprising intravenously administering to the subject a composition comprising about 50 / IO6, about 100 / 106, about 150* 106, or about 200*106nMPCs, wherein the subject exhibits an improvement in SVIWSGR Docket No. 64320-711.601following treatment. In some embodiments, the subject exhibits at least about a 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% improvement in the SVI following treatment compared to baseline or compared to a placebo. In some embodiments, the SVI increases by at least about 2 mL / m2, at least about 2.5 mL / m2, at least about 3 mL / m2, about 3.5 mL / m2, at least about 4 mL / m2, at least about 4.5 mL / m2, at least about 5 mL / m2, at least about 5.5 mL / m2, at least about 6 mL / m2, at least about 6.5 mL / m2, at least about 7 mL / m2, at least about 7.5 mL / m2, at least about 8 mL / m2, at least about 8.5 mL / m2, at least about 9 mL / m2, at least about 9.5 mL / m2, or at least about 10 mL / m2following treatment compared to baseline. In some embodiments, the SVI increases by at least about 2 mL / m2following treatment compared to baseline. In some embodiments, the SVI increases by at least about 4 mL / m2following treatment compared to baseline. In some embodiments, the SVI increases by at least about 5 mL / m2following treatment compared to baseline. In some embodiments, the SVI increases by at least about 6 mL / m2following treatment compared to baseline. In some embodiments, the SVI increases by at least about 9 mL / m2following treatment compared to baseline.6-minute walk test ( 6MWT)

[0150] The 6-minute walk test (6MWT) is a widely used, standardized test that measures the distance a patient can walk in 6 minutes to assess their functional exercise capacity. It is a self-paced test performed in a standard environment where the patient walks back and forth and can rest as needed, with the total distance covered recorded as the score. The 6MWT helps evaluate the degree of functional impairment, guides treatment decisions, and can serve as a predictor of morbidity and mortality. Before and after the walk, the subject’s pulse, blood pressure, and oxygen saturation (SpCh) are measured with subjective ratings of breathlessness. The total distance walked is the main score and is interpreted in the context of a subject’s age, sex, height, weight, and specific health condition. In one aspect, provided herein is a method of treating a subject diagnosed with a HFpEF, or DCM, comprising intravenously administering to the subject a composition comprising about 50*106, about 100* 106, about 150* 106, or about 200*106nMPCs, wherein the subject exhibits an improvement in a 6-minute walk test (6MWT) following treatment. Generally, a greater amount of distance walked corresponds to greater functional exercise capacity, and a lower amount of distance walked corresponds to lower functional exercise capacity. In some embodiments, the subject exhibits at least about a 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% improvement in the 6MWT following treatment compared to baseline or compared to a placebo. In some embodiments, the 6MWT increases by at least about 20 meters following treatment compared to baseline. In some embodiments, the 6MWT increases by at least about 50 meters following treatment compared to baseline. In some embodiments, an increase in the distance walked during the 6MWT corresponds to an improvement following treatment compared to baseline or compared to a placebo. In some embodiment^ the subj ect exhibits at least a 2% improvement in the 6MWT following treatment compared to baseline or compared to a placebo. In some embodiments, the 6MWT increases by at least about 2 meters, at least about 4 meters, at least about 6 meters, at least about 8 meters, at least about 9 meters, at least about 10WSGR Docket No. 64320-711.601meters, at least about 12 meters, at least about 14 meters, at least about 16 meters, at least about 18 meters, at least about 20 meters, at least about 22 meters, at least about 24 meters, at least about 25 meters, at least about 26 meters, at least about 28 meters, at least about 30 meters, at least about 40 meters, or at least about 50 meters following treatment compared to baseline. In some embodiments, the 6MWT increases by at least about 2 meters following treatment compared to baseline. In some embodiments, the 6MWT increases by at least about 9 meters following treatment compared to baseline. In some embodiments, the 6MWT increases by at least about 16 meters following treatment compared to baseline. In some embodiments, the 6MWT increases by at least about 22 meters following treatment compared to baseline. In some embodiments, the 6MWT increases by at least about 25 meters following treatment compared to baseline. In some embodiments, the 6MWT increases by at least about 50 meters following treatment compared to baseline.Kansas City Cardiomyopathy Questionnaire (KCCQ)

[0151] The Kansas City Cardiomyopathy Questionnaire (KCCQ) is a 23 -item self-administered questionnaire used to measure a subject’s perception of their own health status, which includes heart failure symptoms, impact on physical and social function, and how their heart failure impacts their quality of life (QOL) within a 2- week recall period. The KCCQ tool quantifies the following six distinct domains and two summary scores. The six KCCQ domains include (1) KCCQ Symptom Domain, (2) KCCQ Physical Function Domain, (3) KCCQ Quality of Life Domain, (4) KCCQ Social Limitation Domain, (5) KCCQ Self-efficiency Domain, and (6) KCCQ Symptom Stability Domain. The two KCCQ summary scores include (1) Clinical Summary Score and (2) Overall Summary Score. An overall symptom score is generally used in analyses; subscale scores for both frequency and severity are also available. The KCCQ Symptom Domain quantifies the frequency and burden of clinical symptoms in heart failure, such as, for example, fatigue, shortness of breath, paroxysmal nocturnal dyspnea and a subject’s edema or swelling. The KCCQ Physical Function Domain measures the limitations subjects experience due to heart failure symptoms in performing routine activities. Activities are common, gender-neutral, and generalizable across cultures, while also capturing a range of exertional requirements. The KCCQ Quality of Life Domain is designed to reflect a subject’s assessment of their quality of life, given the current status of their heart failure. The KCCQ Social Limitation Domain quantifies the extent to which heart failure symptoms impair a subject’s ability to interact in a number of gender-neutral social activities. The KCCQ Self-efficacy Domain quantifies a subject’s perceptions of how to prevent heart failure exacerbations and manage complications when they arise. This scale is not included in the summary scores. The KCCQ Symptom Stability Domain measures recent changes in a subject’s symptoms, their shortness of breath, fatigue or swelling, and compares a subject’s frequency of heart failure symptoms at the time of completing the KCCQ with their frequency 2 weeks ago. As a measure of change, it is most interpretable as a baseline assessment of the stability of a subject’s symptoms at the start of a study and shortly thereafter, as a measure of the acute response to treatment. This domain is not included in the summary scores. In one aspect, provided herein is a method of treating a subject diagnosed with a HFpEF, comprising intravenously administering to the subject a compositionWSGR Docket No. 64320-711.601comprising about 50*106, about lOOxlO6, about 150xl06, or about 200xl06nMPCs, wherein the subject exhibits an improvement as determined by a Kansas City Cardiomyopathy Questionnaire (KCCQ) following treatment. In some embodiments, the subject exhibits at least about a 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% improvement in the KCCQ following treatment compared to baseline or compared to a placebo. In some embodiments, the KCCQ increases by about 5, about 10, about 15, about 20, about 25, or about 30 points following treatment compared to baseline. In some embodiments, the subject improves from a “good to fair health status” to a “good to excellent health status” as determined by the KCCQ following treatment compared to baseline. A KCCQ score of below 75 points indicates good to fair health status and a score of 75 or above indicates good to excellent health status. In some embodiments, the subject exhibits at least a 2% improvement in the KCCQ following treatment compared to baseline or compared to a placebo. In some embodiments, the KCCQ increases by at least about 3, at least about 4, at least about 5, at least about 6, at least about 7, at least about 8, at least about 9, at least about 10, at least about 11, at least about 12, at least about 13, at least about 14, at least about 15, at least about 16, at least about 17, at least about 18, at least about 19, at least about 20, at least about 21, at least about 22, at least about 23, at least about 24, at least about 25, or at least about 30 points following treatment compared to baseline. In some embodiments, the KCCQ increases by at least about 9 points following treatment compared to baseline. In some embodiments, the KCCQ increases by at least about 17 points following treatment compared to baseline. In some embodiments, the KCCQ increases by at least about 18 points following treatment compared to baseline. In some embodiments, the KCCQ increases by at least about 20 points following treatment compared to baseline. In some embodiments, the KCCQ increases by at least about 21 points following treatment compared to baseline, n some embodiments, the subject improves from a “good to fair health status” to a “good to excellent health status” as determined by the KCCQ following treatment compared to baselineLeft Ventricular (L V) Filling Pressure or a Diastolic Dysfunction (E / e ’ mean)

[0152] Left ventricular filling pressure or a diastolic dysfunction was assessed by measurements of each patient’s tissue Doppler-derived E / e’ ratio. A normal E / e’ ratio is generally considered to be less than 8. A ratio greater than about 15 suggests elevated filling pressures, a ratio greater than about 13 is correlated with a disease state, and a ratio between about 8 and about 13 is correlated with an intermediate range where other echocardiographic findings are necessary to determine diastolic function. The E / e’ ratio is calculated by dividing the peak E-wave velocity by the average peak early diastolic mitral annular velocity (e1). This ratio is generally measured on both the septal and lateral mitral annulus and averaged. In one aspect, provided herein is a method of improving a left ventricular filling pressure or a diastolic dysfunction in a subject diagnosed with aHFpEF, or DCM, comprising intravenously administering to the subject a composition comprising about 50*106, about lOOxlO6, about 150xl06, or about 200xl06nMPCs, wherein the subject exhibits an improvement in left ventricular filling pressure or diastolic dysfunction following treatment. In some embodiments, the subject exhibits at least about a 2% improvement in the left ventricular filling pressure following treatment compared to baseline orWSGR Docket No. 64320-711.601compared to a placebo. In some embodiments, the subject exhibits at least about a 2% improvement in the diastolic dysfunction following treatment compared to baseline or compared to a placebo. In some embodiments, anE / e’ mean of the subject improves from a diseased level (>13) to a non- diseased level (<13) following treatment compared to baseline. In some embodiments, an E / e’ mean of the subject decreases by a score of at least about 0.5, at least about 0.75, at least about 1, at least about 1.25, at least about 1.5, at least about 1.75, at least about 2, at least about 2.25, at least about 2.5, at least about 2.75, at least about 3, at least about 3.25, at least about 3.5, at least about 3.75, at least about 4, at least about 4.5, or at least about 5 following treatment compared to baseline. In some embodiments, an E / e’ mean of the subject decreases by a score of at least about 0.5 following treatment compared to baseline. In some embodiments, an E / e’ mean of the subject decreases by a score of at least about 1 following treatment compared to baseline. In some embodiments, an E / e’ mean of the subject decreases by a score of at least about 1.5 following treatment compared to baseline. In some embodiments, an E / e’ mean of the subject decreases by a score of at least about 2 following treatment compared to baseline. In some embodiments, an E / e’ mean of the subject decreases by a score of at least about 2.25 following treatment compared to baseline. In some embodiments, an E / e’ mean of the subject decreases by at least about 2% following treatment compared to baseline. In some embodiments, the subject exhibits at least about a 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% improvement in the left ventricular filling pressure following treatment compared to baseline or compared to a placebo. In some embodiments, the subject exhibits at least about a 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% improvement in the diastolic dysfunction following treatment compared to baseline or compared to a placebo. In some embodiments, an E / e’ mean of the subject improves from a diseased level (>13) to anon-diseased level (<13) following treatment compared to baseline. In some embodiments, an E / e’ mean of the subject decreases by a score of at least about 0.5 following treatment compared to baseline. In some embodiments, an E / e’ mean of the subject decreases by at least about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% following treatment compared to baseline.N-terminal pro-B-type natriuretic peptide (NT-proBNP)

[0153] NT-proBNP Reduction and HF Biomarkers: the nMPC secretome leads to a significant decrease in NT-proBNP level, a key biomarker of heart failure severity. This reduction is mediated by improved ventricular relaxation, reduced myocardial stress, and anti-inflammatory effects. N-terminal pro-B-type natriuretic peptide levels are measured in the blood of patients. In one aspect, provided herein is a method of decreasing a level of an N-terminal pro-B-type natriuretic peptide (NT-proBNP) in a subject diagnosed with a HFpEF, or DCM, comprising intravenously administering to the subject a composition comprising about 50*106, about 100 / IO6. about 150 / 106, or about 200 / 106nMPCs, wherein the subject exhibits a decreased level of the NT-proBNP following treatment. In some embodiments, the subject to be treated has an elevated level of NT-proBNP prior to treatment. In some embodiments, the subject to be treated has a level of NT-proBNP of >240 pg / mL prior to treatment. In certain embodiments, theWSGR Docket No. 64320-711.601subject to be treated has a level of NT-proBNP of >100 pg / mL prior to treatment. In certain other embodiments, the subject to be treated has a level of NT-proBNP of <100 pg / mL prior to treatment. In some embodiments, the subject to be treated has a level of NT-proBNP of <240 pg / mL following treatment. In some other embodiments, the subject to be treated has a level of NT-proBNP of <100 pg / mL following treatment. In some embodiments, NT-proBNP levels vary depending on age and other factors. In certain embodiments, a level of NT-proBNP of less than about 125 pg / mL is associated with a lower likelihood to have heart failure. In one embodiment, a level of NT-proBNP of between about 125 and about 900 pg / mL is associated with possible heart failure. In some embodiments, the subject exhibits at least about a 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% decrease in the level of NT-proBNP of <240 pg / mL following treatment compared to baseline. In some embodiments, the subject exhibits a decrease in the level of NT-proBNP of at least about 2 pg / mL, 4 pg / mL, 6 pg / mL, 8 pg / mL, 10 pg / mL, about 20 pg / mL, about 30 pg / mL, about 40 pg / mL, about 50 pg / mL, about 60 pg / mL, about 70 pg / mL, about 80 pg / mL, about 90 pg / mL, about 100 pg / mL, about 110 pg / mL, about 120 pg / mL, about 130 pg / mL, about 140 pg / mL, about 150 pg / mL, about 160 pg / mL, about 170 pg / mL, about 180 pg / mL, about 190 pg / mL, about 200 pg / mL, about 210 pg / mL, about 220 pg / mL, about 230 pg / mL, about 240 pg / mL, about 250 pg / mL, about 260 pg / mL, about 270 pg / mL, about 280 pg / mL, about 290 pg / mL, about 300 pg / mL, or more, following treatment compared to baseline. In some embodiments, the subject exhibits a decrease in the level of NT-proBNP of at least about 2 pg / mL following treatment compared to baseline. In some embodiments, the subject exhibits a decrease in the level of NT-proBNP of at least about 10 pg / mL following treatment compared to baseline. In some embodiments, the subject exhibits a decrease in the level of NT-proBNP of at least about 12 pg / mL following treatment compared to baseline. In some embodiments, the subject exhibits a decrease in the level of NT-proBNP of at least about 20 pg / mL following treatment compared to baseline. In some embodiments, the subject exhibits a decrease in the level of NT-proBNP of at least about 30 pg / mL following treatment compared to baseline. In some embodiments, the subject exhibits a decrease in the level of NT-proBNP of at least about 40 pg / mL following treatment compared to baseline. In some embodiments, the subject exhibits a decrease in the level of NT-proBNP of at least about 50 pg / mL following treatment compared to baseline. In some embodiments, the subject exhibits a blood level of NT-proBNP of over about 125 pg / mL, about 150 pg / mL, about 175 pg / mL, about 200 mg / mL, about 225 pg / mL, about 250 pg / mL, or about 275 pg / mL prior to treatment. In some embodiments, the subject exhibits a blood level of NT-proBNP of at least about 10 pg / mL, about 20 pg / mL, about 30 pg / mL, about 40 pg / mL, about 50 pg / mL, about 60 pg / mL, about 70 pg / mL, about 80 pg / mL, about 90 pg / mL, about 100 pg / mL, about 110 pg / mL, about 120 pg / mL, about 130 pg / mL, about 140 pg / mL, about 150 pg / mL, about 160 pg / mL, about 170 pg / mL, about 180 pg / mL, about 190 pg / mL, about 200 pg / mL, about 210 pg / mL, about 220 pg / mL, about 230 pg / mL, about 240 pg / mL, about 250 pg / mL, about 260 pg / mL, about 270 pg / mL, about 280 pg / mL, about 290 pg / mL, about 300 pg / mL prior to treatment. In some embodiments, the subject exhibits a blood level ofWSGR Docket No. 64320-711.601NT-proBNP of over about 250 pg / mL, about 300 pg / mL, about 400 pg / mL, about 500 pg / mL, about 600 pg / mL, about 700 pg / mL, about 800 pg / mL, about 900 pg / mL, or more prior to treatment.Estimated Glomerular Filtration Rate (eGFR)

[0154] Estimated glomerular filtration rate is a calculation from a blood test that estimates a subject’s kidney’s efficiency in fdtering waste and excess fluid from blood. A normal eGFR is generally about 90 milliliters per minute per 1.73 square meters (mL / min / 1.73 m2) or higher, but the number decreases with age. An eGFR below 60 mL / min / 1.73 m2for three months or more, especially with signs of kidney damage like protein in urine, can be indicative of chronic kidney disease (CKD). A low eGFR are characteristic of poor kidney function, and eGFR may be used to diagnose, stage, monitor kidney disease, and adjust medications. In some embodiments, the subject to be treated has a reduced eGFR prior to treatment. In some embodiments, the subj ect to be treated has an eGFR lower than about 89 mL / min / 1.73 m2, about 85 mL / min / 1.73 m2, about 80 mL / min / 1.73 m2, about 75 mL / min / 1.73 m2, about 70 mL / min / 1.73 m2, about 65 mL / min / 1.73 m2, about 60 mL / min / 1.73 m2, about 55 mL / min / 1.73 m2, about 50 mL / min / 1.73 m2, or about 45 mL / min / 1.73 m2prior to treatment. In some embodiments, the subject to be treated has an eGFR lower than about 80 mL / min / 1.73 m2prior to treatment. In some embodiments, the subject to be treated has an eGFR lower than about 70 mL / min / 1.73 m2prior to treatment. In some embodiments, the subject to be treated has an eGFR lower than about 60 mL / min / 1.73 m2prior to treatment. In some embodiments, the subject exhibits at least about a 2% increase in an eGFR of at least about 0.5 mL / min / 1.73 m2, about 1 mL / min / 1.73 m2, about 1.5 mL / min / 1.73 m2, about 2 mL / min / 1.73 m2, about 2.5 mL / min / 1.73 m2, about 3 mL / min / 1.73 m2, about 3.5 mL / min / 1.73 m2, about 4 mL / min / 1.73 m2, about 4.5 mL / min / 1.73 m2, about 5 mL / min / 1.73 m2, about 5.5 mL / min / 1.73 m2, about 6 mL / min / 1.73 m2, about 6.5 mL / min / 1.73 m2, about 7 mL / min / 1.73 m2, about 7.5 mL / min / 1.73 m2, about 8 mL / min / 1.73 m2, about 8.5 mL / min / 1.73 m2, about 9 mL / min / 1.73 m2, about 9.5 mL / min / 1.73 m2, about 10 mL / min / 1.73 m2, about 11 mL / min / 1.73 m2, about 12 mL / min / 1.73 m2, about 13 mL / min / 1.73 m2, about 14 mL / min / 1.73 m2, about 15 mL / min / 1.73 m2, about 17.5 mL / min / 1.73 m2, or about 20 mL / min / 1.73 m2following treatment compared to baseline. In some embodiments, the subject exhibits an increase in an eGFR of at least about 0.5 mL / min / 1.73 m2following treatment compared to baseline. In some embodiments, the subject exhibits an increase in an eGFR of at least about 1 mL / min / 1.73 m2following treatment compared to baseline. In some embodiments, the subject exhibits an increase in an eGFR of at least about 4 mL / min / 1.73 m2following treatment compared to baseline. In some embodiments, the subject exhibits an increase in an eGFR of at least about 6 mL / min / 1.73 m2following treatment compared to baseline. In some embodiments, the subject exhibits an increase in an eGFR of at least about 8 mL / min / 1.73 m2following treatment compared to baseline. In some embodiments, the subject exhibits an increase in an eGFR of at least about 9 mL / min / 1.73 m2following treatment compared to baseline. In some embodiments, the subject exhibits an increase in an eGFR of at least about 10 mL / min / 1.73 m2following treatment compared to baseline. In some embodiments, the subject exhibits an increase in an eGFR of at least about 11 mL / min / 1.73 m2following treatment compared to baseline. In some embodiments, the subject exhibits an increase in an eGFR of at least aboutWSGR Docket No. 64320-711.60112 mL / min / 1.73 m2following treatment compared to baseline. In some embodiments, the subj ect exhibits an increase in an eGFR of at least about 13 mL / min / 1.73 m2following treatment compared to baseline.High-Sensitivity C-Reactive Protein (hs-CRP)

[0155] hs-CRP is a blood test that measures levels of C-reactive protein (CRP), which is an inflammatory marker produced by the liver in response to inflammation. The normal range for hs-CRP is typically less than 1.0 mg / L, and low hs-CRP levels generally correspond to a lack of inflammation. An hs-CRP range of between about 1.0 and 3.0 mg / L indicates moderate risk for heart attack, stroke, and other cardiovascular issues, even in otherwise healthy individuals. An hs-CRP value above about 3.0 mg / L indicates a high risk for cardiovascular disease. Elevated hs-CRP levels indicate inflammation in the body, and can be associated with an increased risk of heart disease, stroke, and other cardiovascular events. A value above about 10 mg / L corresponds to a marked elevation corresponding to significant inflammation caused by factors, including, but not limited to, infections, autoimmune diseases, heart disease, and cancer. From baseline to Day 56, subjects administered the nMPCs were observed to experience a decrease in hs-CRP in a range between about 0.2 mg / L and 2.1 mg / L. In some embodiments, the subject to be treated has an elevated level of CRP prior to treatment as assessed by a high- sensitivity C-Reactive Protein (hs-CRP) blood test. In some embodiments, the subject to be treated has a CRP level greater than about 1.0 mg / L, about 1.5 mg / L, about 3.0 mg / L, about 5.0 mg / L, or about 10.0 mg / L prior to treatment. In some embodiments, the subject to be treated has a CRP level greater than about 1.0 mg / L prior to treatment. In some embodiments, the subject to be treated has a CRP level greater than about 1.5 mg / L prior to treatment. In some embodiments, the subject to be treated has a CRP level greater than about 2.0 mg / L prior to treatment. In some embodiments, the subject to be treated has a CRP level greater than about 2.5 mg / L prior to treatment. In some embodiments, the subject to be treated has a CRP level greater than about 3.0 mg / L prior to treatment. In some embodiments, the subject exhibits at least about a 2% decrease in CRP level of at least about 0.1 mg / mL, about 0.2 mg / mL, about 0.3 mg / mL, about 0.4 mg / mL, about 0.5 mg / mL, about 0.75 mg / mL, about 1.0 mg / mL, about 1.5 mg / mL, about 2.0 mg / mL, about 2.5 mg / mL, or about 3.0 mg / mL following treatment compared to baseline. In some embodiments, the subject exhibits a decrease in CRP level of at least about 0.1 mg / mL following treatment compared to baseline. In some embodiments, the subject exhibits a decrease in CRP level of at least about 0.2 mg / mL following treatment compared to baseline. In some embodiments, the subject exhibits a decrease in CRP level of at least about 0.5 mg / mL following treatment compared to baseline. In some embodiments, the subj ect exhibits a decrease in CRP level of at least about 1.0 mg / mL following treatment compared to baseline. In some embodiments, the subject exhibits a decrease in CRP level of at least about 2.0 mg / mL following treatment compared to baseline.End-Diastolic Volume Index (EDVI)

[0156] The end-diastolic volume index (EDVI) is the amount of blood in a heart ventricle at the end of diastole (or end-diastolic volume, EDV) divided by a patient’s body surface area (BSA). EDVI is a parameter used to assess the heart’s ability to fill with blood and its overall function. EDVI helps determine the preload, which is the blood volume that stretches the heart muscle before it contracts.WSGR Docket No. 64320-711.601EDVI is determined using techniques like, for example, but not limited to, cardiac MRI, or other imaging modalities. End-diastolic volume tends to decrease with age. Generally, men have larger total blood volume than women. Body surface area also influences blood volume. In one aspect, provided herein is a method of increasing end-diastolic volume in a subject diagnosed with aHFpEF, comprising intravenously administering to the subject a composition comprising about 50* 106, about 100* 106, about 150* 106, or about 200* 106nMPCs, wherein the subject exhibits an increase in end-diastolic volume following treatment. In some embodiments, the subj ect to be treated has a low end-diastolic volume prior to treatment. In some instances, a low end-diastolic volume corresponds to reduced filling of the ventricles and lower cardiac output. In some embodiments, the subject to be treated is male and has a left ventricular end-diastolic volume of less than about 60 mL / m2, about 55 mL / m2, about 50 mL / m2, about 45 mL / m2, about 40 mL / m2, about 35 mL / m2, or about 30 mL / m2prior to treatment. In some embodiments, the subject to be treated is female and has a left ventricular end-diastolic volume of less than about 56 mL / m2, about 55 mL / m2, about 54 mL / m2, about 53 mL / m2, about 52 mL / m2, about 51 mL / m2, about 50 mL / m2, about 45 mL / m2, about 40 mL / m2, about 35 mL / m2, or about 30 mL / m2prior to treatment. In some embodiments, the subj ect to be treated is male and has a right ventricular end-diastolic volume of less than about 64 mL / m2, 60 mL / m2, about 55 mL / m2, about 50 mL / m2, about 45 mL / m2, about 40 mL / m2, about 35 mL / m2, or about 30 mL / m2prior to treatment. In some embodiments, the subject to be treated is female and has a right ventricular end-diastolic volume of less than about 57 mL / m2, 56 mL / m2, about 55 mL / m2, about 54 mL / m2, about 53 mL / m2, about 52 mL / m2, about 51 mL / m2, about 50 mL / m2, about 45 mL / m2, about 40 mL / m2, about 35 mL / m2, or about 30 mL / m2prior to treatment. In some embodiments, a normal left ventricular end-diastolic volume for a male subject is from about 60 to about 109 mL / m2. In some embodiments, anormal left ventricular end-diastolic volume for a male subject is from about 56 mL / m2to about 96 mL / m2. In some embodiments, anormal left ventricular end-diastolic volume for a male subject is from about 64 mL / m2to about 115 mL / m2. In some embodiments, anormal left ventricular end-diastolic volume for a male subject is from about 57 mL / m2to about 99 mL / m2. In some embodiments, the subject to be treated has an increase in EDVI of at least about 0.5 mL / m2, about 0.75 mL / m2, about 1.0 mL / m2, about 1.25 mL / m2, about 1.5 mL / m2, about 1.75 mL / m2, about 2.0 mL / m2, about 2.25 mL / m2, about 2.5 mL / m2, about 2.75 mL / m2, about 3.0 mL / m2, about 3.25 mL / m2, about 3.5 mL / m2, about 3.75 mL / m2, about 4.0 mL / m2, about 4.25 mL / m2, about 4.5 mL / m2, about 4.75 mL / m2, about 5.0 mL / m2, about 5.25 mL / m2, about 5.5 mL / m2, about 5.75 mL / m2, about 6.0 mL / m2, about 6.25 mL / m2, about 6.5 mL / m2, about 6.75 mL / m2, about 7.0 mL / m2, about 7.25 mL / m2, about 7.5 mL / m2, about 7.75 mL / m2, about 8.0 mL / m2, about 8.25 mL / m2, about 8.5 mL / m2, about 8.75 mL / m2, about 9.0 mL / m2, about 9.25 mL / m2, about 9.5 mL / m2, about 9.75 mL / m2, or about 10.0 mL / m2following treatment compared to baseline. In some embodiments, the subject to be treated has in increase in EDVI of at least about 2 mL / m2following treatment compared to baseline. In some embodiments, the subject to be treated has in increase in EDVI of at least about 5 mL / m2following treatment compared to baseline. In some embodiments, the subject to be treated has in increase in EDVI of at least about 7 mL / m2following treatment compared to baseline. In some embodiments, the subject toWSGR Docket No. 64320-711.601be treated has in increase in EDVI of at least about 9 mL / m2following treatment compared to baseline. In some embodiments, the subject to be treated has in increase in EDVI of at least about 10 mL / m2following treatment compared to baseline. In some embodiments, the subject exhibits at least about a 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% increase in EDVI following treatment compared to baseline.Dilated Cardiomyopathy

[0157] According to the World Health Organization, dilated cardiomyopathy is characterized by dilatation and impaired contraction of the left ventricle or both ventricles. It may be idiopathic, familial / genetic, viral and / or immune, alcoholic / toxic, or associated with recognized cardiovascular disease in which the degree of myocardial dysfunction is not explained by the abnormal loading conditions or the extent of ischemic damage. Histology is nonspecific. Presentation is usually with heart failure, which is often progressive. Arrhythmias, thromboembolism, and sudden death are common and may occur at any stage. Patients of DCM may also have symptoms comprising, for example, shortness of breath; swelling in the legs, ankles, feet, or abdomen; chest pain or pressure; fatigue; irregular heart rhythm, fluttering, murmur, or rapid pulse; coughing; loss of appetite; and / or reduced exercise ability.

[0158] While familial occurrence of DCM has been reported in a significant minority of cases, DCM’s origins often have been linked to autoimmune and inflammatory responses to possible viral infection. Endothelial dysfunction increases oxidative / nitrosative damage and inflammation, which stresses the failing myocardium. Impaired endothelial function and increased markers of inflammation are two of the many factors implicated in the etiology of DCM. Because the heart has limited regenerative capacity, stem cell-derived therapies, such as those described herein, can reduce systemic inflammation represent a viable new therapeutic modality for the treatment of DCM.

[0159] Cardiomyopathy is a condition that affects the heart muscle, changing its shape and function. Cardiomyopathy causes the heart to lose its ability to pump blood well. In some cases, the heart rhythm also becomes disturbed. This leads to arrhythmias (irregular heartbeats). Symptoms of cardiomyopathy in DCM patients include shortness of breath, chest pain, rapid heartbeats, and swelling in the legs, ankles, feet, stomach, and neck veins. One or more of the following tests may be recommended to diagnose DCM and / or efficacy of treatment with the methods described herein include, but are not limited to, those tests which are described above for HFpEF.

[0160] Neonatal cardiac mesenchymal progenitor cells and / or their secretomes and / or exosomes described herein can be used to reduce the likelihood or severity of, inhibit, or treat one or more symptoms of DCM. Subjects to be treated by the methods described herein are diagnosed as having DCM. Diagnosis can be measured through, for example, an echocardiogram (ultrasound of the heart), to assess the size and function of the heart chambers. Other diagnostic assessments comprise an electrocardiogram (ECG) to check heart rhythm, a chest X-ray to visualize heart size, blood tests, a physical examination, and a medical history review. Neonatal cardiac mesenchymal progenitor cells and / or their secretomes and / or exosomes described herein can be used to reduce the likelihood or severity of, inhibit, or treat one or more symptoms of dilated cardiomyopathy (DCM). In some embodiments,WSGR Docket No. 64320-711.601DCM can be a symptom resulting from causes comprising any one of genetic conditions, infections (e.g. , HIV, Lyme disease, Chagas disease), use of chemotherapy drugs, diabetes mellitus, thyroid disease, hepatitis, autoimmune illnesses, exposure to heavy metals, nutritional deficiencies, stress cardiomyopathy (e.g., Takotsubo cardiomyopathy), or other heart conditions (e.g., heart disease, heart attack, or coronary artery disease).

[0161] In any of such methods, a symptom of DCM is improved by 2% or more, or by 2-fold or more, following treatment as compared to a placebo or compared to the subject prior to treatment. In some cases, a symptom is decreased about 1.1 to about 10-fold, about 1.5 to about 10-fold, about 2 to about 10-fold, about 3 to about 10-fold, about 4 to about 10-fold, about 1.1 to about 5 -fold, about 1.1 to about 6-fold, about 1.1 to about 7-fold, about 1.1 to about 8-fold, about 1.1 to about 9-fold, about 2 to about 5-fold, about 2 to about 6-fold, about 2 to about 7-fold, about 2 to about 8-fold, about 2 to about 9-fold, about 3 to about 6-fold, about 3 to about 7-fold, about 3 to about 8-fold, about 3 to about 9-fold, about 4 to about 7-fold, about 4 to about 8-fold, about 4 to about 9-fold, at least about 1.1-fold, at least about 1.5-fold, at least about 2-fold, at least about 2.5-fold, at least about 3-fold, at least about 3.5-fold, at least about 4-fold, at least about 5-fold, or at least about 10-fold, compared to a subject treated with a placebo or compared to the subj ect prior to treatment. In some embodiments, a symptom is improved about 1.1 to about 10-fold, about 1.5 to about 10-fold, about 2 to about 10-fold, about 3 to about 10-fold, about 4 to about 10-fold, about 1.1 to about 5-fold, about 1.1 to about 6-fold, about 1.1 to about 7-fold, about 1.1 to about 8-fold, about 1.1 to about 9-fold, about 2 to about 5-fold, about 2 to about 6-fold, about 2 to about 7-fold, about 2 to about 8-fold, about 2 to about 9-fold, about 3 to about 6-fold, about 3 to about 7-fold, about 3 to about 8-fold, about 3 to about 9-fold, about 4 to about 7-fold, about 4 to about 8-fold, about 4 to about 9-fold, at least about 1.1 -fold, at least about 1.5-fold, at least about 2-fold, at least about 2.5-fold, at least about 3-fold, at least about 3.5-fold, at least about 4-fold, at least about 5-fold, or at least about 10-fold, compared to a subject treated with a placebo or compared to the subject prior to treatment.

[0162] In some embodiments, a symptom of DCM improves by at least about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% as compared to after treatment with a placebo and as compared to a symptom of the disease or condition prior to treatment with any composition described herein.

[0163] In some embodiments, a symptom of dilated cardiomyopathy (DCM) improves by at least about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% as compared to after treatment with a placebo and as compared to a symptom of the disease or condition prior to treatment with any composition described herein. In certain embodiments, the symptom of a disease or condition comprises low cardiac performance and / or low left ventricular ejection fraction (LVEF). In some embodiments, the treatment improves cardiac performance by about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% as compared to a placebo or compared to the subject prior to administration of the nMPCs. In other embodiments, the treatment improves cardiac performance by at least about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%,WSGR Docket No. 64320-711.60120%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% as compared to a placebo or compared to the subject prior to administration of the nMPCs. In some embodiments, the treatment improves left ventricular ejection fraction (LVEF) by about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% as compared to a placebo or compared to the subject prior to administration of the nMPCs. In some embodiments, the treatment improves left ventricular ejection fraction (LVEF) by at least about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% as compared to a placebo or compared to the subject prior to administration of the nMPCs. In some embodiments, an improvement in LVEF is a change in percentage of the measured LVEF to fall within standard range considered clinically normal. In some embodiments, the standard range considered clinically normal is an LVEF between about 50% and about 70%, about 50% and about 60%, about 50% and about 55%, about 55% and about 60%, about 60% and about 65%, about 60% and about 70%, or about 65% and about 70%. In some embodiments, the standard range considered mild dysfunction is an LVEF between about 40% and about 49%. In some embodiments, the standard range considered moderate dysfunction is an LVEF between about 30% and about 39%. In some embodiments, the standard range considered severe dysfunction is an LVEF less than about 30%. In some embodiments, an improvement in LVEF is a change in percentage of the measured LVEF to be above about 50%. In some embodiments, an improvement in LVEF is an increase in percentage of the measured LVEF prior to administration of nMPCs and / or their products as described herein. In some embodiments, an improvement in LVEF is an increase in percentage of the measured LVEF by at least about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% above the initial LVEF percentage prior to administration of nMPCs and / or their products as described herein. In certain other embodiments, the symptom of a disease or condition comprises a high plasma concentration or reading of N-terminal pro-B-type natriuretic peptide (NT-proBNP). In some embodiments, the treatment improves NT-proBNP reading by at least about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99%, such that NT-proBNP levels are considered clinically normal, as compared to treatment with a placebo or compared to the subject prior to administration of the nMPCs. In some embodiments, the symptom of a disease or condition comprises low score for the 6-minute walk test (6MWT). In some embodiments, the treatment improves 6MWT score by at least about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99%, as compared to the score after treatment with a placebo or compared to the subject prior to administration of the nMPCs. In some other embodiments, the symptom of a disease or condition comprises a high Modified Ross score. In some embodiments, the treatment improves a Modified Ross score by at least about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99%, such that the Modified Ross score is considered clinically normal, as compared to treatment with a placebo orWSGR Docket No. 64320-711.601compared to the subject prior to administration of the nMPCs. In certain other embodiments, the symptom of a disease or condition comprises a high end-diastolic volume (EDV) in the left ventricle (LV), or LV EDV. In some embodiments, the treatment improves LV EDV by at least about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99%, such that LV EDV is considered clinically normal, as compared to treatment with a placebo or compared to the subject prior to administration of the nMPCs. In some embodiments, the symptom of a disease or condition comprises a high end-systolic volume (ESV) in the left ventricle (LV), or LV ESV. In some embodiments, the treatment improves LV ESV by at least about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99%, such that LV ESV is considered clinically normal, as compared to treatment with a placebo or compared to the subject prior to administration of the nMPCs. In yet other embodiments, the treatment improves systolic dysfunction by at least about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99%, such that systolic dysfunction is considered clinically normal, as compared to treatment with a placebo or compared to the subject prior to administration of the nMPCs. In yet other embodiments, the treatment improves left ventricular (LV) dilation by at least about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99%, such that LV dilation is considered clinically normal, as compared to treatment with a placebo or compared to the subject prior to administration of the nMPCs.

[0164] The nMPCs and / or their cell products as provided herein can produce clinically relevant effects such as the potential to block cytokine storms to reduce inflammation. nMPCs’ expression of unique proteins and miRNA can downregulate fibrotic, inflammatory, and oxidative stress pathways (ERK / MAPK Signaling pathway) while promoting cellular growth, survival, and proliferation pathways. Pathways related to angiogenesis, immunomodulation, energy production, and cardiomyocyte proliferation while reducing oxidative stress, inflammation, and fibrosis are improved by nMPCs.

[0165] In certain embodiments, the symptom of DCM comprises high levels of pro-inflammatory cytokines (e.g., Interleukin (IL)- ip, IL-6, IL-8, IL-12, IL-17a, IL-18, MCP-1, tumor necrosis factor (TNF)-a, interferon gamma (IFN-y)). In some embodiments, the treatment reduces levels of pro-inflammatory cytokines by at least about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% as compared to a placebo or compared to the subject prior to administration of nMPCs and / or their products (e.g., secretomes, exosomes, peptides, proteins, nucleic acids, etc.), such that the level of pro-inflammatory cytokines is considered clinically normal. In an embodiment, the treatment reduces levels of IL-ip by at least about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% as compared to a placebo or compared to the subject prior to administration of nMPCs and / or their products. In one embodiment, the treatment reduces levels of IL-6 by at least about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99% orWSGR Docket No. 64320-711.601100% as compared to a placebo or compared to the subject prior to administration of nMPCs and / or their products. In another embodiment, the treatment reduces levels of IL-8 by at least about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% as compared to a placebo or compared to the subject prior to administration of nMPCs and / or their products. In yet another embodiment, the treatment reduces levels of IL-12 by at least about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% as compared to a placebo or compared to the subject prior to administration of nMPCs and / or their products. In certain other embodiments, the treatment reduces levels of IL-17a by at least about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% as compared to a placebo or compared to the subject prior to administration of nMPCs and / or their products. In another embodiment, the treatment reduces levels of IL- 18 by at least about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% as compared to a placebo or compared to the subject prior to administration of nMPCs and / or their products. In one embodiment, the treatment reduces levels ofMCP-1 by at least about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% as compared to a placebo or compared to the subject prior to administration of nMPCs and / or their products. In another embodiment, the treatment reduces levels of TNF-a by at least about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% as compared to a placebo or compared to the subject prior to administration of nMPCs and / or their products. In some embodiments, the treatment reduces levels of IFN-y by at least about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% as compared to a placebo or compared to the subject prior to administration of nMPCs and / or their products. In another embodiment, the treatment reduces levels of TNF-a, IL-8, MCP-1, IL-17a, and IFN-y by at least about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% as compared to a placebo or compared to the subject prior to administration of nMPCs and / or their products. In another embodiment, the treatment reduces levels of TNF-a, IL-8, and MCP-1 by at least about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% as compared to a placebo or compared to the subject prior to administration of the nMPCs and / or their products. In another embodiment, the treatment reduces levels of IL-17a and IFN-y by at least about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% as compared to a placebo or compared to the subject prior to administration of the nMPCs and / or their products. In some embodiments, the treatment reduces oxidative stress in a subject by at least about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%,WSGR Docket No. 64320-711.601or 100% as compared to a placebo or compared to the subject prior to administration of nMPCs and / or their products. In some embodiments, the treatment improves motor neuron condition in a subject by at least about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% as compared to a placebo or compared to the subject prior to administration of nMPCs and / or their products. In some embodiments, the treatment improves motor function or control in a subject by at least about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% as compared to a placebo or compared to the subject prior to administration of nMPCs and / or their products. In some embodiments, the treatment reduces muscle twitching or cramping in a subject by at least about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% as compared to a placebo or compared to the subject prior to administration of nMPCs and / or their products. In certain embodiments, administration of a composition described herein inhibits or reduces motor neuron loss in a subject by at least about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or 100% as compared to a placebo or compared to the subject prior to administration of nMPCs and / or their products.Kidney Disease

[0166] Compositions described herein by me utilized to treat a kidney disease. In one instance, the kidney disease comprises an acute kidney injury. In another instance, the kidney disease comprises an acute kidney disease. In another instance, the kidney disease comprises a chronic kidney disease.Symptoms to be treated include, but are not limited to, fatigue, swelling in the legs, feet, and hands, shortness of breath, nausea, loss of appetite, bone pain, or a combination thereof.

[0167] Estimated glomerular filtration rate is a calculation from a blood test that estimates a subject’s kidney’s efficiency in fdtering waste and excess fluid from blood. A normal eGFR is generally about 90 milliliters per minute per 1.73 square meters (mL / min / 1.73 m2) or higher, but the number decreases with age. An eGFR below 60 mL / min / 1.73 m2for three months or more, especially with signs of kidney damage like protein in urine, can be indicative of chronic kidney disease (CKD). A low eGFR are characteristic of poor kidney function, and eGFR may be used to diagnose, stage, monitor kidney disease, and adjust medications. In some embodiments, the subject to be treated has a reduced eGFR prior to treatment. In some embodiments, the subj ect to be treated has an eGFR lower than about 89 mL / min / 1.73 m2, about 85 mL / min / 1.73 m2, about 80 mL / min / 1.73 m2, about 75 mL / min / 1.73 m2, about 70 mL / min / 1.73 m2, about 65 mL / min / 1.73 m2, about 60 mL / min / 1.73 m2, about 55 mL / min / 1.73 m2, about 50 mL / min / 1.73 m2, or about 45 mL / min / 1.73 m2prior to treatment. In some embodiments, the subject to be treated has an eGFR lower than about 80 mL / min / 1.73 m2prior to treatment. In some embodiments, the subject to be treated has an eGFR lower than about 70 mL / min / 1.73 m2prior to treatment. In some embodiments, the subject to be treated has an eGFR lower than about 60 mL / min / 1.73 m2prior to treatment. In some embodiments, the subject exhibits at least about a 2% increase in an eGFR of at least about 0.5 mL / min / 1.73 m2, about 1 mL / min / 1.73 m2, about 1.5 mL / min / 1.73 m2, about 2 mL / min / 1.73WSGR Docket No. 64320-711.601m2, about 2.5 mL / min / 1.73 m2, about 3 mL / min / 1.73 m2, about 3.5 mL / min / 1.73 m2, about 4 mL / min / 1.73 m2, about 4.5 mL / min / 1.73 m2, about 5 mL / min / 1.73 m2, about 5.5 mL / min / 1.73 m2, about 6 mL / min / 1.73 m2, about 6.5 mL / min / 1.73 m2, about 7 mL / min / 1.73 m2, about 7.5 mL / min / 1.73 m2, about 8 mL / min / 1.73 m2, about 8.5 mL / min / 1.73 m2, about 9 mL / min / 1.73 m2, about 9.5 mL / min / 1.73 m2, about 10 mL / min / 1.73 m2, about 11 mL / min / 1.73 m2, about 12 mL / min / 1.73 m2, about 13 mL / min / 1.73 m2, about 14 mL / min / 1.73 m2, about 15 mL / min / 1.73 m2, about 17.5 mL / min / 1.73 m2, or about 20 mL / min / 1.73 m2following treatment compared to baseline. In some embodiments, the subject exhibits an increase in an eGFR of at least about 0.5 mL / min / 1.73 m2following treatment compared to baseline. In some embodiments, the subject exhibits an increase in an eGFR of at least about 1 mL / min / 1.73 m2following treatment compared to baseline. In some embodiments, the subject exhibits an increase in an eGFR of at least about 4 mL / min / 1.73 m2following treatment compared to baseline. In some embodiments, the subject exhibits an increase in an eGFR of at least about 6 mL / min / 1.73 m2following treatment compared to baseline. In some embodiments, the subject exhibits an increase in an eGFR of at least about 8 mL / min / 1.73 m2following treatment compared to baseline. In some embodiments, the subject exhibits an increase in an eGFR of at least about 9 mL / min / 1.73 m2following treatment compared to baseline. In some embodiments, the subject exhibits an increase in an eGFR of at least about 10 mL / min / 1.73 m2following treatment compared to baseline. In some embodiments, the subject exhibits an increase in an eGFR of at least about 11 mL / min / 1.73 m2following treatment compared to baseline. In some embodiments, the subject exhibits an increase in an eGFR of at least about 12 mL / min / 1.73 m2following treatment compared to baseline. In some embodiments, the subj ect exhibits an increase in an eGFR ofatleast about 13 mL / min / 1.73 m2following treatment compared to baseline. In some embodiments, the subject exhibits an increase in an eGFR of at least about 14 mL / min / 1.73 m2following treatment compared to baseline. In some embodiments, the subject exhibits an increase in an eGFR of at least about 15 mL / min / 1.73 m2following treatment compared to baseline. In some embodiments, the subject exhibits an increase in an eGFR of at least about 16 mL / min / 1.73 m2following treatment compared to baseline. In some embodiments, the subject exhibits an increase in an eGFR of at least about 17 mL / min / 1.73 m2following treatment compared to baseline. In some embodiments, the subject exhibits an increase in an eGFR of at least about 18 mL / min / 1.73 m2following treatment compared to baseline. In some embodiments, the subject exhibits an increase in an eGFR of at least about 19 mL / min / 1.73 m2following treatment compared to baseline. In some embodiments, the subj ect exhibits an increase in an eGFR of at least about 20 mL / min / 1.73 m2following treatment compared to baseline. In some embodiments, the subject exhibits an increase in eGFR of from below normal (> 60 mL / min / 1.73 m2) to above normal following treatment compared to baseline. In some embodiments, the patient exhibits such increases within 28 days±3 of the first dose. In some embodiments, the patient exhibits such increases within 30 days±3 of the first dose. In other embodiments, the exhibits such increases within 56±3 days of the first dose.

[0168] hs-CRP is a blood test that measures levels of C-reactive protein (CRP), which is an inflammatory marker produced by the liver in response to inflammation. The normal range for hs-CRP isWSGR Docket No. 64320-711.601typically less than 1.0 mg / L, and lowhs-CRP levels generally correspond to a lack of inflammation. An hs-CRP range of between about 1.0 and 3.0 mg / L indicates moderate risk for heart attack, stroke, and other cardiovascular issues, even in otherwise healthy individuals. An hs-CRP value above about 3.0 mg / L indicates a high risk for cardiovascular disease. Elevated hs-CRP levels indicate inflammation in the body and can be associated with an increased risk of heart disease, stroke, and other cardiovascular events. A value above about 10 mg / L corresponds to a marked elevation corresponding to significant inflammation caused by factors, including, but not limited to, infections, autoimmune diseases, heart disease, and cancer. From baseline to Day 56, subjects administered the nMPCs were observed to experience a decrease in hs-CRP in a range between about 0.2 mg / L and 2.1 mg / L. In some embodiments, the subject to be treated has an elevated level of CRP prior to treatment as assessed by a high- sensitivity C-Reactive Protein (hs-CRP) blood test. In some embodiments, the subject to be treated has a CRP level greater than about 1.0 mg / L, about 1.5 mg / L, about 3.0 mg / L, about 5.0 mg / L, or about 10.0 mg / L prior to treatment. In some embodiments, the subject to be treated has a CRP level greater than about 1.0 mg / L prior to treatment. In some embodiments, the subject to be treated has a CRP level greater than about 1.5 mg / L prior to treatment. In some embodiments, the subject to be treated has a CRP level greater than about 2.0 mg / L prior to treatment. In some embodiments, the subject to be treated has a CRP level greater than about 2.5 mg / L prior to treatment. In some embodiments, the subject to be treated has a CRP level greater than about 3.0 mg / L prior to treatment. In some embodiments, the subject exhibits at least about a 2% decrease in CRP level of at least about 0.1 mg / mL, about 0.2 mg / mL, about 0.3 mg / mL, about 0.4 mg / mL, about 0.5 mg / mL, about 0.75 mg / mL, about 1.0 mg / mL, about 1.5 mg / mL, about 2.0 mg / mL, about 2.5 mg / mL, or about 3.0 mg / mL following treatment compared to baseline. In some embodiments, the subject exhibits a decrease in CRP level of at least about 0.1 mg / mL following treatment compared to baseline. In some embodiments, the subject exhibits a decrease in CRP level of at least about 0.2 mg / mL following treatment compared to baseline. In some embodiments, the subject exhibits a decrease in CRP level of at least about 0.5 mg / mL following treatment compared to baseline. In some embodiments, the subj ect exhibits a decrease in CRP level of at least about 1.0 mg / mL following treatment compared to baseline. In some embodiments, the subject exhibits a decrease in CRP level of at least about 2.0 mg / mL following treatment compared to baseline.

[0169] Subjects to be treated can be from about 4 to about 18 years of age, from about 19 to about 25 years of age, or 26 years of age or older. In one embodiment, the subject to be treated is about 4 years of age. In another embodiment, the subject to be treated is about 5 years of age. In another embodiment, the subj ect to be treated is about 6 years of age. In another embodiment, the subject to be treated is about 7 years of age. In another embodiment, the subject to be treated is about 8 years of age. In another embodiment, the subject to be treated is about 9 years of age. In another embodiment, the subject to be treated is about 10 years of age. In another embodiment, the subject to be treated is about 11 years of age. In another embodiment, the subject to be treated is about 12 years of age. In another embodiment, the subject to be treated is about 13 years of age. In another embodiment, the subject to be treated is about 14 years of age. In another embodiment, the subject to be treated is about 15 years of age. In anotherWSGR Docket No. 64320-711.601embodiment, the subject to be treated is about 16 years of age. In another embodiment, the subject to be treated is about 17 years of age. In another embodiment, the subj ect to be treated is about 18 years of age. In another embodiment, the subject to be treated is about 19 years of age. In another embodiment, the subject to be treated is about 20 years of age. In another embodiment, the subject to be treated is about 21 years of age. In another embodiment, the subject to be treated is about 22 years of age. In another embodiment, the subject to be treated is about 23 years of age. In another embodiment, the subject to be treated is about 24 years of age. In another embodiment, the subject to be treated is about 25 years of age. In another embodiment, the subject to be treated is about 26 years of age. In another embodiment, the subject to be treated is about 27 years of age. In another embodiment, the subject to be treated is about 28 years of age. In another embodiment, the subject to be treated is about 29 years of age. In another embodiment, the subject to be treated is about 30+ years of age. In any of such embodiments, the subject can be biologically male. In any of such embodiments, the subject can be biologically female. A subject to be treated with the methods described herein can exhibit an improved quality of life following treatment. Alternatively, or in addition, a subject to be treated with the methods described herein can exhibit an improved quantity of life following treatment. Administration can be via any suitable method including, but not limited to, intravenous infusion.

[0170] The nMPCs, secretomes, and / or exosomes as provided herein are useful for treating kidney disease.

[0171] In any of such methods, a symptom of kidney disease is improved by 2% or more, or by 2-fold or more, following treatment as compared to a placebo or compared to the subject prior to treatment. In some cases, a symptom is decreased about 1.1 to about 10-fold, about 1.5 to about 10-fold, about 2 to about 10-fold, about 3 to about 10-fold, about 4 to about 10-fold, about 1.1 to about 5-fold, about 1.1 to about 6-fold, about 1.1 to about 7-fold, about 1.1 to about 8-fold, about 1.1 to about 9-fold, about 2 to about 5-fold, about 2 to about 6-fold, about 2 to about 7-fold, about 2 to about 8-fold, about 2 to about 9-fold, about 3 to about 6-fold, about 3 to about 7-fold, about 3 to about 8-fold, about 3 to about 9-fold, about 4 to about 7-fold, about 4 to about 8-fold, about 4 to about 9-fold, at least about 1.1 -fold, at least about 1.5-fold, at least about 2-fold, at least about 2.5-fold, at least about 3-fold, at least about 3.5-fold, at least about 4-fold, at least about 5-fold, or at least about 10-fold, compared to a subject treated with a placebo or compared to the subject prior to treatment. In some embodiments, a symptom is improved about 1.1 to about 10-fold, about 1.5 to about 10-fold, about 2 to about 10-fold, about 3 to about 10-fold, about 4 to about 10-fold, about 1.1 to about 5 -fold, about 1.1 to about 6-fold, about 1.1 to about 7-fold, about 1.1 to about 8-fold, about 1.1 to about 9-fold, about 2 to about 5-fold, about 2 to about 6-fold, about 2 to about 7-fold, about 2 to about 8-fold, about 2 to about 9-fold, about 3 to about 6-fold, about 3 to about 7-fold, about 3 to about 8-fold, about 3 to about 9-fold, about 4 to about 7-fold, about 4 to about 8-fold, about 4 to about 9-fold, at least about 1.1 -fold, at least about 1.5-fold, at least about 2-fold, at least about 2.5-fold, at least about 3-fold, at least about 3.5-fold, at least about 4-fold, at least about 5-fold, or at least about 10-fold, compared to a subject treated with a placebo or compared to the subject prior to treatment.WSGR Docket No. 64320-711.601

[0172] In some embodiments, a symptom of kidney disease improves by at least about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% as compared to after treatment with a placebo and as compared to a symptom of the disease or condition prior to treatment with any composition described herein.nMPC Efficacy In-Line with Efficacy of GLP-1 Agonists

[0173] nMPCs can improve KCCQ and 6MWT results on par with incretins and more than SGLT2 inhibitors, which are standards of care for HFpEF. Incretins are gut hormones that increase insulin secretion after a meal, while SGLT2 inhibitors are medications that work by blocking the kidneys’ ability to reabsorb sugar, causing it to be excreted in urine. SGLT2 inhibitors facilitate the removal of glucose through the urine to lower blood sugar levels. In some embodiments, nMPCs, nMPC secretome, nMPC exosomes, an nMPC total secretome, or a combination thereof, can improve KCCQ and 6MWT by 2% or more, or by 2-fold or more, following treatment as compared to treatment with a standard of care.

[0174] In any of such embodiments, the subject to be treated can be a mammal, wherein the mammal is a human. In some embodiments, the human is a child of from birth to 18 years of age. In some embodiments, the human is a child about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 years of age. In some embodiments, the human is an adult of over 18 years of age. In some embodiments, the human is an adult over about 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100 years of age. In other embodiments, the subject is ambulatory. In yet other embodiments, the subject is non-ambulatory.

[0175] In some instances, a first dose of nMPCs is delivered by intravenous infusion over the course of about 10, 15, 30, 45, 60, or 75 minutes. In one non-limiting example, a dose of nMPCs is delivered by intravenous infusion over the course of from about 30 minutes to about 90 minutes (e.g. , 60 minutes). In another non-limiting example, a dose of nMPCs is delivered by intravenous infusion over the course of from about 30 minutes to about 180 minutes (e.g., 90 minutes). In certain embodiments, the composition is administered to the subject until a symptom of HFpEF is resolved. In some embodiments, the administration frequency or application frequency comprises at least about once daily (e.g, once every 24 hours), twice daily (e.g., once every 12 hours), thrice daily (e.g, once every 8 hours), once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once a week (e.g., once every 7 days), twice a week, thrice a week, once a month, twice a month, thrice a month, or four times a month until a symptom of HFpEF is resolved. In one embodiment, the administration frequency or application frequency is at least about once daily (e.g., once every 24 hours). In one embodiment, the administration frequency or application frequency is at least about once a week. In another embodiment, the administration frequency or application frequency is at least about twice a week. In yet another embodiment, the administration frequency or application frequency is at least about thrice a week. In other embodiments, the administration frequency or application frequency is at least about once a month. In other embodiments, the administration frequency or application frequency is at least about once everyWSGR Docket No. 64320-711.601two months. In one embodiment, the administration frequency or application frequency is at least about once every 56 days. In yet another embodiment, the administration frequency or application frequency is at least about once every 60 days.Dosing and Dosing Schedules

[0176] In certain aspects, the compositions comprising neonatal cardiac mesenchymal progenitor cells (nMPCs), nMPC secretome, nMPC exosomes, an nMPC total secretome, or a combination thereof, are formulated in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form, as used herein, refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with a pharmaceutical carrier. The specification for the dosage unit forms of the present disclosure is dictated by, and directly dependent on, the unique characteristics of the compositions and the particular therapeutic effect to be achieved, and the limitations inherent in the art of compounding such an agent for the treatment of subjects. In various embodiments, the administration can be in repeated doses, such as two, three, four, four or more sequentially applied doses. In various embodiments, repeated or sequentially applied doses are provided for the treatment of a disease and / or condition. In some embodiments, the disease and / or condition can be chronic or acute. In various embodiments, repeated or sequentially applied doses are provided for the treatment of a symptom of an acute disease and / or condition. In various embodiments, the repeated or sequentially applied doses are provided for treatment of a symptom of a chronic disease and / or condition. In certain embodiments, repeated or sequentially applied doses are provided for the treatment of a symptom of Heart Failure with Preserved Ejection Fraction (HFpEF). In certain embodiments, repeated or sequentially applied doses are provided for the treatment of a symptom of dilated cardiomyopathy (DCM). In certain embodiments, repeated or sequentially applied doses are provided for the treatment of a symptom of kidney disease, optionally, wherein the kidney disease comprises an acute kidney injury, an acute kidney disease, or a chronic kidney disease. In certain embodiments, nMPCs described herein are administered to the subject once every twenty-eight (28)±3 days. In certain embodiments, the nMPCs are administered to the subject once every twenty-eight (28) days. In certain embodiments, nMPCs described herein are administered to the subject once every thirty (30)±3 days. In certain embodiments, the nMPCs are administered to the subject once every thirty (30) days. In certain embodiments, the nMPCs are administered to the subject once every 6 weeks ±3 days. In certain embodiments, a subject is administered a first dose of the nMPCs at day 0 and subsequent doses of the nMPCs every 28 days±3 days. In certain embodiments, a subject is administered a first dose of the nMPCs at day 0 and a second dose of the nMPCs at week 6±3 days. In certain embodiments, a subject is administered a first dose of the nMPCs at day 0 and subsequent doses of the nMPCs every 6 weeks±3 days. In certain embodiments, a subject is administered a first dose of the nMPCs at day 0 and subsequent doses of the nMPCs every 30±3 days. In certain embodiments, the subject is administered the nMPCs at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 times or more.WSGR Docket No. 64320-711.601

[0177] As used herein, “first dose” and “starting dose” represent the first dose out of one or more doses administered to a subject. In some embodiments, the method as described herein comprises administering to the human subject in need thereof is administered at least 1 dose, at least 2 doses, at least 3 doses, at least 4 doses, at least 5 doses, or at least 6 doses. In one non-limiting embodiment, a subject in need thereof is administered at least 1 dose. In another embodiment, a subject in need thereof is administered at least 2 doses. In another embodiment, the first dose comprises about 0.5 *106cells. In an embodiment, the first dose comprises about 10 / IO6cells. In another embodiment, the first dose comprises about 100 / 106cells. In another embodiment, the first dose comprises about 150 / IO6cells. In one embodiment, the first dose comprises about 200 / IO6cells. In another embodiment, the first dose comprises about 300 / 106cells. In another embodiment, the first dose comprises about 400 / IO6cells. In some embodiments, the method as described herein comprises administering to the human subject a pharmaceutical composition comprising the nMPCs, nMPC secretome, nMPC exosomes, an nMPC total secretome, or a combination thereof, at a first dose comprising an amount of from about 40 x 106nMPCs to about 400 x 106nMPCs per dose, and one or more further maintenance doses, wherein the one or more further maintenance doses contain a dose amount that is the same as the first dose amount. In some instances, a single dose of nMPCs is delivered by intravenous infusion over the course of at least about 10, 15, 30, 45, 60, 75, 90, 100, 120, 180, or 200 minutes. In one non-limiting example, a single dose of nMPCs is delivered by intravenous infusion over the course of about 60 minutes. In another non-limiting example, a single dose of nMPCs is delivered by intravenous infusion over the course of about 90 minutes. In yet another non-limiting example, a single dose of nMPCs is delivered by intravenous infusion over the course of about 180 minutes.

[0178] In some embodiments, at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24doses are administered. In some embodiments, at most 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24doses are administered. In certain embodiments, a single dose of nMPCs, nMPC secretome, nMPC exosomes, an nMPC total secretome, or a combination thereof, is administered about once every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 weeks. In an embodiment, a single dose of nMPCs, nMPC secretome, nMPC exosomes, an nMPC total secretome, or a combination thereof, is administered about once every 2 weeks. In an embodiment, a single dose of nMPCs, nMPC secretome, nMPC exosomes, an nMPC total secretome, or a combination thereof, is administered about once every 4 weeks. In an embodiment, a single dose of nMPCs, nMPC secretome, nMPC exosomes, an nMPC total secretome, or a combination thereof, is administered about once every 6 weeks. In an embodiment, a single dose of nMPCs, nMPC secretome, nMPC exosomes, an nMPC total secretome, or a combination thereof, is administered about once every 8 weeks. In some embodiments, the nMPCs are administered to the subject once about every seven (7) days. In some embodiments, the nMPCs are administered to the subject once about every fourteen (14) days. In other embodiments, the nMPCs are administered to the subject once about every twenty-eight (28) days. In some embodiments, the nMPCs are administered to the subject for from about 1 to about 50 years. In some embodiments, the nMPCs are administered to the subject for about 1, 2, 3, 4, 5, 6, 7, 8, 9,WSGR Docket No. 64320-711.60110, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 99 years. In some embodiments, thenMPCs is administered to the subject for at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 years. In some embodiments, the nMPCs are administered to the subject for at most about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 99 years. In some embodiments, the nMPCs are administered to the subject for about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, or about 24 months. In some embodiments, the nMPCs are administered to the subject for about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, about 30, about 31, about 32, about 33, about 34, about 35, about 36, about 37, about 38, about 39, about 40 years, or more.

[0179] In certain embodiments, the first dose is the first of one of more doses. In some embodiments, the first dose contains the nMPCs at a dose amount of about l*106, about 2*106, about 3*106, about 4*106, about 5*106, about 6*106, about 7*106, about 8*106, about 9*106, about 10xl06, about 15xl06, about 20xl06, about 25 / IO6, about 30xl06, about 35*106, about 40xl06, about 45*106, about 50xl06, about 55*10...

Claims

1. WSGR Docket No. 64320-711.601CLAIMSWhat is claimed:

1. A method of treating heart failure with preserved ejection fraction (HFpEF), dilated cardiomyopathy (DCM), or a kidney disease in a subject in need thereof, comprising administering human, neonatal cardiac mesenchymal progenitor cells (nMPCs), an nMPC secretome (conditioned medium), nMPC exosomes, or any combination thereof, whereby HFpEF is treated.

2. The method of claim 1, wherein the method treats HFpEF.

3. The method of claim 1 or 2, wherein the method treats DCM.

4. The method of any one of claims 1-3, wherein the method treats the kidney disease.

5. The method of any one of claims 1-3, wherein nMPCs are (a) positive for cell surface protein expression of c-kit (CD117), Ki67, CD44, CD73, CD47, CD105, CD90, and / or Nkx2.5 and (b) negative for protein expression of CD34, CD45, CD31, PECAM-1, tryptase, GATA4, ISL1, SSEA3, and / or SSEA4.

6. The method of any one of claims 1-5, wherein the nMPCs are further positive for protein expression of PDL1, OCT3 / 4, NANOG, KLF4, or SOX2.

7. The method of any one of claims 1-5, wherein the nMPCs are further positive for protein expression of PDL1, OCT3 / 4, NANOG, KLF4, and SOX2.

8. The method of any one of claims 1-7, wherein the nMPCs are further negative for protein expression of pl6INK4aup to at least passage 8.

9. The method of any one of claims 1-8, wherein the nMPCs are (a) positive for protein expression ofc-kit (CD117), Ki67, CD44, CD73, CD47, CD105, CD90, Nkx2.5, PDL1, OCT3 / 4, NANOG, KLF4, or SOX2 and (b) negative for protein expression of CD34, CD45, CD31, PECAM-1, tryptase, GATA4, ISL1, SSEA3, SSEA4, or pl6INK4a.

10. The method of any one of claims 1-8, wherein the nMPCs are (a) positive for protein expression ofc-kit (CD117), Ki67, CD44, CD73, CD47, CD105, CD90, Nkx2.5, PDL1, OCT3 / 4, NANOG, KLF4, and SOX2 and (b) negative for protein expression of CD34, CD45, CD31, PECAM-1, tryptase, GATA4, ISL1, SSEA3, SSEA4, and pl6INK4a.

11. The method of any one of claims 1-10, wherein the nMPCs are genetically engineered to overexpress HGF, SCF, SDF-la, ANG1, VEGFA, PDGFB, bFGF, HSP20, and / Akt.

12. The method of any one of claims 1-11, wherein the nMPCs are (a) positive for protein expression ofc-kit (CD117), Ki67, CD44, CD73, CD47, CD105, CD90, Nkx2.5, PDL1, OCT3 / 4, NANOG, KLF4, and SOX2; (b) negative for protein expression of CD34, CD45, CD31, PECAM-1, tryptase, GATA4, ISL1, SSEA3, SSEA4, andpl6INK4a, and (c) genetically engineered to overexpress HGF, SCF, SDF-la, ANG1, VEGFA, PDGFB, bFGF, HSP20, or Akt.

13. The method of any one of claims 1-12, wherein the nMPCs are genetically engineered to express or to overexpress HGF, SCF, SDF-la, ANG1, VEGFA, PDGFB, bFGF, HSP20, and Akt.

14. The method of any one of claims 1-13, wherein the nMPCs are allogeneic.

15. The method of any one of claims 1-14, wherein the subject is administered the nMPC secretome.WSGR Docket No. 64320-711.60116. The method of any one of claims 1-15, wherein the nMPC secretome is positive for protein expression of HGF, SCF, SDF-la, ANG1, VEGFA, PDGFB, bFGF, HSP20, Akt, or HSF1.

17. The method of any one of claims 1-15, wherein the nMPC secretome is positive for protein expression of HGF, SCF, SDF-la, ANG1, VEGFA, PDGFB, bFGF, HSP20, Akt, and HSF1.

18. The method of any one of claims 1-17, wherein the nMPC secretome is positive for protein expression of one, two, three, four, five, six, seven, eight, nine, ten, or more of FUS, TAF15, CAP2, SNX9, PSMB7, SUM01, EIF3A, ECHI, HNRNPL, NTM, ANG, ERP44, NAA38, RRM2B, RAB1A, RAB1B, PGRMC1, ERH, TIGAR, ITGA2, SGTA, AR1C1, AKR1C2, DNASE2, HSP90AB4P, ANGPTL2, SF3B2, GREM1, ARF3, ARF1, ARF5, LSM5, PSMD9, SUGT1, ALDH1A3, PDGFRB, HIST1H1C, SP100, G6PD, PPIL1, SNRPD1, FDPS, RAB6B, RAB6A, DCTD, GLB1, ARIH1, IST1, HNRNPU, ULBP2, RAET1G, ERAP2, CDC42, EDF1, LIPG, FKBP4, RBMX, RBMXL1, RPL30, THY1, AP2M1, RPS16, FHL3, BZW1, BZW2, EIF4G1, PFDN4, CLTB, PIR, MVP, ECU, DCI, ALYREF, RPS10, PPP3CA, TAX1BP3, PPA1, DDX39B, DDX39A, GNPNAT1, LIMA1, SNRPD3, ADH5, ENAH, DYNLL1, DYNLL2, HUWE1, HMGB2, PTMS, UCHL3, PFDN2, DYNLRB1, HDGFRP2, INF2, HPRT1, EIF2S2, ADAMT7, EIF3C, EIF3CL, RPS5, VPS35, CS, ECHS1, UBQLN1, GBP2, GBP1, SF3B1, RANBP1, GNS, HLA-B, UBXN1, GNPDA1, IGF2, EIF3B, TCEB1, VASP, GSR, HLA-A, HLA-HIGF2, NUDT5, COPE, HNRNPA3, SRI, HNRNPC, MMP10, EWSR1, IPO7, YARS, TMPO, HNRNPH1, HLA-A, PDGFC, IL1B, S100A10, TXNDC2, DPY30, LAMP1, LYPLA1, CBR1, ARHGAP1, TPR, NAMPT, NAMPTL, CXCL2, EIF4A2, RPS4X, PABPN1, PHLDB1, NAP1L4, DDX6, PSMC3, MAP7D1, OSCAR, TES, NMT1,NMT2, MAT2A, PRMT1, C0X17, SELM, CARS, PPP2CA, PPP2CB, VEGFC, VPS26A, PXN, PAWR, STRAP, RAB11A, RAB11B, EIF5, COPZ1, COPS3, CHMP4B, PDXK, RALA, RALB, SEC13, FHL2,TOM1, PYCARD, PDLIM4, RBBP4, RBBP7, RPS20, SRSF1, DLD, SNRPE, EIF4EBP1, RPLPO, RPLP0P6, LSM3, SLC16A3, CSE1L, NUCKS1, TSNAX, RPSA, RPSAP58, AP1B1, EIF2S1, LCP1, PSMD4, AARS, SRSF2, SFRS2, TRIP10, CLTA, USO1, VBP1, UBE2K, MRPL12, UAP1, HIST1H1B, YBX3, RPL10A, IDH1, SNRPN, SNRPB, PCK2, EIF6, MMP3, DHX9, MATR3, UBE2D2, UBE2D3, PTRF, ACTR1A, LAMA1, PDCD6IP, QARS, HN1L, PLBD2, OS9, ILF3, ISOCI, PPP1R7, MAPK1, PDCD1LG2, GOLGB1, HSPA9, ACBD3, BTF3, UBE2I, SRRT, EIF4H, FERMT2, EIF3G, PARVA, DBNL, BOLA2, MAPRE1, PRDX5, STX12, EIF1, SMS, GRPEL1, OAF, SYNCRIP, ECE1, VAPA, PCNP, PSME1, EIF3J, C14orfl66, DDX1, AKR1B1, SRP9, PCMT1, XPO1, MMP9, RPS7, NRCAM, FKBP3, SSB, DSC3, XRCC5, CCT6A, LIF, SERPINA9, SND1, ANP32B, G3BP1, GPC6, GLOD4, RRBP1, TGFB1, USP14, PLAUR, CXCL3, FASN, COPB2, TARDBP, TNFAIP6, RPS3, NDUFAB1, LMNB1, COL16A1, PSMF1, PHGDH, PRKCDBP, CXCL5, YAP1, TROVE2, MACF1, EIF5B, STX7, PFDNS, APOA1, PDAP1, STX12, EIF3K, FH, RBM8A, EIF1, RPS2, PTGR1, EEA1, CAB39, DCTN2, GDF15, MYL9, TCP1, RPS12, RAD23A, SKP1, PDLIM1, HSPH1, PSMB3, SUB1, API5, TWF2, KTN1, DYNC1H1, SNRNP70, MCFD2, PPP1R18, PTGES3, APEX1, TNKS1BP1, FUBP1, VAT1, PAFAH1B1, CBX1, PTK7, HNRPDL, ZNF185, DYNC1I2, KHDRBS1, SFPQ, PDCD5, TRIM28, PPIC, NARS, PCBP2, CD2AP, PSMA1, CAPRIN1, KHSRP, NSFL1C, PPP1R12A, NUDC, MFAP2, IGF2R, RGMB, PABPC1,WSGR Docket No. 64320-711.601MAN1A1, DDB1, PTBP1, FBN2, CNBP, 0TUB1, NASP, HSPD1, EEF1D, RNPEP, CRKL, HNRNPAB, EIF3F, PAICS, ILF2, COPB1, PA2G4, COPA, NT5E, HMGA1, SF1, XRCC6, GNB2L1, MEI, MTAP, CCT2, ARCN1, PEPD, and EPB41L3.

19. The method of any one of claims 1-17, wherein the nMPC secretome is positive for protein expression of one, two, three, four, five, six, seven, eight, nine, ten, or more of PPP1CA, PPP1CC, STI 3. ST13P5, ST13P4, HMGB1, HMGB1P1, HNRNPA1, HNRNPA1L2, NEDD8, N EDD8-MDP1, YBX1, YBX2, CCT7, HNRNPH3, LTBP1, UBE2N, IL8, CYCS, LGALS1, IL6, PGAM1, YWHAH, TXN, ARHGDIB, PSMA3, RAN, TPM3, BASP1, HSPA8, ITGAV, PPIA, NACA, HSP90AB1, PCBP1, CAP1, NUTF2, PSMA5, CAPZA1, RPLP1, GLO1, ACTG1, ICAM1, SDC4, SOD2, PSMB4, TFPI2, C1QBP, NAP1L1, HSP90AA1, SET,ENO1,CCT3,GOT2,HSPE1, PGM3, PLIN3, CNDP2, PGD, SH3BGRL, TLN1, HSP90AB2P, GOT1, HNRNPAO, FTH1, TPD52L2, UGP2, AHNAK, CCT8, PSMA7, CCT4, SRPX2, CLIC4, KPNB1, AP2B1, 42254, and PAFAH1B2.

20. The method of any one of claims 1-17, wherein the nMPC secretome is positive for protein expression of one, two, three, four, five, six, seven, eight, nine, ten, or more of PPP1CA, PPP1CC, STI 3. ST13P5, ST13P4, HMGB1, HMGB1P1, HNRNPA1, HNRNPA1L2, NEDD8, N EDD8-MDP1, YBX1, YBX2, CCT7, HNRNPH3, LTBP1, UBE2N, IL8, CYCS, LGALS1, IL6, PGAM1, YWHAH, TXN, ARHGDIB, PSMA3, RAN, TPM3, BASP1, HSPA8, ITGAV, PPIA, NACA, HSP90AB1, PCBP1, CAP1, NUTF2, PSMA5, CAPZA1, RPLP1, GLO1, ACTG1, ICAM1, SDC4, SOD2, PSMB4, TFPI2, C1QBP, NAP1L1, HSP90AA1, SET,ENO1,CCT3,GOT2,HSPE1, PGM3, PLIN3, CNDP2, PGD, SH3BGRL, TLN1, HSP90AB2P, GOT1, HNRNPAO, FTH1, TPD52L2, UGP2, AHNAK, CCT8, PSMA7, CCT4, SRPX2, CLIC4, KPNB1, AP2B1, and PAFAH1B2.

21. The method of any one of claims 1-20, wherein a symptom of HFpEF, DCM, or kidney disease is improved by 2% or more, or by 2-fold or more, following treatment as compared to treatment with a placebo or compared to the subject prior to treatment.

22. The method of claim 21, wherein the symptom is an elevated level of C-reactive protein, soluble interleukin- 1 (IL-1) receptor-like 1, growth differentiation factor 15 (GDF15), tumor necrosis factor alpha (TNFa), or a combination thereof.

23. The method of claim 21 or 22, wherein the symptom further comprises coronary artery disease, hypertension, valvular heart disease, cardiomyopathy, infiltrative disorders (e.g., amyloidosis), diabetes mellitus, congenital heart disease, pericardial disease, atrial fibrillation, cardiac toxins, myocardial dysfunction, metabolic dysfunction, vascular dysfunction, renal dysfunction, inflammatory dysfunction, or a combination thereof.

24. The method of any one of claims 1-23, wherein treatment improves ventricular relaxation.

25. The method of claim 24, wherein treatment improves ventricular relaxation by about 2% or more compared to treatment with a placebo or compared to the subject prior to administration of the nMPCs.

26. The method of any one of claims 1-25, wherein treatment improves cardiac performance.WSGR Docket No. 64320-711.60127. The method of claim 26, wherein the improvement in cardiac performance comprises an improvement in early-to-late ventricular filling (E / A) ratio, left ventricle (LV) relaxation, LV end-diastolic pressure, and / or lung congestion.

28. The method of claim 26 or 27, wherein the improvement in cardiac performance comprises a reduction in Tau (r) and / or end-diastolic pressure volume relationship.

29. The method of any one of claims 26-28, wherein treatment improves cardiac performance by about 2% or more compared to treatment with a placebo or compared to the subject prior to administration of the nMPCs.

30. The method of claim 4, wherein the kidney disease comprises an acute kidney injury.

31. The method of claim 4, wherein the kidney disease comprises an acute kidney disease.

32. The method of claim 4, wherein the kidney disease comprises a chronic kidney disease.

33. The method of any one of claims 1-32, wherein a symptom of the kidney disease is improved by 2% or more, or by 2-fold or more, following treatment as compared to treatment with a placebo or compared to the subject prior to treatment.

34. The method of claim 33, wherein the symptom comprises fatigue, swelling in the legs, feet, and hands, shortness of breath, nausea, loss of appetite, bone pain, kidney failure, or a combination thereof.

35. The method of any one of claims 1-34, wherein treatment reduces one or more symptoms, improves quality of life, prevents disease progression, reduces hospitalizations, and / or effectively manages underlying comorbidities.

36. The method of any one of claims 1-35, wherein a dose of the nMPCs comprises from about 15 million to about 250 million nMPCs.

37. The method of any one of claims 1-35, wherein a dose of the nMPCs comprises from about 35 million to about 65 million nMPCs.

38. The method of any one of claims 1-35, wherein a dose of the nMPCs comprises from about 45 million to about 55 million nMPCs.

39. The method of any one of claims 1-38, wherein a dose of the nMPCs comprises about 50 million nMPCs.

40. The method of any one of claims 1-35, wherein a dose of the nMPCs comprises from about 85 million to about 115 million nMPCs.

41. The method of any one of claims 1-35, wherein a dose of the nMPCs comprises from about 95 million to about 105 million nMPCs.

42. The method of claim 40 or 41, wherein a dose of the nMPCs comprises about 100 million nMPCs.

43. The method of any one of claims 1-35, wherein a dose of the nMPCs comprises from about 135 million to about 165 million nMPCs.

44. The method of any one of claims 1-35, wherein a dose of the nMPCs comprises from about 145 million to about 155 million nMPCs.WSGR Docket No. 64320-711.60145. The method of claim 43 or 44, wherein a dose of the nMPCs comprises about 150 million nMPCs.

46. The method of any one of claims 1-35, wherein a dose of the nMPCs comprises from about 185 million to about 215 million nMPCs.

47. The method of claim 46, wherein a dose of the nMPCs comprises from about 195 million to about 205 million nMPCs.

48. The method of claim 46 or 47, wherein a dose of the nMPCs comprises about 200 million nMPCs.

49. The method of any one of claims 1-35, wherein a dose of the nMPCs comprises from about 235 million to about 265 million nMPCs.

50. The method of claim 49, wherein a dose of the nMPCs comprises from about 245 million to about 255 million nMPCs.

51. The method of claim 49 or 50, wherein a dose of the nMPCs comprises about 250 million nMPCs.

52. The method of any one of claims 1-51, wherein the administering is intravenous (IV) inj ection or intravenous (IV) catheter.

53. The method of any one of claims 1-52, wherein the nMPCs are administered into the heart of the subject via intramyocardial transplantation.

54. The method of any one of claims 1-51, wherein the nMPCs are administered to the subject once every twenty-eight (28)±3 days.

55. The method of any one of claims 1-51, wherein the nMPCs are administered to the subject once every thirty (30)±3 days.

56. The method of any one of claims 1-51, wherein the nMPCs are administered to the subject once every twenty-eight (28) days.

57. The method of any one of claims 1-51, wherein the nMPCs are administered to the subject once every thirty (30) days.

58. The method of any one of claims 1-51, wherein the nMPCs are administered to the subject once every 6 weeks ±3 days.

59. The method of any one of claims 1-58, wherein the nMPCs are administered to the subject for from about 1 to about 100 years.

60. The method of claim 59, wherein the nMPCs are administered to the subj ect for about 1 , about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, or about 24 months.

61. The method of claim 59, wherein the nMPCs are administered to the subj ect for about 1 , about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, aboutWSGR Docket No. 64320-711.60124, about 25, about 26, about 27, about 28, about 29, about 30, about 31, about 32, about 33, about 34, about 35, about 36, about 37, about 38, about 39, about 40 years, or more.

62. The method of any one of claims 1-61, wherein the method further comprises administering to the subject one or more additional therapeutic agent(s).

63. The method of claim 62, wherein the one or more additional therapeutic agent(s) comprise(s) an aldosterone antagonist, an angiotensin-converting enzyme inhibitor (ACEi), an angiotensin receptor blocker (ARB), a beta blocker, a blood thinner, a calcium channel blocker, digoxin, a diuretic, metformin, a statin, a sodium-glucose cotransporter-2 (SGLT2) inhibitor, and / or a glucagon- 1 receptor agonist.

64. The method of any one of claims 1-63, wherein the subject is a mammal.

65. The method of claim 64, wherein the mammal is a human.

66. The method of claim 64, wherein the human is a child of from birth to 18 years of age.

67. The method of claim 64, wherein the human is a child of from about 4 years of age to about 18 years of age.

68. The method of claim 64, wherein the human is an adult of 18 years of age or older.

69. The method of any one claims 1-68, further comprising administering exosomes.

70. The method of claim 69, wherein the nMPC exosomes are positive for protein expression of HGF, SCF, SDF-la, ANG1, VEGFA, PDGFB, bFGF, HSP20, Akt, and / or HSF1.

71. The method of claim 69 or 70, wherein the nMPC exosomes are positive for expression of CD81 and / or CD63.

72. The method of any one of claims 69-71, wherein the conditioned medium or exosomes are negative for protein expression of IGF 1.

73. The method of any one of claims 1-72, wherein the nMPCs are non-naturally occurring.

74. The method of any one of claims 1-73, wherein the nMPCs are not xenogenic.

75. The method of any one of claims 1-74, wherein the nMPCs are infused via IV catheter for from about 45 minutes to about 90 minutes.

76. The method of any one of claims 1-75, wherein the nMPCs are infused via IV catheter for about 60 minutes.

77. The method of any one of claims 1-76, wherein the subject is screened at one or more times prior to treatment, during treatment, and / or after treatment.

78. The method of claim 77, wherein screening comprises a physical evaluation.

79. The method of claim 77 or 78, wherein screening comprises assessment of blood pressure, heart rate, respiratory rate, temperature, and / or oxygen saturation.

80. The method of any one of claims 77-79, wherein screening comprises analysis of: urinalysis / microscopy, urine protein to creatinine ratio, measurement of N-terminal Pro-Brain Natriuretic Peptide (NT-proBNP), high-sensitivity cardiac troponin test (hs-cTnT), High Sensitivity C-reactive protein (hs-CRP) measurement, cytokine analysis (e.g, IL-6, IL-8, IL-10, transforming growth factor, beta receptor II (TGF- RII), interleukin la (IL-la), interferon gamma (IFN-y), transforming growth factor alpha (TGF-a), and / or tumor necrosis factor receptor 1 (TNF-RI)), virusWSGR Docket No. 64320-711.601serology (e.g, hepatitis A, B, and C viruses, and / or anti -HIV type 1), Exosome Biomarker Analysis (e.g., human leukocyte antigen (HL A)), Human Leukocyte Antigen (HL A) Phenotyping, PBMC Inflammatory Biomarker Analysis (e.g., inflammatory cells such as, for example, CD4+, CD17+, CD25+, CD68+, CD163+) and serum levels of cytokines (e.g., IL-6, IL-8, TNF-alpha), a 6-Minute Walk Test (MWT), a Borg Dyspnea Score, a Kansas City Cardiomyopathy Questionnaire (KCCQ), a New York Heart Association (NYHA) Functional Classification, a hematology assessment, a clinical chemistry assessment, an echocardiogram, and / or an electrocardiogram.

81. The method of any one of claims 1-80, wherein the subject is pre-treated with Hydrocortisone and / or a Hl blocker.

82. The method of any one of claims 1-81, wherein the subject is administered a first dose of the nMPCs at day 0 and a second dose of the nMPCs at day 28±3 days.

83. The method of any one of claims 1-82, wherein the subject is administered a first dose of the nMPCs at day 0 and subsequent doses of the nMPCs every 28 days±3 days.

84. The method of any one of claims 1-83, wherein the subject is administered a first dose of the nMPCs at day 0 and a second dose of the nMPCs at week 6±3 days.

85. The method of any one of claims 1-84, wherein the subject is administered a first dose of the nMPCs at day 0 and subsequent doses of the nMPCs every 6 weeks±3 days.

86. The method of any one of claims 1-85, wherein the subject is administered a first dose of the nMPCs at day 0 and subsequent doses of the nMPCs every 30±3 days.

87. The method of any one of claims 1-86, wherein the subject is assessed at 7-day intervals following treatment.

88. The method of any one of claims 1-87, wherein N-terminal pro-brain natriuretic peptide (NT-proBNP) in the subject is reduced by at least about 2% compared to treatment with a placebo or compared to the subject prior to treatment.

89. The method of any one of claims 1-88, wherein a proinflammatory cytokine in the subject is reduced by at least about 2% compared to treatment with a placebo or compared to the subject prior to treatment.

90. The method of any one of claims 1-89, wherein troponin levels are reduced by at least about 2% compared to treatment with a placebo or compared to the subject prior to treatment in a High -sensitivity troponin (hs-cTn) test.

91. The method of any one of claims 1-90, wherein a two-dimensional transthoracic echocardiography (2D-TTE) parameter (e’ velocity and E / e’ ratio) screening result of the subject is improved by at least about 2% compared to treatment with a placebo or compared to the subject prior to treatment.

92. The method of any one of claims 1-91, wherein the subject has an improved quality of life following treatment compared to treatment with a placebo or compared to the subject prior to treatment.

93. The method of any one of claims 1-92, wherein the subject has a left ventricular ejection fraction (LVEF) of about 50% or more prior to administration of the nMPCs.WSGR Docket No. 64320-711.60194. The method of any one of claims 1-93, wherein the subject does not have an LVEF of between about 41% and about 49% prior to administration of the nMPCs.

95. The method of any one of claims 1-94, wherein the subject does not have an LVEF of less than about 40% prior to administration of the nMPCs.

96. The method of any one of claims 1-95, wherein the method treats a kidney disease and the symptom to be treated comprises fatigue, swelling in the legs, feet, and hands, shortness of breath, nausea, loss of appetite, bone pain, or a combination thereof.

97. The method of any one of claims 1-96, wherein the subject is biologically a male.

98. The method of any one of claims 1-96, wherein the subject is biologically a female.

99. The method of any one of claims 1-98, wherein the subject is from about 1 to about 10 years of age, from about 11 to about 20 years of age, from about 21 to about 30 years of age, from about 31 to about 40 years of age, from about 51 to about 60 years of age, from about 71 to about 80 years of age, from about 81 to about 90 years of age, or about 91+ years of age100. The method of any one of claims 1-99, wherein the subject has one or more risk factors comprising a positive smoker identity; weight in excess (overweight); obesity; diabetes; hypertension; a valvular disease; sleep apnea; pulmonary hypertension; a chronic obstructive pulmonary disease; an iron deficiency with or without anemia; coronary artery disease; atrial fibrillation; a dysrhythmia; a tachyarrhythmia; atrial fibrillation; an acute kidney injury or worsening chronic kidney disease; an infection; ischemia; increased salt intake or water retention; a medication noncompliance; antihypertensive medication noncompliance; diuretics medication noncompliance; racial identification as black, white, Latino, or Hispanic; racial non-identification as Latino or Hispanic; hyponatremia; hypochloremia; dysregulation of lipid metabolism; hypertriglyceridemia; metabolic dysfunction-associated steatotic liver disease (MASLD; nonalcoholic fatty liver disease or NAFLD); hypothyroidism; hyperthyroidism; low triiodothyronine syndrome; or an elevated natriuretic peptide level.

101. The method of any one of claims 1-100, wherein the nMPCs are stable in storage at a temperature for a period of time.

102. The method of claim 101, wherein the temperature is about 4 °C, 1 °C, 0 °C, -10 °C, -20 °C, or -80 °C.

103. The method of claim 101 or 102, wherein the period of time is at least about 1, 2, 3, 4, 5, 6, or 7 days; at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks; or at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months.

104. The method of any one of claims 101-103, wherein the nMPCs are stored in cell cryopreservation media-CSIO (CRYOSTOR®; Sigma- Aldrich, Israel).

105. The method of any one of claims 101-104, wherein the nMPCs are thawed in a 37 °C water bath until a single ice crystal remained prior to administration to the subject.

106. The method of claim 105, wherein the nMPCs are further washed with a volume of Complete Medium (CM).WSGR Docket No. 64320-711.601107. The method of claim 106, wherein the nMPCs are washed twice with a volume of Complete Medium (CM).

108. The method of claim 105 or 106, wherein the volume is at least about 10 ml.

109. The method of any one of claims 1-108, wherein the nMPCs are:(a) positive for protein expression of 1, 2, 3, 4, 5, 6, 7, or 8 of c-kit (CD117), Ki67, CD44, CD73, CD47, CD105, CD90, andNkx2.5;(b) negative for protein expression of 1, 2, 3, 4, 5, 6, 7, 8, or 9 of CD34, CD45, CD31, PECAM-1, tryptase, GATA4, ISL1, SSEA3, and SSEA4;(c) positive for protein expression of 1, 2, 3, 4, or 5 of PDL1, OCT3 / 4, NANOG, KLF4, and SOX2; and / or(d) negative for protein expression of pl6INK4aup to at least passage 8.

110. The method of any one of claims 1-109, wherein the nMPCs are:(a) positive for protein expression of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 of c-kit (CD117), Ki67, CD44, CD73, CD47, CD105, CD90, Nkx2.5, PDL1, OCT3 / 4, NANOG, KLF4, and SOX2; and(b) negative for protein expression of 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 of CD34, CD45, CD31, PECAM-1, tryptase, GATA4, ISL1, SSEA3, SSEA4, and pl6INK4a.

111. The method of any one of claims 1-110, wherein the nMPCs are: (a) positive for protein expression of Ki67 or Nkx2.5, (b) positive for cell surface protein expression of c-Kit (CD117), CD44, CD73, CD47, CD105, and / or CD90, (c) positive for miRNA expression of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and / or miR-374b-5p, and (d) negative for protein expression of CD34, CD45, CD31, PECAM-1, tryptase, GATA4, ISL1, SSEA3, SSEA4, and / or pl6INK4a.

112. The method of any one of claims 1-111, wherein the nMPCs are (a) positive for protein expression of Ki67 or Nkx2.5, (b) positive for cell surface protein expression of c-Kit (CD117), CD44, CD73, CD47, CD105, or CD90, (c) positive for miRNA expression of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, or miR-374b-5p, and (d) negative for protein expression of CD34, CD45, CD31, PECAM-1, tryptase, GATA4, ISL1, SSEA3, SSEA4, or pl6INK4a.

113. The method of any one of claims 1-112, wherein the nMPCs are (a) positive for protein expression of Ki67 andNkx2.5, (b) positive for cell surface protein expression of c-Kit (CD117), CD44, CD73, CD47, CD105, and CD90, (c) positive for miRNA expression of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and miR-374b-5p, and (d) negative for protein expression of CD34, CD45, CD31, PECAM-1, tryptase, GATA4, ISL1, SSEA3, SSEA4, and pl6INK4a.

114. The method of any one of claims 1-113, wherein the nMPCs are (a) positive for protein expression of Ki67, Nkx2.5, OCT3 / 4, NANOG, KLF4, HSF1, and / or SOX2, (b) positive for cell surface protein expression of c-kit (CD117), CD44, CD73, CD47, CD105, CD90, and / or PDL1, (c) positive for miRNA expression of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and / or miR-374b-5p, and (d) negative for protein expression of CD34, CD45, CD31, PECAM-1, tryptase, GATA4, ISL1, SSEA3, SSEA4, and / or pl6INK4a.WSGR Docket No. 64320-711.601115. The method of any one of claims 1-114, wherein the nMPCs are (a) positive for protein expression of Ki67, Nkx2.5, OCT3 / 4, NANOG, KLF4, HSF1, or SOX2, (b) positive for cell surface protein expression of c-kit (CD117), CD44, CD73, CD47, CD105, CD90, or PDL1, (c) positive for miRNA expression of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, or miR-374b-5p, and (d) negative for protein expression of CD34, CD45, CD31, PECAM-1, tryptase, GATA4, ISL1, SSEA3, SSEA4, or pl6INK4a.

116. The method of any one of claims 1-115, wherein the nMPCs are (a) positive for protein expression of Ki67, Nkx2.5, OCT3 / 4, NANOG, KLF4, HSF1, and SOX2, (b) positive for cell surface protein expression of c-kit (CD117), CD44, CD73, CD47, CD105, CD90, and PDL1, (c) positive for miRNA expression of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and miR-374b-5p, and (d) negative for protein expression of CD34, CD45, CD31, PECAM-1, tryptase, GATA4, ISL1, SSEA3, SSEA4, and pl6INK4a.

117. The method of any one of claims 1-116, wherein the nMPCs are genetically engineered to overexpress HGF, SCF, SDF-la, ANG1, VEGFA PDGFB, bFGF, HSP20, Akt, miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and / or miR-374b-5p.

118. The method of any one of claims 1-116, wherein the nMPCs are genetically engineered to overexpress 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 of HGF, SCF, SDF-la, ANG1, VEGFA, PDGFB, bFGF, HSP20,Akt, miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and miR-374b-5p.

119. The method of any one of claims 1-118, wherein the nMPCs are (a) positive for protein expression of Ki67, Nkx2.5, OCT3 / 4, NANOG, KLF4, HSF1, and / or SOX2, (b) positive for cell surface protein expression of c-Kit (CD117), CD44, CD73, CD47, CD105, CD90, and / or PDL1, (c) positive for miRNA expression of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and / or miR-374b-5p, (d) negative for protein expression of CD34, CD45, CD31, PECAM-1, tryptase, GATA4, ISL1, SSEA3, SSEA4, and / or pl6INK4a, and (e) genetically engineered to overexpress HGF, SCF, SDF-la, ANG1, VEGFA, PDGFB, bFGF, HSP20,Akt, miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and / or miR-374b-5p.

120. The method of any one of claims 1-119, wherein the nMPCs are (a) positive for protein expression of Ki67, Nkx2.5, OCT3 / 4, NANOG, KLF4, HSF1, and SOX2, (b) positive for cell surface protein expression of c-Kit (CD117), CD44, CD73, CD47, CD105, CD90, and PDL1, (c) positive for miRNA expression of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and miR-374b-5p, (d) negative for protein expression of CD34, CD45, CD31, PECAM-1, tryptase, GATA4, ISL1, SSEA3, SSEA4, and pl6INK4a, and (e) genetically engineered to overexpress HGF, SCF, SDF-la, ANG1, VEGFA, PDGFB, bFGF, HSP20,Akt, miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and miR-374b-5p.

121. The method of any one of claims 1-120, wherein the nMPCs are:(a) positive for protein expression of 1, 2, 3, 4, 5, 6, or 7 of Ki67, Nkx2.5, OCT3 / 4, NANOG, KLF4, HSF1, and SOX2;WSGR Docket No. 64320-711.601(b) positive for cell surface protein expression of 1, 2, 3, 4, 5, 6, or 7 of c-Kit (CD117), CD44, CD73, CD47, CD105, CD90, and PDL1;(c) positive for miRNA expression of 1, 2, 3, 4, 5, or 6 of miR-31-3p, miR-31-5p, miR- 3613-5p, miR-582-3p, miR-7641, and miR-374b-5p,(d) negative for protein expression of 1, 2, 3, 4, 5, 6, 7, 8, or 9 of CD34, CD45, CD31, PECAM-1, tryptase, GATA4, ISL1, SSEA3, and SSEA4; and / or(e) negative for protein expression of pl6INK4aup to at least passage 8.

122. The method of any one of claims 1-121, wherein the nMPCs are:(a) positive for protein expression of 1, 2, 3, 4, 5, 6, or 7 of Ki67, Nkx2.5, OCT3 / 4, NANOG, KLF4, HSF1, and SOX2;(b) positive for cell surface protein expression of 1, 2, 3, 4, 5, 6, or 7 of c-Kit (CD117), CD44, CD73, CD47, CD105, CD90, and PDL1;(c) positive for miRNA expression of 1, 2, 3, 4, 5, or 6 of miR-31-3p, miR-31-5p, miR- 3613-5p, miR-582-3p, miR-7641, and miR-374b-5p; and(d) negative for protein expression of 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 of CD34, CD45, CD31, PECAM-1, tryptase, GATA4, ISL1, SSEA3, SSEA4, and pl6INK4a.

123. The method of any one of claims 1-122, wherein the administering the nMPCs is at a dose of about 5.0 / IO7nMPCs per kilogram (kg) of weight of the subject.

124. The method of any one of claims 1-122, wherein the administering the nMPCs is at a dose of about 2. Ox 108nMPCs per kilogram (kg) of weight of the subject.

125. The method of any one of claims 1-122, wherein the administering the nMPCs is at a dose of about 2.5xl08nMPCs per kilogram (kg) of weight of the subject.

126. The method of any one of claims 1-122, wherein the administering the nMPCs is at a dose of about 0.7xl06nMPCs per kilogram (kg) of weight of the subject.

127. The method of any one of claims 1-122, wherein the administering the nMPCs is at a dose of about 1.43xl06nMPCs per kilogram (kg) of weight of the subject.

128. The method of any one of claims 1-122, wherein the administering the nMPCs is at a dose of about 2.85xl06nMPCs per kilogram (kg) of weight of the subject.

129. A composition comprising allogeneic, human nMPCs, wherein the nMPCs are (a) positive for protein expression of c-kit (CD117), Ki67, CD44, CD73, CD47, CD105, CD90, and / or Nkx2.5 and (b) negative for protein expression of CD34, CD45, CD31, PECAM-1, tryptase, GATA4, ISL1, SSEA3, and / or SSEA4.

130. The composition of claim 129, wherein the nMPCs are (a) positive for protein expression of c-kit (CD117), Ki67, CD44, CD74, CD47, CD105, CD90, andNkx2.5 and (b) negative for protein expression of CD34, CD45, CD31, PECAM-1, tryptase, GATA4, ISL1, SSEA3, and SSEA4.

131. The composition of claim 129 or 130, wherein the nMPCs are further positive for protein expression of PDL1, OCT3 / 4, NANOG, KLF4, and / or SOX2.WSGR Docket No. 64320-711.601132. The composition of any one of claims 129-131, wherein the nMPCs are further negative for protein expression of pl6INK4aup to at least passage 8.

133. The composition of any one of claims 129-132, wherein the composition further comprises conditioned medium or exosomes.

134. The composition of claim 133, wherein the composition further comprises conditioned medium and exosomes.

135. The composition of claim 133 or 134, wherein the conditioned medium or exosomes are positive for protein expression of HGF, SCF, SDF-la, ANG1, VEGFA, PDGFB, bFGF, HSP20, Akt, and / or HSF1.

136. The composition of any one of claims 133-135, wherein the conditioned medium or exosomes are negative for protein expression of IGF1.

137. The composition of any one of claims 133-136, wherein the nMPCs are genetically engineered.

138. The composition of claim 137, wherein the nMPCs are genetically engineered to overexpress one or more paracrine factors.

139. The composition of claim 137 or 138, wherein the nMPCs are genetically engineered to overexpress HGF, SCF, SDF-la, ANG1, VEGFA, PDGFB, bFGF, HSP20, or Akt.

140. The composition of claim 139, wherein the nMPCs are genetically engineered to overexpress HGF, SCF, SDF-la, ANG1, VEGFA, PDGFB, bFGF, HSP20, and Akt.

141. The composition of claim 139 or 140, wherein the nMPCs are genetically engineered to overexpress 1, 2, 3, 4, 5, 6, 7, 8, or 9 of HGF, SCF, SDF-la, ANG1, VEGFA, PDGFB, bFGF, HSP20, and Akt.

142. The composition of any one of claims 133-141, wherein the nMPC secretome or nMPC exosomes are positive for protein expression of one or more of the proteins in Table 5.

143. The composition of any one of claims 129-142, wherein the cells are obtained from a subject who is biologically a female.

144. The composition of any one of claims 129-142, wherein the cells are obtained from a subject who is biologically a male.

145. The composition of any one of claims 129-144, wherein the nMPCs are:(a) positive for protein expression of 1, 2, 3, 4, 5, 6, 7, or 8 of c-kit (CD117), Ki67, CD44, CD73, CD47, CD105, CD90, and Nkx2.5;(b) negative for protein expression of 1, 2, 3, 4, 5, 6, 7, 8, or 9 of CD34, CD45, CD31, PECAM-1, tryptase, GATA4, ISL1, SSEA3, and SSEA4;(c) positive for protein expression of 1, 2, 3, 4, or 5 of PDL1, OCT3 / 4, NANOG, KLF4, and SOX2; and / or(d) negative for protein expression of pl6INK4aup to at least passage 8.

146. The composition of any one of claims 129-144, wherein the nMPCs are:WSGR Docket No. 64320-711.601(a) positive for protein expression of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 of c-kit (CD117), Ki67, CD44, CD73, CD47, CD105, CD90, Nkx2.5, PDL1, OCT3 / 4, NANOG, KLF4, and SOX2; and(b) negative for protein expression of 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 of CD34, CD45, CD31, PECAM-1, tryptase, GATA4, ISL1, SSEA3, SSEA4, and pl6INK4a.

147. A composition comprising cryopreserved allogeneic, human nMPCs, wherein the cryopreserved allogeneic, human nMPCs are (a) positive for protein expression of c-kit (CD117), Ki67, CD44, CD73, CD47, CD105, CD90, and / or Nkx2.5 and (b) negative for protein expression of CD34, CD45, CD31, PECAM-1, tryptase, GATA4, ISL1, SSEA3, and / or SSEA4.

148. The composition of claim 147, wherein the cryopreserved allogeneic, human nMPCs are further positive for protein expression of PDL1, OCT3 / 4, NANOG, KLF4, and / or SOX2.

149. The composition of claim 147 or 148, wherein the cryopreserved allogeneic, human nMPCs are further negative for protein expression of pl6INK4aup to at least passage 8.

150. The composition of any one of claims 147-149, wherein the composition further comprises cryopreserved conditioned medium or exosomes.

151. The composition of claim 150, wherein the composition further comprises cryopreserved conditioned medium and cryopreserved exosomes.

152. The composition of any one of claims 147-151, wherein the nMPCs are:(a) positive for protein expression of 1, 2, 3, 4, 5, 6, 7, or 8 of c-kit (CD117), Ki67, CD44, CD73, CD47, CD105, CD90, andNkx2.5;(b) negative for protein expression of 1, 2, 3, 4, 5, 6, 7, 8, or 9 of CD34, CD45, CD31, PECAM-1, tryptase, GATA4, ISL1, SSEA3, and SSEA4;(c) positive for protein expression of 1, 2, 3, 4, or 5 of PDL1, OCT3 / 4, NANOG, KLF4, and SOX2; and / or(d) negative for protein expression of pl6INK4aup to at least passage 8.

153. The composition of any one of claims 147-152, wherein the nMPCs are:(a) positive for protein expression of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 of c-kit (CD117), CD44, CD73, CD47, Ki67, CD105, CD90, Nkx2.5, PDL1, OCT3 / 4, NANOG, KLF4, and SOX2; and(b) negative for protein expression of 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 of CD34, CD45, CD31, PECAM-1, tryptase, GATA4, ISL1, SSEA3, SSEA4, and pl6INK4a.

154. The composition of any one of claims 147-153, wherein the nMPCs do not express 42254.

155. A method of improving a stroke volume index (SVI) in a subject diagnosed with aHFpEF, DCM, or a kidney disease, comprising intravenously administering to the subject a composition comprising about 50*106, about 100*106, about 150xl06, or about 200xl06nMPCs, wherein the subject exhibits an improvement in SVI following treatment.

156. The method of claim 155, wherein the subject exhibits at least a 2% improvement in the SVI following treatment compared to baseline or compared to a placebo.WSGR Docket No. 64320-711.601157. The method of claim 155 or 156, wherein the SVI increases by at least about 2 mL / m2, at least about 2.5 mL / m2, at least about 3 mL / m2, about 3.5 mL / m2, at least about 4 mL / m2, at least about 4.5 mL / m2, at least about 5 mL / m2, at least about 5.5 mL / m2, at least about 6 mL / m2, at least about 6.5 mL / m2, at least about 7 mL / m2, at least about 7.5 mL / m2, at least about 8 mL / m2, at least about 8.5 mL / m2, at least about 9 mL / m2, at least about 9.5 mL / m2, or at least about 10 mL / m2following treatment compared to baseline.

158. The method of any one of claims 155-157, wherein the SVI increases by at least about 2 mL / m2following treatment compared to baseline.

159. The method of any one of claims 155-157, wherein the SVI increases by at least about 4 mL / m2following treatment compared to baseline.

160. The method of any one of claims 155-157, wherein the SVI increases by at least about 5 mL / m2following treatment compared to baseline.

161. The method of any one of claims 155-157, wherein the SVI increases by at least about 6 mL / m2following treatment compared to baseline.

162. The method of any one of claims 155-157, wherein the SVI increases by at least about 9 mL / m2following treatment compared to baseline.

163. A method of treating a subject diagnosed with a HFpEF, DCM, or a kidney disease, comprising intravenously administering to the subject a composition comprising about 50* 106, about 100* 106, about 150* 106, or about 200* 106nMPCs, wherein the subject exhibits an improvement in a 6-minute walk test (6MWT) following treatment.

164. The method of claim 163, wherein the subject exhibits at least a 2% improvement in the 6MWT following treatment compared to baseline or compared to a placebo.

165. The method of claim 163 or 164, wherein the 6MWT increases by at least about 2 meters, at least about 4 meters, at least about 6 meters, at least about 8 meters, at least about 9 meters, at least about 10 meters, at least about 12 meters, at least about 14 meters, at least about 16 meters, at least about 18 meters, at least about 20 meters, at least about 22 meters, at least about 24 meters, at least about 25 meters, at least about 26 meters, at least about 28 meters, at least about 30 meters, at least about 40 meters, or at least about 50 meters following treatment compared to baseline.

166. The method of any one of claims 163-165, wherein the 6MWT increases by at least about 2 meters following treatment compared to baseline.

167. The method of any one of claims 163-165, wherein the 6MWT increases by at least about 9 meters following treatment compared to baseline.

168. The method of any one of claims 163-165, wherein the 6MWT increases by at least about 16 meters following treatment compared to baseline.

169. The method of any one of claims 163-165, wherein the 6MWT increases by at least about 22 meters following treatment compared to baseline.

170. The method of any one of claims 163-165, wherein the 6MWT increases by at least about 25 meters following treatment compared to baseline.WSGR Docket No. 64320-711.601171. The method of any one of claims 163-165, wherein the 6MWT increases by at least about 50 meters following treatment compared to baseline.

172. A method of treating a subject diagnosed with a HFpEF, DCM, or a kidney disease, comprising intravenously administering to the subject a composition comprising about 50* 106, about 100* 106, about 150 / IO6, or about 200 / IO6nMPCs, wherein the subject exhibits an improvement as determined by a Kansas City Cardiomyopathy Questionnaire (KCCQ) following treatment.

173. The method of claim 172, wherein the subject exhibits at least a 2% improvement in the KCCQ following treatment compared to baseline or compared to a placebo.

174. The method of claim 172 or 173, wherein the KCCQ increases by at least about 3, at least about 4, at least about 5, at least about 6, at least about 7, at least about 8, at least about 9, at least about 10, at least about 11, at least about 12, at least about 13, at least about 14, at least about 15, at least about 16, at least about 17, at least about 18, at least about 19, at least about 20, at least about 21, at least about 22, at least about 23, at least about 24, at least about 25, or at least about 30 points following treatment compared to baseline.

175. The method of any one of claims 172-174, wherein the KCCQ increases by at least about 9 points following treatment compared to baseline.

176. The method of any one of claims 172-174, wherein the KCCQ increases by at least about 17 points following treatment compared to baseline.

177. The method of any one of claims 172-174, wherein the KCCQ increases by at least about 18 points following treatment compared to baseline.

178. The method of any one of claims 172-174, wherein the KCCQ increases by at least about 20 points following treatment compared to baseline.

179. The method of any one of claims 172-174, wherein the KCCQ increases by at least about 21 points following treatment compared to baseline.

180. The method of any one of claims 172-179, wherein the subject improves from a “good to fair health status” to a “good to excellent health status” as determined by the KCCQ following treatment compared to baseline.

181. A method of improving a left ventricular filling pressure or a diastolic dysfunction in a subject diagnosed with a HFpEF, DCM, or a kidney disease, comprising intravenously administering to the subject a composition comprising about 50 / 106, about lOOxlO6, about 150 / 106, or about 200 / 106nMPCs, wherein the subject exhibits an improvement in left ventricular filling pressure or diastolic dysfunction following treatment.

182. The method of claim 181, wherein the subject exhibits at least about a 2% improvement in the left ventricular filling pressure following treatment compared to baseline or compared to a placebo.

183. The method of claim 181 or 182, wherein the subject exhibits at least about a 2% improvement in the diastolic dysfunction following treatment compared to baseline or compared to a placebo.

184. The method of any one of claims 181-183, wherein an E / e’ mean of the subject improves from a diseased level (>13) to a non- diseased level (<13) following treatment compared to baseline.WSGR Docket No. 64320-711.601185. The method of any one of claims 181-184, wherein an E / e’ mean of the subject decreases by a score of at least about 0.5, at least about 0.75, at least about 1, at least about 1.25, at least about 1.5, at least about 1.75, at least about 2, at least about 2.25, at least about 2.5, at least about 2.75, at least about 3, at least about 3.25, at least about 3.5, at least about 3.75, at least about 4, at least about 4.5, or at least about 5 following treatment compared to baseline.

186. The method of any one of claims 181-185, wherein an E / e’ mean of the subject decreases by a score of at least about 0.5 following treatment compared to baseline.

187. The method of any one of claims 181-185, wherein an E / e’ mean of the subject decreases by a score of at least about 1 following treatment compared to baseline.

188. The method of any one of claims 181-185, wherein an E / e’ mean of the subject decreases by a score of at least about 1.5 following treatment compared to baseline.

189. The method of any one of claims 181-185, wherein an E / e’ mean of the subject decreases by a score of at least about 2 following treatment compared to baseline.

190. The method of any one of claims 181-185, wherein an E / e’ mean of the subject decreases by a score of at least about 2.25 following treatment compared to baseline.

191. The method of any one of claims 181-190, wherein an E / e’ mean of the subject decreases by at least about 2% following treatment compared to baseline.

192. A method of decreasing a level of a N-terminal pro-B-type natriuretic peptide (NT-proBNP) in a subject diagnosed with a HFpEF, DCM, or a kidney disease, comprising intravenously administering to the subject a composition comprising about 50*106, about 100*106, about 150*106, or about 200*106nMPCs, wherein the subject exhibits a decreased level of the NT-proBNP following treatment.

193. The method of claim 192, wherein the subject to be treated has an elevated level of NT-proBNP prior to treatment.

194. The method of claim 192 or 193, wherein the subject to be treated has a level of NT-proBNP of >240 pg / mL prior to treatment.

195. The method of any one of claims 192-194, wherein the subject to be treated has a level of NT-proBNP of <240 pg / mL following treatment.

196. The method of any one of claims 192-195, wherein the subject exhibits at least about a 2% decrease in the level of NT-proBNP following treatment compared to baseline.

197. The method of any one of claims 192-196, wherein the subject exhibits a decrease in the level of NT-proBNP of at least about 2 pg / mL, 4 pg / mL, 6 pg / mL, 8 pg / mL, 10 pg / mL, about 20 pg / mL, about 30 pg / mL, about 40 pg / mL, about 50 pg / mL, about 60 pg / mL, about 70 pg / mL, about 80 pg / mL, about 90 pg / mL, about 100 pg / mL, about 110 pg / mL, about 120 pg / mL, about 130 pg / mL, about 140 pg / mL, about 150 pg / mL, about 160 pg / mL, about 170 pg / mL, about 180 pg / mL, about 190 pg / mL, about 200 pg / mL, about 210 pg / mL, about 220 pg / mL, about 230 pg / mL, about 240 pg / mL, about 250 pg / mL, about 260 pg / mL, about 270 pg / mL, about 280 pg / mL, about 290 pg / mL, about 300 pg / mL, or more, following treatment compared to baseline.WSGR Docket No. 64320-711.601198. The method of any one of claims 192-197, wherein the subject exhibits a decrease in the level of NT- proBNP of at least about 2 pg / mL following treatment compared to baseline.

199. The method of any one of claims 192-197, wherein the subject exhibits a decrease in the level of NT- proBNP of at least about 10 pg / mL following treatment compared to baseline.

200. The method of any one of claims 192-197, wherein the subject exhibits a decrease in the level of NT- proBNP of at least about 12 pg / mL following treatment compared to baseline.

201. The method of any one of claims 192-197, wherein the subject exhibits a decrease in the level of NT-proBNP of at least about 20 pg / mL following treatment compared to baseline.

202. The method of any one of claims 192-197, wherein the subject exhibits a decrease in the level of NT-proBNP of at least about 30 pg / mL following treatment compared to baseline.

203. The method of any one of claims 192-197, wherein the subject exhibits a decrease in the level of NT-proBNP of at least about 40 pg / mL following treatment compared to baseline.

204. The method of any one of claims 192-197, wherein the subject exhibits a decrease in the level of NT-proBNP of at least about 50 pg / mL following treatment compared to baseline.

205. The method of any one of claims 192-204, wherein the subject exhibits a blood level of NT-proBNP of over about 125 pg / mL, about 150 pg / mL, about 175 pg / mL, about 200 mg / mL, about 225 pg / mL, about 250 pg / mL, or about 275 pg / mL prior to treatment.

206. The method of any one of claims 192-205, wherein the subject exhibits a blood level of NT-proBNP of at least about 10 pg / mL, about 20 pg / mL, about 30 pg / mL, about 40 pg / mL, about 50 pg / mL, about 60 pg / mL, about 70 pg / mL, about 80 pg / mL, about 90 pg / mL, about 100 pg / mL, about 110 pg / mL, about 120 pg / mL, about 130 pg / mL, about 140 pg / mL, about 150 pg / mL, about 160 pg / mL, about 170 pg / mL, about 180 pg / mL, about 190 pg / mL, about 200 pg / mL, about 210 pg / mL, about 220 pg / mL, about 230 pg / mL, about 240 pg / mL, about 250 pg / mL, about 260 pg / mL, about 270 pg / mL, about 280 pg / mL, about 290 pg / mL, about 300 pg / mL prior to treatment.

207. The method of any one of claims 192-206, wherein the subject exhibits a blood level of NT-proBNP of over about 250 pg / mL, about 300 pg / mL, about 400 pg / mL, about 500 pg / mL, about 600 pg / mL, about 700 pg / mL, about 800 pg / mL, about 900 pg / mL, or more prior to treatment.

208. A method of increasing an estimated glomerular filtration rate (eGFR) (mL / min / 1.73 m2) in a subject diagnosed with a HFpEF, DCM, or a kidney disease, comprising intravenously administering to the subject a composition comprising about 50*106, about 100*106, about 150*106, or about 200*106nMPCs, wherein the subject exhibits an increased eGFR following treatment.

209. The method of claim 208, wherein the subject to be treated has a reduced eGFR prior to treatment.

210. The method of claim 208 or 209, wherein the subject to be treated has an eGFR lower than about 89 mL / min / 1.73 m2, about 85 mL / min / 1.73 m2, about 80 mL / min / 1.73 m2, about 75 mL / min / 1.73 m2, about 70 mL / min / 1.73 m2, about 65 mL / min / L73 m2, about 60 mL / min / 1.73 m2, about 55 mL / min / 1.73 m2, about 50 mL / min / 1.73 m2, or about 45 mL / min / 1.73 m2prior to treatment.WSGR Docket No. 64320-711.601211. The method of any one of claims 208-210, wherein the subject to be treated has an eGFR lower than about 80 mL / min / 1.73 m2prior to treatment.

212. The method of any one of claims 208-210, wherein the subject to be treated has an eGFR lower than about 70 mL / min / 1.73 m2prior to treatment.

213. The method of any one of claims 208-210, wherein the subject to be treated has an eGFR lower than about 60 mL / min / 1.73 m2prior to treatment.

214. The method of any one of claims 208-213, wherein the subject exhibits at least about a 2% increase in an eGFR of at least about 0.5 mL / min / 1.73 m2, about 1 mL / min / 1.73 m2, about 1.5 mL / min / 1.73 m2, about 2 mL / min / 1.73 m2, about 2.5 mL / min / 1.73 m2, about 3 mL / min / 1.73 m2, about 3.5 mL / min / 1.73 m2, about 4 mL / min / 1.73 m2, about 4.5 mL / min / 1.73 m2, about 5 mL / min / 1.73 m2, about 5.5 mL / min / 1.73 m2, about 6 mL / min / 1.73 m2, about 6.5 mL / min / 1.73 m2, about 7 mL / min / 1.73 m2, about 7.5 mL / min / 1.73 m2, about 8 mL / min / 1.73 m2, about 8.5 mL / min / 1.73 m2, about 9 mL / min / 1.73 m2, about 9.5 mL / min / 1.73 m2, about 10 mL / min / 1.73 m2, about 11 mL / min / 1.73 m2, about 12 mL / min / 1.73 m2, about 13 mL / min / 1.73 m2, about 14 mL / min / 1.73 m2, about 15 mL / min / 1.73 m2, about 17.5 mL / min / 1.73 m2, or about 20 mL / min / 1.73 m2following treatment compared to baseline.

215. The method of any one of claims 208-214, wherein the subject exhibits an increase in an eGFR of at least about 0.5 mL / min / 1.73 m2following treatment compared to baseline.

216. The method of any one of claims 208-214, wherein the subject exhibits an increase in an eGFR of at least about 1 mL / min / 1.73 m2following treatment compared to baseline.

217. The method of any one of claims 208-214, wherein the subject exhibits an increase in an eGFR of at least about 4 mL / min / 1.73 m2following treatment compared to baseline.

218. The method of any one of claims 208-214, wherein the subject exhibits an increase in an eGFR of at least about 6 mL / min / 1.73 m2following treatment compared to baseline.

219. The method of any one of claims 208-214, wherein the subject exhibits an increase in an eGFR of at least about 8 mL / min / 1.73 m2following treatment compared to baseline.

220. The method of any one of claims 208-214, wherein the subject exhibits an increase in an eGFR of at least about 9 mL / min / 1.73 m2following treatment compared to baseline.

221. The method of any one of claims 208-214, wherein the subject exhibits an increase in an eGFR of at least about 10 mL / min / 1.73 m2following treatment compared to baseline.

222. The method of any one of claims 208-214, wherein the subject exhibits an increase in an eGFR of at least about 11 mL / min / 1.73 m2following treatment compared to baseline.

223. The method of any one of claims 208-214, wherein the subject exhibits an increase in an eGFR of at least about 12 mL / min / 1.73 m2following treatment compared to baseline.

224. The method of any one of claims 208-214, wherein the subject exhibits an increase in an eGFR of at least about 13 mL / min / 1.73 m2following treatment compared to baseline.

225. A method of reducing a level of C-reactive protein (CRP) (mg / L) in a subject diagnosed with a HFpEF, DCM, or a kidney disease, comprising intravenously administering to the subject a composition comprising about 50*106, about 100*106, about 150*106, or about 200*106nMPCs, wherein the subjectWSGR Docket No. 64320-711.601exhibits a decreased level of CRP as assessed by a high-sensitivity C-Reactive Protein (hs-CRP) blood test following treatment.

226. The method of claim 225, wherein the subject to be treated has an elevated level of CRP prior to treatment as assessed by a high-sensitivity C-Reactive Protein (hs-CRP) blood test.

227. The method of claim 225 or 226, wherein the subject to be treated has a CRP level greater than about 1.0 mg / L, about 1.5 mg / L, about 3.0 mg / L, about 5.0 mg / L, or about 10.0 mg / L prior to treatment.

228. The method of any one of claims 225-227, wherein the subject to be treated has a CRP level greater than about 1.0 mg / L prior to treatment.

229. The method of any one of claims 225-227, wherein the subject to be treated has a CRP level greater than about 1.5 mg / L prior to treatment.

230. The method of any one of claims 225-227, wherein the subject to be treated has a CRP level greater than about 2.0 mg / L prior to treatment.

231. The method of any one of claims 225-227, wherein the subject to be treated has a CRP level greater than about 2.5 mg / L prior to treatment.

232. The method of any one of claims 225-227, wherein the subject to be treated has a CRP level greater than about 3.0 mg / L prior to treatment.

233. The method of any one of claims 225-232, wherein the subject exhibits at least about a 2% decrease in CRP level of at least about 0.1 mg / L, about 0.2 mg / L, about 0.3 mg / L, about 0.4 mg / L, about 0.5 mg / L, about 0.75 mg / L, about 1.0 mg / L, about 1.5 mg / L, about 2.0 mg / L, about 2.5 mg / L, or about 3.0 mg / L following treatment compared to baseline.

234. The method of any one of claims 225-233, wherein the subject exhibits a decrease in CRP level of at least about 0.1 mg / L following treatment compared to baseline.

235. The method of any one of claims 225-233, wherein the subject exhibits a decrease in CRP level of at least about 0.2 mg / L following treatment compared to baseline.

236. The method of any one of claims 225-233, wherein the subject exhibits a decrease in CRP level of at least about 0.5 mg / L following treatment compared to baseline.

237. The method of any one of claims 225-233, wherein the subject exhibits a decrease in CRP level of at least about 1.0 mg / L following treatment compared to baseline.

238. The method of any one of claims 225-233, wherein the subject exhibits a decrease in CRP level of at least about 2.0 mg / L following treatment compared to baseline.

239. A method of increasing an end-diastolic volume index (EDVI) in a subject diagnosed with a HFpEF, DCM, or a kidney disease, comprising intravenously administering to the subject a composition comprising about 50*106, about 100*106, about 150*106, or about 200*106nMPCs, wherein the subject exhibits an increased EDVI following treatment.

240. The method of claim 239, wherein the subject to be treated has a low EDVI prior to treatment.

241. The method of claim 239 or 240, wherein the subject to be treated has an EDVI less about 60 mL / m2, about 55 mL / m2, about 50 mL / m2, about 45 mL / m2, about 40 mL / m2, about 35 mL / m2, or about 30 mL / m2prior to treatment.WSGR Docket No. 64320-711.601242. The method of any one of claims 239-241, wherein the subject to be treated has an EDVI less than about 60 mL / m2prior to treatment.

243. The method of any one of claims 239-241, wherein the subject to be treated has an EDVI less than about 50 mL / m2prior to treatment.

244. The method of any one of claims 239-241, wherein the subject to be treated has an EDVI less than about 40 mL / m2prior to treatment.

245. The method of any one of claims 239-241, wherein the subject to be treated has an EDVI less than about 30 mL / m2prior to treatment.

246. The method of any one of claims 239-245, wherein the subject exhibits at least about a 2% increase in EDVI of at least about 0.5 mL / m2, about 0.75 mL / m2, about 1.0 mL / m2, about 1.25 mL / m2, about 1.5 mL / m2, about 1.75 mL / m2, about 2.0 mL / m2, about 2.25 mL / m2, about 2.5 mL / m2, about 2.75 mL / m2, about 3.0 mL / m2, about 3.25 mL / m2, about 3.5 mL / m2, about 3.75 mL / m2, about 4.0 mL / m2, about 4.25 mL / m2, about 4.5 mL / m2, about 4.75 mL / m2, about 5.0 mL / m2, about 5.25 mL / m2, about 5.5 mL / m2, about 5.75 mL / m2, about 6.0 mL / m2, about 6.25 mL / m2, about 6.5 mL / m2, about 6.75 mL / m2, about 7.0 mL / m2, about 7.25 mL / m2, about 7.5 mL / m2, about 7.75 mL / m2, about 8.0 mL / m2, about 8.25 mL / m2, about 8.5 mL / m2, about 8.75 mL / m2, about 9.0 mL / m2, about 9.25 mL / m2, about 9.5 mL / m2, about 9.75 mL / m2, or about 10.0 mL / m2following treatment compared to baseline.

247. The method of any one of claims 239-246, wherein the subject exhibits an increase in EDVI of at least about 2.0 mL / m2following treatment compared to baseline.

248. The method of any one of claims 239-246, wherein the subject exhibits an increase in EDVI of at least about 3.0 mL / m2following treatment compared to baseline.

249. The method of any one of claims 239-246, wherein the subject exhibits an increase in EDVI of at least about 4.0 mL / m2following treatment compared to baseline.

250. The method of any one of claims 239-246, wherein the subject exhibits an increase in EDVI of at least about 5.0 mL / m2following treatment compared to baseline.

251. The method of any one of claims 155-250, wherein the subject is administered the nMPCs once about every 28±3 days or about every 6 weeks±3 days.

252. The method of any one of claims 155-250, wherein, the subject is administered the nMPCs once about every 30±3 days.

253. The method of any one of claims 155-252, wherein the subject is administered the nMPCs at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 times or more.

254. The method of any one of claims 155-253, wherein the subject is administered about 50* 106nMPCs per dose.

255. The method of any one of claims 155-253, wherein the subject is administered about 100*106nMPCs per dose.

256. The method of any one of claims 155-253, wherein the subject is administered about 150*106nMPCs per dose.WSGR Docket No. 64320-711.601257. The method of any one of claims 155-253, wherein the subject is administered about 200xl06nMPCs per dose.

258. The method of any one of claims 155-257, wherein the subject exhibits an improvement for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23 months (or more) following treatment.

259. The method of any one of claims 155-257, wherein the subject exhibits an improvement for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23 years (or more) following treatment.

260. The method of any one of claims 155-259, wherein, when the subject exhibits a reduction in improvement, a slowing of improvement, or a worsening of at least a symptom of HFpEF, DCM, or a kidney disease, following treatment, the subject is administered at least one more doses of the nMPCs.

261. The method of any one of claims 155-260, wherein the administering the nMPCs is at a dose of about 5.0 / IO7nMPCs per kilogram (kg) of weight of the subject.

262. The method of any one of claims 155-260, wherein the administering the nMPCs is at a dose of about 2. Ox 108nMPCs per kilogram (kg) of weight of the subject.

263. The method of any one of claims 155-260, wherein the administering the nMPCs is at a dose of about 2.5xl08nMPCs per kilogram (kg) of weight of the subject.

264. The method of any one of claims 155-260, wherein the administering the nMPCs is at a dose of about 0.7xl06nMPCs per kilogram (kg) of weight of the subject.

265. The method of any one of claims 155-260, wherein the administering the nMPCs is at a dose of about 1.43xl06nMPCs per kilogram (kg) of weight of the subject.

266. The method of any one of claims 155-260, wherein the administering the nMPCs is at a dose of about 2.85xl06nMPCs per kilogram (kg) of weight of the subject.

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