Extracellular vesicle compositions for treating lumbar facet joint syndrome

Abstract

A method for treating lumbar facet joint syndrome by applying a combination of extracellular vesicles and proteins.

Description

[0001] Cross-referencing This application claims the benefit of U.S. Provisional Patent Application No. 63 / 596,900, filed November 7, 2023, and U.S. Provisional Patent Application No. 63 / 712,038, filed October 25, 2024, each of which is incorporated herein by reference in its entirety. Background Technology

[0002] Low back pain is one of the most common musculoskeletal complaints worldwide. Based on the criteria of the International Association for the Study of Pain, the lumbar facet joints are recognized as the source of persistent low back pain in 15%–45% of patients with chronic low back pain. Pain associated with the lumbar facet joints can occur due to trauma, spinal strain, poor biomechanics, and age-related disc degeneration. Over time, irritation of the facet joints (also known as facet joints) leads to inflammation and pain. Existing treatments for low back pain involving the lumbar facet joints include initial conservative treatments such as physical therapy, chiropractic, acupuncture, manual therapy, and NSAIDs. Therapeutic injections (such as intra-articular injections, medial branch nerve blocks consisting of steroids and local anesthetics) and radiofrequency ablation are also commonly used, but usually produce limited long-term relief.

[0003] Lumbar facet joint syndrome is characterized by moderate to severe low back pain causing significant functional deficits. Injections, including autologous platelet-rich plasma (PRP) injections, radiofrequency denervation, and steroid injections, are long-term treatment interventions for lumbar facet joint syndrome. However, studies have shown that these therapies offer only short- to medium-term benefits. Some existing injections are associated with multiple health risks, such as steroid injections, which can increase blood sugar levels, decrease bone mineral density, and increase the risk of vertebral fractures. PRP injections are also accompanied by a range of problems, including increased inflammation due to cell death, and issues with cell count and donor viability. Therefore, exploring new injectable treatments is crucial. Summary of the Invention

[0004] In some respects, this article provides a method for treating lumbar facet joint syndrome in a subject in need, the method comprising administering to the subject a composition comprising one or more extracellular vesicles (EVs); wherein at least 80% of the EVs are CD63+, CD9-, or CD81-.

[0005] In some respects, this document provides a method for treating lumbar facet joint syndrome in a subject of need, the method comprising administering to the subject a composition comprising one or more extracellular vesicles (EVs); wherein the one or more EVs comprise hsa-miR-125b-5p, hsa-miR-145-5p, hsa-miR-191-5p, hsa-miR-199a-3p, hsa-miR-21-5p, hsa-miR-221-3p, hsa-miR-222-3p, hsa-mi The miRNA sequences are R-22-3p, hsa-miR-23a-3p, hsa-miR-23b-3p, hsa-miR-27a-3p, hsa-miR-27b-3p, hsa-miR-29a-3p, hsa-miR-29c-3p, hsa-miR-31-5p, hsa-miR-320a, hsa-miR-34a-5p, hsa-miR-423-3p, hsa-miR-424-5p, or hsa-miR-940, or combinations of two or more thereof. The miRNA sequences are available at https: / / www.mirbase.org / .

[0006] In some respects, this article provides a method for treating lumbar facet joint syndrome in subjects of need, the method comprising administering to the subject a composition comprising ferritin, IGFBP-4 (insulin-like growth factor binding protein-4), IL-1 R6 (interleukin-1 receptor 6), LAMP2 (lysosome-associated membrane glycoprotein 2), bIG-H3 (transforming growth factor-β-inducible protein ig-h3), GPR115 (adhesion G protein-coupled receptor F4), CD63 antigen, CD109 antigen, serine protease inhibitor F1 (Serpin F1) (pigment epithelium-derived factor), IGFBP-6 (insulin-like growth factor binding protein-6), HS3ST4 (heparin sulfate glucosamine 3-O-sulfotransferase 4), OPN (osteopontin), PAI-1 (plasminogen activator inhibitor-1 or SERPINE 1), cathepsin B, IGFBP-2 (insulin-like growth factor binding protein-2), and semaphorin 6C. 6C), IGF-2 (insulin-like growth factor-2), Sortilin, serine protease inhibitor B6, Dkk-3 (Dickkopf-related protein 3), CNTF (ciliary neurotrophic factor), TSP-1 (platelet-reactive protein 1), GM-CSF Ra (granulocyte-macrophage colony-stimulating factor receptor subunit α), coagulation regulatory protein, endoglycan, podocalyxin-like protein 2, IGFBP-3 (insulin-like binding protein-3), RGM-C (hepcidin regulatory protein), PF4 (platelet factor 4), MIF (macrophage migration inhibitory factor), TGM4 (protein glutamine-γ-glutamyl transferase 4), periostin, furin, TIMP -1 (MMP tissue inhibitor 1), Decorin, PCK1 (cytosol-type phosphoenolpyruvate carboxykinase), CD9 antigen, CD99 antigen, CA2 (carbonic anhydrase 2), PRDX4 (peroxidase-4), transferrin, DcR3 (tumor necrosis factor receptor superfamily member 6B), GP73 (Golgi membrane protein 1), CD81 antigen, Lumican, or TIMP-2 (MMP tissue inhibitor 2), or a combination of two or more thereof.

[0007] In some implementations, the one or more EVs include hsa-miR-125b-5p, hsa-miR-145-5p, hsa-miR-191-5p, hsa-miR-199a-3p, hsa-miR-21-5p, hsa-miR-221-3p, hsa-miR-222-3p, hsa-miR-22-3p, hsa-miR-23a-3p, hsa-miR- 23b-3p, hsa-miR-27a-3p, hsa-miR-27b-3p, hsa-miR-29a-3p, hsa-miR-29c-3p, hsa-miR-31-5p, hsa-miR-320a, hsa-miR-34a-5p, hsa-miR-423-3p, hsa-miR-424-5p or hsa-miR-940, or a combination of two or more thereof.In some embodiments, the composition comprises ferritin, IGFBP-4 (insulin-like growth factor binding protein-4), IL-1 R6 (interleukin-1 receptor 6), LAMP2 (lysosome-associated membrane glycoprotein 2), bIG-H3 (transforming growth factor-β-inducible protein ig-h3), GPR115 (adhesion G protein-coupled receptor F4), CD63 antigen, CD109 antigen, serine protease inhibitor F1 (pigment epithelial-derived factor), IGFBP-6 (insulin-like growth factor binding protein-6), HS3ST4 (heparanol sulfate glucosamine 3-O-sulfotransferase 4), OPN (osteopontin), and PAI-1 (plasminogen activator inhibitor-1 or sERPINE). 1) Cathepsin B, IGFBP-2 (insulin-like growth factor binding protein-2), brain signaling protein 6C, IGF-2 (insulin-like growth factor-2), sorting protein, serine protease inhibitor B6, Dkk-3 (Dickkopf-related protein 3), CNTF (ciliary neurotrophic factor), TSP-1 (thromboretin-1), GM-CSF Ra (granulocyte-macrophage colony-stimulating factor receptor subunit α), coagulation regulatory protein, endosaccharide, (podocyte protein-like protein 2) IGFBP-3 (insulin-like binding protein-3), RGM-C (hepcidin regulatory protein), PF4 (platelet factor 4), MIF (macrophage migration inhibitory factor), TGM4 (protein glutamine gamma-glutamyl transferase 4), periosteal protein, furin protease, TIMP-1 (MMP tissue inhibitor 1), gypsum proteoglycan, PCK1 (cytosol-type phosphoenolpyruvate carboxykinase), CD9 antigen, CD99 antigen, CA2 (carbonic anhydrase 2), PRDX4 (peroxide reductase-4), transferrin, DcR3 (tumor necrosis factor receptor superfamily member 6B), GP73 (Golgi membrane protein 1), CD81 antigen, luminescent proteoglycan, or TIMP-2 (MMP tissue inhibitor 2), or a combination of two or more thereof.

[0008] In some embodiments, the subject suffers from chronic pain. In some embodiments, the subject suffers from back pain. In some embodiments, the subject suffers from chronic low back pain. In some embodiments, the chronic low back pain causes functional impairment. In some embodiments, the subject suffers from lumbar facet joint degeneration. In some embodiments, the subject has undergone imaging examinations and / or diagnostic nerve blocks to confirm lumbar facet joint syndrome. In some embodiments, the subject experiences improvement after treatment in one or more of the following symptoms: pain, stiffness, range of motion, posture, general health, mood, social interaction, sleep, and / or walking ability, or combinations thereof.

[0009] In some implementations, administration includes intravenous administration.

[0010] In some embodiments, the composition is prepared by a method comprising the steps of: (a) culturing bone marrow mesenchymal stem cells (BM-MSCs) under the following conditions to produce MSC conditioned medium: (i) an oxygen partial pressure below 5%; and (ii) a medium with a pH below 7; (b) harvesting the MSC conditioned medium; and (c) preparing the MSC conditioned medium to produce the composition. In some embodiments, the method comprises preparing the composition prior to administration, wherein the preparation of the composition is performed by a method comprising the steps of: (a) culturing bone marrow mesenchymal stem cells (BM-MSCs) under the following conditions to produce MSC conditioned medium: (i) an oxygen partial pressure below 5%; and (ii) a medium with a pH below 7; (b) harvesting the MSC conditioned medium; and (c) preparing the MSC conditioned medium to produce the composition. In some embodiments, the medium is serum-free. In some embodiments, the medium has a glucose concentration below 4.5 g / L. In some embodiments, preparing the MSC conditioned medium comprises replacing the conditioned medium with a pharmaceutically acceptable formulation. In some embodiments, the pharmaceutically acceptable formulation comprises saline. In some embodiments, the composition contains at least 6 × 10 10 Up to 8 × 10 10 One extracellular vesicle per mL, and administered at doses of 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 mL.

[0011] Disclosed is a method for treating lumbar facet joint syndrome by administering an extracellular vesicle composition derived from bone marrow mesenchymal stem cells. One aspect of this disclosure is a method for treating a subject with lumbar facet joint syndrome, the method comprising administering to the subject a composition comprising a therapeutic mesenchymal stem cell (MSC) secretome composition prepared by a method comprising the steps of: (a) culturing bone marrow-derived MSCs under the following conditions to produce an MSC conditioned medium: (i) an oxygen partial pressure below 5%; and (ii) a medium with a pH below 7; (b) harvesting the MSC conditioned medium; and (c) formulating the MSC conditioned medium to produce the therapeutic MSC secretome composition, wherein the therapeutic MSC secretome composition comprises proteins and extracellular vesicles produced by the bone marrow-derived MSCs in step (a). In some embodiments, the subject suffers from chronic pain. In some embodiments, the subject suffers from back pain. In some embodiments, the subject suffers from chronic low back pain. In some embodiments, the chronic low back pain causes functional impairment. In some embodiments, the subject suffers from lumbar facet joint degeneration. In some embodiments, the subject has undergone imaging examinations and / or diagnostic nerve blocks to confirm lumbar facet joint syndrome. In some embodiments, the subject experiences improvement in one or more of the following symptoms after treatment: pain, stiffness, range of motion, posture, general health, mood, social interaction, sleep, and / or walking ability, or combinations thereof. In some embodiments, the therapeutic MSC secretome composition is administered to the subject at a dose of 60-80 billion extracellular vesicles / mL. In some embodiments, the culture medium is serum-free. In some embodiments, the culture medium has a glucose concentration of less than 4.5 g / L. In some embodiments, at least 80% of the extracellular vesicles in the therapeutic MSC secretome composition are CD63+CD9-CD81-. In some embodiments, the therapeutic MSC secretome composition comprises one or more of the following proteins: ferritin, NUP85, LAMP2, GPR115, serine protease inhibitor F1, OPN, PAI-1, DAPP1, cathepsin B, brain signaling protein 6C, PDGF Rα, sorting protein, serine protease inhibitor B6, Dkk-3, coagulation regulatory protein, PF4, MIF, periostealin, furin, TIMP-1, tectonic proteoglycan, PCK1, CD99, CD63, CD9, CD81, transferrin, DcR3, photoglucan, TIMP-2, SLITRK5, FAP, leptospirin, DPPII, cIAP-1, pentameric protein 3, lactone, enkephalin, albumin, galactolectin-1, UNC5H3, IL-20 Rβ, SREC-II, JAM-C, TNFRI.htPAPP-A, eNOS, MSP R, TPP1, LAMP1, B2M, NCAM-1, HIF-1 α, ST6GAL1, CD99-L2, convolutional protein A4, EMMPRIN, p53, brain signaling protein 7A, NKp80, cysteine ​​protease protein B, osteoadherin, midkine, calreticulin, osteoactivin, leguminase, TAZ, cathepsin L, RBP4, serine protease inhibitor A4, JAM-A, MCSF, LIMPII, OPG, IL-22, galectin-3, MOG, trypsin 3, SIRP α, syndecan-4, IGFBP-4, IL-1 R6 GSTM1, NUP85, LAMP2, Meprin A (membrane-penetrating peptidase), IL-1 F10, bIG-H3, GPR115, TGFb1, Ephrin-A4, CD109, Serine protease inhibitor F1, IGFBP-6, HS3ST4, LRAP, OPN, PAI-1, DAPP1, GDF-9, cathepsin B, IGFBP-2, brain signaling protein 6C, IGF-2, PDGF Rα, sorting protein, Serine protease inhibitor B6, Dkk-3, CNTF, TSP-1, GM-CSF Ra, coagulation regulatory protein, endosaccharides, IGFBP-3, RGM-C, PF4, MIF, TGM4, periosteal protein, furin, TIMP-1, PAPP-A, gliadin proteoglycan, PCK1, arylsulfatase A, CD99, CA2, PRDX4, transferrin, DcR3, GP73, LAIR2, ULBP-4, photoglucan, TIMP-2, TFPI, SOX2, SLITRK5, FAP, spinesin, ENPP-2, CD97, CTACK, integrin α1, EXTL3, IL-18 BPa, PD-L2, PSMA, IL-20 Ra, glyoxalase II, trypsin I, IGF-2R, ADAMTSL-1, erythropoietin, plexin D1 D1), DNMT3A, BCL-2, CL-P1, liver glycoside-B3, FABP6, CHI3L1, FCRLS, TFF3, sphingomyelin, DPPII, cIAP-1, PDGF Rb, pentraxin 3, angiotensinogen.Follicle-stimulating hormone (FSH), CF VII, Persephin, TRAIL R1, THAP11, CD200, CLEC-2, AMIGO, IGFBP-5, PON1, SOX7, GALNT10, Visfatin, Progranulin, PCSK2, GKN1, IL-18, Neprilysin, Stabilin-2, IL-17 RD, Albumin, Follicle-stimulating hormone-like protein 1, MMP-10, FKBP51, LRRC4, Pref-1, Galactoglobin-1, Troponin C, UNC5H3, FLRT2, CD314, Brain signaling protein 6B, Netrin-4, CD27 ligand, IL-20 R β, brain signaling protein 6A, TSK, cytokeratin-8, CHST3, Mcl-1, DPPIV, SREC-II, Norrin, JAM-C, Bcl-10, Wnt-4, LSECtin, Kell, TNF RI, PTP1B, htPAPP-A, IDO, PDGF-CC, Galanin, Activin A, TLR2, SCCA2, FABP1, eNOS, SHP-1, ICOS, C1qTNF9, MMP-1, TC-PTP, IL-24, gp130, C-myc, LILRB4, BMP-2, MIA, CD34, CD63, CD9, CD81, IFNab R2, phosphatidylinositol proteoglycan 2, MSP R, DSCAM, membrane serine protease (Matriptase), KIR2DL3, CD30, siglec-10, CLEC-1, TPP1, ubiquitin+1, ANGPTL4, TWEAK R, nestin-1 (Nidogen-1), CD2, kallikrein 1, TSLP R, LAMP1, TROY, VCAM-1, siglec-11, S100A1, PAR1, thyroid peroxidase, aminopeptidase P2, IL-1 RI, ADAMS, OSM R β, thrombospondin-2, SMPD1, B2M, MFRP, LRP-6, ST3GAL1, NCAM-1 (CD56), Granulase B, Adiponectin, IL-22BP, TPST2, PD-ECGF, LH, LEDGF, Cyr61, ULBP-3, IFNb, THSD1, FGF-23, LAMA4Adipsin, AIF, SorCS2, SULT2A1, CD39L2, Insulin R, HIF-1 α, OX40 ligand, Pax3, UCH-L3, cMASP3, Langerin, Desmin, SOX9, ST6GAL1, MEP1B, CD99-L2, PlexinA4, Brain signaling protein 4D, ROBO2, PDX-1, APRIL, Neuroturin, Kremen-2 (a transmembrane protein with a ring structure), EMMPRIN, activator protein RIB, Neuroligin 2, Epithelial regulatory protein, CASA, MMP-12, GALNT2, CEACAM-5, VEGF R1, DSPG3, SorCS1, Matrix protein-2 (Matrilin-2), sFRP-3, p53, EphB3, NCK1, Brain signaling protein 7A, NKp80, Prolactin, Cysteine ​​protease protein B, Sirtuin 1, FGF-16, FGF R5, NQO-1, Brain signaling protein 6D, FGF-3, GATA-4, VAP-A, CHST2, Pregnancy-associated plasma protein-2 (Pappalysin-2), Syndecan-3, Jagged 1, AKR1C4, Olfactomedin-2, Osteoadhesion, NKp44, Thyroglobulin, IL-21R, Chemerin, EphA1, CD48, MICB, FGF-5, TRANCE, CES2, ULBP-1, Integrin α 5. VAMP-2, FLRG, Ret metaphase factor, CD73, TRAP, proGRP, granzyme H, PRX2, p2'7, salivary lectin-6, dendritic cell-associated C-type lectin-1, CD51, Notch-1, calreticulin, DR3, DCTN1, CDC25B, bone activator, ACE, CA125, HAO-1, ​​PSMA1, FCRLB, BMP-9, CRIM1, LIF, SPINK1, EphB6, RGM-B, HS3ST1, ROR1, CMG-2, 4-1BB ligand, L1CAM-2, p63, cathepsin V, testosterone-2, phosphatidylinositol proteoglycan 5, CD6, salivary lectin-2, asparagine endopeptidase, PRELP, CES1, TAZ, NSE, TECK, HTRA2, HIF-1 β, TAFA1, podocalyxin, RalA, CRELD2, GRAP2, SP-D, BID, GFR α-2, Notch-3, VEGF R3, DLL4, TGFb2, LIGHT,XIAP, ST8SIA1, cathepsin L, 6-Ckine, MIS RII, kallikrein 5, TGM3, FCAR, contactin-2, CD83, IL-1 R3, SALM4, GBA3, ROBO4, OSCAR, VEGF, IGSF3, disaccharide proteoglycan, neurodevelopmental glycosaminoglycan, ILT4, uPAR, Axl, WIF-1, IL-7 Rα, GPR56, CEACAM-3, MCEMP1, FABP2, plexin B3, MEPE, activator RIIA, ANG-2, Cochlin, presenilin 1, NPTXR, SLAM, COMT, SPHK1, RBP4, stalkin-1 (Nectin-1), GUSB, nestin-2 (Nidogen-2), IL-17F, SR-AI, TAFA2, N-cadherin, IL-17B, IL-17 RC, MIP-3b, Cysteine ​​protease protein C, Cysteine ​​protease protein D, AMSH, FcERI, CLEC10A, HGF R, ANG-1, Prolactin R, FGF-20, CD28, Nogo-A, HSD17B1, IL-19, Intestinal peptidase, Cathepsin E, TSLP, TCN2, GDF-15, Epimorphin, GRKS, PD-1, Serine protease inhibitor A4, ADAM23, NOV, Galectin-2, Neuron surface protein 3 beta, TLR3, Sirtuin 2, Numb, IL-28 Rα, IL-33, Lin28, FCRL1, KLF4, NKp30, lymphocyte chemokines, cysteine ​​protease protein SN, JAM-A, calreticulin-2, ErbB4, BMP-8, IL-27 Ra, Fas, IL-4 Ra, kallikrein 14, extracellular matrix protein-3 (Matrilin-3), Olig2, kallikrein 12, CA13, IL-9, stalkin-3, MPIF-1, cysteine ​​protease protein S, ADA, IL-2 Rb, GFR α-1, Smad4, ICAM-1, MEF2C, TREM-1, L-selectin, transmembrane serine protease (Hepsin), CD42b, MCSF, RANK, CHST4, CA8, FCRL3, ASAH2, CF XIV, PYY, HGF, I-TAC, brain signaling protein 4C, SorCS3, Tie-1, IL-31 RA, Arginase 1, POGLUT1, IL-1ra, Podoplanin, TIM-3, CREG, CD300f, uPA, EphA2LRRTM4, LIMPII, Tenascin R, CPE, PECAM-1, DNAM-1, DKK-1, OPG, CPB1, TSH, MMP-2, Salivary lectin-9, ICAM-3, Cysteine ​​protease inhibitor SA, Galactohemagglutinin-4, Pepsinogen II, Desmoglein-3, Stalkin-4, SCF, Serine protease inhibitor A5, PTH, FGF-19, MSP, IL-28A, FGF-12, METAP2, ASAHL, EDIL3, NTAL, EGF R, TAFAS, Galactohemagglutinin-9, vWF-A2, TACE, Activator protein RIM, Cathepsin S, LDL R, BMPR-IA, OX40, IL-13 R2, B7-H4, MMP-13, ANGPTL7, TRAIL R4, IGS F4B, Sirtuin 5, PEAR1, SH2D1A, Cerberus 1, GDF-11, Nrf2, TROP-2, NUDTS, ROR2, EphB4, phosphatidylinositol proteoglycan 1, LAP (TGFb1), Gash, contactin-1, IL-27, UNC5H4, ICAM-2, MBL, HS3ST3B1, RCOR1, IL-10, Rb, XEDAR, IL-22, PILR-α, NRG1-131, FABP4, RGM-A, RELT, TrkC, CSa, SREC-I, neural epithelial stem cell protein, TPO, ErbB3, Kirrel3, FLRT1, galactolectin-3, CXCL16, JAM-B, DR6, Nogo receptor, TLR4, VEGFR2, Tie-2, IL-15 R, Caspr2, LTbR, LAMP, ALCAM, GLP-1, NG2, IL-22, Rα1, AMIGO2, HCC-1, TFPI-2, ULBP-2, desmosome core protein 2, agglutinin, synaptic fusion protein 4, VAMP-1, stalkin-2, FGF-21, Flt-3, GFAP, TIM-1, inhibin A, cadherin-4, PIGF-2, neurogranulin, HE4, IL-23, galactolectin-7, GALNT3, GITR L, CD14, R-spondin 2, CK19, cardiotrophin-1, TREML1, HAPLN1, CD27, ANG-4, salivary lectin-7, CD155, VEGF-C, TNF-α, PGRP-S, SDF-1a, PDGF-AB, GPVI, CD40, SCF R, thromboretin-5, IL-1, RIINeurofeline-2, cadherin-13, E-selectin, GITR, WISP-1, renin, AgRP, MDL-1, ROBO3, RANTES, Endocan, Granulin, hCGb, Mesothelin, TLR1, TRAIL, MOG, DDR1, NGF R, TRAIL R3, Trypsin 3, ARSB, LIF Rα, BAFF R, CD157, Granase A, 2B4, ESAM, IL-1 R4, CXCL14, IL-31, SIRP α, Uromodulin, CTRC, CEACAM-1, TARC, MIP-3a, SDF-1b, NKp46, MCP-3, IL-32 α, TGFb3 FOLR2, CD58, IL-23, CD36, TNFb, Shh-N, Ficolin-1, Reg4, ILT2, Mer, TREM-2, Flt-3L, CDS, IL-6, CD229, Insulin, Synaptic Fusion Protein 6, GRO, Bcl-w, Lipocalin-2, PDGF-AA, IL-2 Ra, Angiogenin, LYVE-1, CD4, RAGE, CDNF, Brevican, NAP-2, PU.1, EDAR, ADAMTS13, Kynureninase, PTH1R, IFN-γ R1, CrkL, B7-1, PARC, Draxin, VE-cadherin, Procalcitonin, SOX15, Kallikrein 11) BCMA, Dendritic Cell-Associated C-Lectin-2 (Dectin-2), EpCAM, HCC-4, TGFa, IP-10, BLAME, CILP-1, PIGF, LOX-1, MCP-2, Resistin, HVEM, ENPP-7, Cohesin-4, IL-2 Rg, MICA, dopa decarboxylase, NPDC-1, MCP-4, EG-VEGF, glycoprotein V, brain signaling protein 4G, IL-12p40, total PSA, IL-15, MAP1D, C1q, TNF4, Dtk, endothelial glycoprotein, ENA-78, Reg3A, MIP-1b, FGF-17, IL-6R, IL-8, galactolectin-8, CA4, cysteine ​​protease protein EM, FUT8, B7-H3, GCP-2, CD40L, MDC, 4-1BB, HO-1, SOST, S100A13Kallikrein 7 or IL-13. In some embodiments, the therapeutic MSC secretome composition comprises one or more of the following nucleic acids: hsa-let-7a-5p, hsa-let-7b-5p, hsa-let-7c-5p, hsa-let-7d-3p, hsa-let-7e-5p, hsa-let-7g-5p, hsa-let-7i, hsa-let-7i-5p, hsa-miR-100-5p, hsa-miR-103a-3p, hsa-miR-106a-5p, hsa-miR-106b-5p, hsa-mir-10b, hsa-miR-10b- 5p, hsa-mir-1246, hsa-miR-1246, hsa-miR-125a-5p, hsa-miR-125b-5p, hsa-miR-130a-3p, hsa-mir-130b, hsa-miR-130b-3p, hsa-miR-132 -3p, hsa-miR-136-5p, hsa-miR-138-5p, hsa-miR-139-5p, hsa-mir-140, hsa-miR-140-3p, hsa-miR-145-5p, hsa-mir-146a, hsa-miR-146a- 5p, hsa-miR-148a-3p, hsa-miR-152-3p, hsa-miR-15a-5p, hsa-miR-15b-5p, hsa-mir-16-1, hsa-mir-16-2, hsa-miR-16-5p, hsa-miR-1'7-5p, hsa-miR-1 81a-5p, hsa-miR-191-5p, hsa-miR-193a-5p, hsa-miR-193b-3p, hsa-miR-19'7-3p, hsa-miR-199a-3p, hsa-miR-199a-5p, hsa-miR-199b-5p, hsa-miR-19 a-3p, hsa-miR-19b-3p, hsa-miR-20a-5p, hsa-mir-203a, hsa-miR-203a-3p, hsa-miR-214-3p, hsa-mir-21, hsa-miR-21-3p, hsa-miR-21-5p, hsa-mir-22 1. hsa-miR-221-3p, hsa-mir-222, hsa-miR-222-3p, hsa-miR-22-3p, hsa-miR-23a-3p, hsa-miR-23b-3p, hsa-mir-24-1, hsa-mir-24-2, hsa-miR-24-3p,hsa-mir-25, hsa-miR-25-3p, hsa-miR-26a-5p, hsa-miR-27a-3p, hsa-mir-27b, hsa-miR-27b-3p, hsa-miR-29a-3p, hsa-miR-29c-3p, hsa-miR-30a-5p, hsa-miR-30a-5p, hsa-miR-30b-5p, hsa-miR-30c-5p, hsa-mir-30d, hsa-miR-30d-5p, hsa-mir-30e, hsa-miR-30e-5p, hsa-miR-31-3p, hsa-miR-31-5p, hsa-miR-320a, hsa-miR-342-3p, hsa-miR-345-5p, hsa-miR-34a-5p, hsa-miR-361-5p, hsa-miR-376a-3p, hsa-miR-376c-3p, hsa-miR-423-3p, hsa-miR-423-5p, hsa-miR-424-5p, hsa-miR-484, hsa-mir-486-1, hsa-mir-486-2, hsa-miR-486-5p, hsa-miR-570-3p, hsa-miR-574-3p, hsa-miR-663a, hsa-miR-874-3p, hsa-mir-92a-1, hsa-mir-92a-2, hsa-miR-92a-3p, hsa-miR-92b-3p, hsa-mir-93, hsa-miR-93-5p, hsa-miR-940, hsa-miR-99a-5p or hsa-miR-99b-5p.

[0012] One aspect of this disclosure is a method for treating lumbar facet joint syndrome in a subject, the method comprising administering to the subject a composition comprising a therapeutic MSC secretome composition containing extracellular vesicles, wherein at least 80% of the extracellular vesicles in the therapeutic MSC secretome composition are CD63+CD9-CD81-. In some embodiments, the therapeutic MSC secretome composition further comprises one or more of the following proteins: ferritin, NUP85, LAMP2, GPR115, serine protease inhibitor F1, OPN, PAI-1, DAPP1, cathepsin B, brain signaling protein 6C, PDGF Rα, sorting protein, serine protease inhibitor B6, Dkk-3, coagulation regulatory protein, PF4, MIF, periosteal protein, furin, TIMP-1, tectonic proteoglycan, PCK1, CD99, CD63, CD9, CD81, transferrin, DcR3, photoglucan, TIMP-2, SLITRK5, FAP, leptospirin, DPPII, cIAP-1, pentameric protein 3, lactone, enkephalin, albumin, galactolectin-1, UNC5H3, IL-20 Rβ, SREC-II, JAM-C, TNF. RI, htPAPP-A, eNOS, MSPR, TPP1, LAMP1, B2M, NCAM-1, HIF-1 α, ST6GAL1, CD99-L2, convolutional protein A4, EMMPRIN, p53, brain signaling protein 7A, NKp80, cysteine ​​protease protein B, osteoadhesion, mid-term factor, calreticulin, osteoactivin, asparagine endopeptidase, TAZ, cathepsin L, RBP4, serine protease inhibitor A4, JAM-A, MCSF, LIMPII, OPG, IL-22, galactoglobulin-3, MOG, trypsin 3, SIRP α, cohesin-4, IGFBP-4, IL-1, R6 GSTM1, NUP85, LAMP2, transmembrane peptidase A, IL-1 F10, bIG-H3, GPR115, TGFb1, liver glycoside-A4, CD109, serine protease inhibitor F1, IGFBP-6, HS3ST4, aminopeptidase LRAP, OPN, PAI-1, DAPP1, GDF-9, cathepsin B, IGFBP-2, brain signaling protein 6C, IGF-2, PDGF Rα, sorting protein, serine protease inhibitor B6, Dkk-3, CNTF, TSP-1, GM-CSF Ra, coagulation regulatory protein, endosaccharide, IGFBP-3, RGM-C, PF4, MIF, TGM4, periostealin, furin, TIMP-1, PAPP-A, dermal proteoglycan, PCK1, arylsulfatase A, CD99, CA2, PRDX4, transferrinDcR3, GP73, LAIR2, ULBP-4, photoglucan, TIMP-2, TFPI, SOX2, SLITRK5, FAP, spinal cord protein, ENPP-2, CD97, CTACK, integrin α1, EXTL3, IL-18 BPa, PD-L2, PSMA, IL-20 Ra, glyoxalase II, trypsin I, IGF-2R, ADAMTSL-1, erythropoietin, globulin D1, DNMT3A, BCL-2, CL-P1, hepatocyte glycoside-B3, FABP6, CHI3L1, FCRLS, TFF3, leptospirin, DPPII, cIAP-1, PDGF Rb, pentamericin 3, angiotensinogen, follicle-stimulating hormone, CF VII, persephin, TRAIL R1, THAP11, CD200, CLEC-2, AMIGO, IGFBP-5, PON1, SOX7, GALNT10, endothelin, granulosa protein precursor, PCSK2, GKN1, IL-18, enkephalin, stabilizer-2, IL-17 RD, albumin, follicle-stimulating protein 1, MMP-10, FKBP51, LRRC4, Pref-1, galactoglobin-1, troponin C, UNC5H3, FLRT2, CD314, brain signaling protein 6B, cytokeratin-4, CD27 ligand, IL-20 Rβ, brain signaling protein 6A, TSK, cytokeratin-8, CHST3, Mcl-1, DPPIV, SREC-II, norin, JAM-C, Bcl-10, Wnt-4, LSECtin, Kell, TNF RI, PTP1B, htPAPP-A, IDO, PDGF-CC, Glycopropyl peptide, Activator Protein A, TLR2, SCCA2, FABP1, eNOS, SHP-1, ICOS, C1qTNF9, MMP-1, TC-PTP, IL-24, gp130, C-myc, LILRB4, BMP-2, MIA, CD34, CD63, CD9, CD81, IFNab R2, Phosphatidylinositol Proteoglycan 2, MSP R, DSCAM, Membrane-type Serine Protease, KIR2DL3, CD30, Salivary Agglutinin-10, CLEC-1, TPP1, Ubiquitin+1, ANGPTL4, TWEAK R, Nestin-1, CD2, Kallikrein 1, TSLP R, LAMP1, TROY, VCAM-1, salivary immunoglobulin-11, S100A1, PAR1, thyroid peroxidase, aminopeptidase P2, IL-1 RI, ADAMS, OSM Rβ, thromboretin-2, SMPD1, B2M, MFRP, LRP-6, ST3GAL1, NCAM-1 (CD56), granzyme B, lipofuscin, IL-22BPTPST2, PD-ECGF, LH, LEDGF, Cyr61, ULBP-3, IFNb, THSD1, FGF-23, LAMA4, lipoprotein, AIF, SorCS2, SULT2A1, CD39L2, insulin R, HIF-1 α, OX40 ligand, Pax3, UCH-L3, cMASP3, Langerin, desmin, SOX9, ST6GAL1, MEP1B, CD99-L2, conglomerate A4, brain signaling protein 4D, ROBO2, PDX-1, APRIL, neuronal rankin, transmembrane protein-2 with ring structure, EMMPRIN, activator protein RIB, neuroligand 2, epithelial regulatory protein, CASA, MMP-12, GALNT2, CEACAM-5, VEGF R1, DSPG3, SorCS1, extracellular matrix protein-2, sFRP-3, p53, EphB3, NCK1, brain signaling protein 7A, NKp80, prolactin, cysteine ​​agonist protein B, Sirtuin 1, FGF-16, FGF R5, NQO-1, brain signaling protein 6D, FGF-3, GATA-4, VAP-A, CHST2, pregnancy-associated plasma protein-2, cohesin-3, serrated protein 1, AKR1C4, olfactory mesrin-2, osteoadhesion, NKp44, thyroglobulin, IL-21R, chemokines, EphA1, CD48, MICB, FGF-5, TRANCE, CES2, ULBP-1, integrin α 5. VAMP-2, FLRG, Ret metaphase factor, CD73, TRAP, proGRP, granzyme H, PRX2, p2'7, salivary lectin-6, dendritic cell-associated C-type lectin-1, CD51, Notch-1, calreticulin, DR3, DCTN1, CDC25B, bone activator, ACE, CA125, HAO-1, ​​PSMA1, FCRLB, BMP-9, CRIM1, LIF, SPINK1, EphB6, RGM-B, HS3ST1, ROR1, CMG-2, 4-1BB ligand, L1CAM-2, p63, cathepsin V, testosterone-2, phosphatidylinositol proteoglycan 5, CD6, salivary lectin-2, asparagine endopeptidase, PRELP, CES1, TAZ, NSE, TECK, HTRA2, HIF-1 β, TAFA1, podocyte protein, RalA, CRELD2, GRAP2, SP-D, BID, GFRα-2, Notch-3, VEGF R3, DLL4, TGFb2, LIGHT, XIAP, ST8SIA1, cathepsin L, 6-Ckine, MIS RII, kallikrein 5, TGM3, FCAR, contactin-2, CD83, IL-1 R3, SALM4GBA3, ROBO4, OSCAR, VEGF, IGSF3, disaccharide proteoglycans, neurodevelopmental proteins, ILT4, uPAR, Axl, WIF-1, IL-7Rα, GPR56, CEACAM-3, MCEMP1, FABP2, plexin B3, MEPE, activator RIIA, ANG-2, Cochlin, progerin 1, NPTXR, SLAM, COMT, SPHK1, RBP4, stalkin-1, GUSB, nestin-2, IL-17F, SR-AI, TAFA2, N-cadherin, IL-17B, IL-17RC, MIP-3b, cysteine ​​protease C, cysteine ​​protease D, AMSH, FcERI, CLEC10A, HGF R, ANG-1, prolactin R, FGF-20, CD28, Nogo-A, HSD17B1, IL-19, intestinal peptidase, cathepsin E, TSLP, TCN2, GDF-15, epidermal morphogenetics, GRKS, PD-1, serine protease inhibitor A4, ADAM23, NOV, galactoglobulin-2, neuronal surface protein 3β, TLR3, Sirtuin 2, Numb, IL-28 Rα, IL-33, Lin28, FCRL1, KLF4, NKp30, lymphocyte chemokine, cysteine ​​protease protein SN, JAM-A, calreticulin-2, ErbB4, BMP-8, IL-27 Ra, Fas, IL-4 Ra, kallikrein 14, extracellular matrix protein-3, Oligo2, kallikrein 12, CA13, IL-9, stalk protein-3, MPIF-1, cysteine ​​protease protein S, ADA, IL-2 Rb, GFR α-1, Smad4, ICAM-1, MEF2C, TREM-1, L-selectin, transmembrane serine protease, CD42b, MCSF, RANK, CHST4, CA8, FCRL3, ASAH2, CF XIV, PYY, HGF, I-TAC, brain signaling protein 4C, SorCS3, Tie-1, IL-31 RA, Arginase 1, POGLUT1, IL-1ra, Flatfoot protein, TIM-3, CREG, CD300f, uPA, EphA2, LLRTM4, LIMPII, Tenosynovin R, CPE, PECAM-1, DNAM-1, DKK-1, OPG, CPB1, TSH, MMP-2, Salivary lectin-9, ICAM-3, Cysteine ​​protease inhibitor SA, Galactohemagglutinin-4, Pepsinogen II, Desmosome core protein-3, Stalk protein-4, SCF, Serine protease inhibitor A5, PTH, FGF-19, MSP, IL-28A, FGF-12, METAP2, ASAHLEDIL3, NTAL, EGF R, TAFAS, galactoglobulin-9, vWF-A2, TACE, activator protein RIM, cathepsin S, LDL R, BMPR-IA, OX40, IL-13 R2, B7-H4, MMP-13, ANGPTL7, TRAIL R4, IGSF4B, Sirtuin 5, PEAR1, SH2D1A, Cerberus1, GDF-11, Nrf2, TROP-2, NUDTS, ROR2, EphB4, phosphatidylinositol proteoglycan 1, LAP (TGFb1), Gash, contactin-1, IL-27, UNC5H4, ICAM-2, MBL, HS3ST3B1, RCOR1, IL-10 Rb, XEDAR, IL-22, PILR-α, NRG1-131, FABP4, RGM-A, RELT, TrkC, CSa, SREC-I, neural epithelial stem cell protein, TPO, ErbB3, Kirrel3, FLRT1, galactoglobulin-3, CXCL16, JAM-B, DR6, Nogo receptor, TLR4, VEGF R2, Tie-2, IL-15 R, Caspr2, LTbR, LAMP, ALCAM, GLP-1, NG2, IL-22 Rα1, AMIGO2, HCC-1, TFPI-2, ULBP-2, desmosome core protein 2, agglutinin, synaptic fusion protein 4, VAMP-1, stalkin-2, FGF-21, Flt-3, GFAP, TIM-1, inhibin A, cadherin-4, PIGF-2, neurogranulin, HE4, IL-23 R, galactoglobulin-7, GALNT3, GITR L, CD14, R-vertebral protein 2, CK19, cardiotrophin-1, TREML1, HAPLN1, CD27, ANG-4, salivary immunoglobulin-7, CD155, VEGF-C, TNF RII, PGRP-S, SDF-1a, PDGF-AB, GPVI, CD40, SCF R, platelet-reactive protein-5, IL-1 RII, neurofeedin-2, cadherin-13, E-selectin, GITR, WISP-1, renin, AgRP, MDL-1, ROBO3, RANTES, endothelial cell-specific molecules, particulate lysin, hCGb, mesothelin, TLR1, TRAIL, MOG, DDR1, NGF R, TRAIL R3, trypsin 3, ARSB, LIF Rα, BAFF R, CD157, Granulase A, 2B4, ESAM, IL-1R4, CXCL14, IL-31, SIRP α, Urinary Modulatory Protein, CTRC, CEACAM-1, TARC, MIP-3a, SDF-1b, NKp46MCP-3, IL-32α, TGFb3, FOLR2, CD58, IL-23, CD36, TNFb, Shh-N, fibrinogen-1, Reg4, ILT2, Mer, TREM-2, Flt-3L, CDS, IL-6, CD229, Insulin, Synaptic Fusion Protein 6, GRO, Bcl-w, Lipocrine-2, PDGF-AA, IL-2 Ra, Angiopoietin, LYVE-1, CD4, RAGE, CDNF, Short Proteoglycan, NAP-2, PU.1, EDAR, ADAMTS13, Kynurenase, PTH1R, IFN-γ R1, CrkL, B7-1, PARC, Draxin, VE-cadherin, procalcitonin, SOX15, kallikrein 11, BCMA, dendritic cell-associated C-lectin-2, EpCAM, HCC-4, TGFa, IP-10, BLAME, CILP-1, PIGF, LOX-1, MCP-2, resistin, HVEM, ENPP-7, cohesin-4, IL-2 Rg, MICA, dopa decarboxylase, NPDC-1, MCP-4, EG-VEGF, glycoprotein V, brain signaling protein 4G, IL-12p40, total PSA, IL-15, MAP1D, C1q, TNF4, Dtk, endothelial glycoprotein, ENA-78, Reg3A, MIP-1b, FGF-17, IL-6R, IL-8, galactolectin-8, CA4, cysteine ​​protease protein EM, FUT8, B7-H3, GCP-2, CD40L, MDC, 4-1BB, HO-1, SOST, S100A13, kallikrein 7 or IL-13. In some embodiments, the extracellular vesicles comprise one or more of the following nucleic acids: hsa-let-7a-5p, hsa-let-7b-5p, hsa-let-7c-5p, hsa-let-7d-3p, hsa-let-7e-5p, hsa-let-7g-5p, hsa-let-7i, hsa-let-7i-5p, hsa-miR-100-5p, hsa-miR-103a-3p, hsa-miR-106a-5p, hsa-miR-10 6b-5p, hsa-mir-10b, hsa-miR-10b-5p, hsa-mir-1246, hsa-miR-1246, hsa-miR-125a-5p, hsa-miR-125b-5p, hsa-miR -130a-3p, hsa-mir-130b, hsa-miR-130b-3p, hsa-miR-132-3p, hsa-miR-136-5p, hsa-miR-138-5p, hsa-miR-139-5p,hsa-mir-140, hsa-miR-140-3p, hsa-miR-145-5p, hsa-mir-146a, hsa-miR-146a- 5p、hsa-miR-148a-3p、hsa-miR-152-3p、hsa-miR-15a-5p、hsa-miR-15b-5p、hsa-mir-16-1、hsa-mir-16-2、hsa-miR-16-5p、hsa-miR-1'7- 5p、hsa-miR-181a-5p、hsa-miR-191-5p、hsa-miR-193a-5p、hsa-miR- 193b-3p、hsa-miR-19'7-3p、hsa-miR-199a-3p、hsa-miR-199a-5p、hs a-miR-199b-5p, hsa-miR-19a-3p, hsa-miR-19b-3p, hsa-miR-20a-5p, hsa-mir-203a, hsa-miR-203a-3p, hsa-miR-214-3p, hsa-mir-21, hsa-miR-21-3p, hsa-miR-21-5p, hsa-mir-221, hsa-miR-221-3p, hsa-mir-222, hsa-miR-222-3p, hsa-miR-22-3p, hsa-miR-23a-3p, hsa-miR -23b-3p, hsa-mir-24-1, hsa-mir-24-2, hsa-miR-24-3p, hsa-mir-25, hsa-miR-25-3p, hsa-miR-26a-5p, hsa-miR-27a-3p, hsa-mir-27b, hsa-miR-27b-3p, hsa-miR-29a-3p, hsa-miR-29c-3p, hsa-miR-30a-5p, hsa-miR-30a-5p, hsa-miR-30b-5p, hsa-miR-30c-5p, hsa-mir-30d hsa-miR-30d-5p, hsa-mir-30e, hsa-miR-30e-5p, hsa-miR-31-3p, hsa-miR-31-5p, hsa-miR-320a, hsa-miR-342-3p, hsa-miR-345-5p, hsa-miR-34a-5p, hsa-miR-361-5p, hsa-miR-376a-3p, hsa-miR-376c-3p, hsa-miR-423-3p, hsa-miR-423-5p, hsa-miR-424-5p, hsa-miR-484hsa-mir-486-1, hsa-mir-486-2, hsa-miR-486-5p, hsa-miR-570-3p, hsa-miR-574-3p, hsa-miR-663a, hsa-miR-874-3p, hsa-mir-92a-1, hsa-mir-92a-2, hsa-miR-92a-3p, hsa-miR-92b-3p, hsa-mir-93, hsa-miR-93-5p, hsa-miR-940, hsa-miR-99a-5p, or hsa-miR-99b-5p. In some embodiments, the subject suffers from chronic pain. In some embodiments, the subject suffers from back pain. In some embodiments, the subject suffers from chronic low back pain. In some embodiments, the chronic low back pain causes functional impairment. In some embodiments, the subject suffers from lumbar facet joint degeneration. In some embodiments, the subject has undergone imaging examinations and / or diagnostic nerve blocks to confirm lumbar facet joint syndrome. In some embodiments, the subject has a diagnosis of degenerative facet joint low back pain for at least 6 months, involving one, two, or three facet joint segments. In some embodiments, the subject experiences improvement after treatment in one or more of the following symptoms: pain, stiffness, range of motion, posture, general health, mood, social interaction, sleep, and / or walking ability, and combinations thereof.

[0013] One aspect of this disclosure is a method for treating lumbar facet joint syndrome in a subject, the method comprising administering to the subject a composition comprising a therapeutic mesenchymal stem cell (MSC) secretome composition containing extracellular vesicles (EVs), wherein the therapeutic MSC secretome comprises: (i) ferritin, NUP85, LAMP2, GPR115, serine protease inhibitor F1, OPN, PAI-1, DAPP1, cathepsin B, brain signaling protein 6C, PDGF R α, Sorting protein, serine protease inhibitor B6, Dkk-3, coagulation regulator protein, PF4, MIF, periosteal protein, furin, TIMP-1, dermal proteoglycan, PCK1, CD99, CD63, CD9, CD81, transferrin, DcR3, photoglycan, TIMP-2, SLITRK5, FAP, leptospirin, DPPII, cIAP-1, pentameric protein 3, lactone, enkephalin, albumin, galactoglobin-1, UNC5H3, IL-20, β-reactive protein, SREC-II, JAM-C, TNF-α, htPAPP-A, eNOS, MSP, TPP1, LAMP1, B2M, NCAM-1, HIF-1 α, ST6GAL1, CD99-L2, conglomerate A4, EMMPRIN, p53, brain signaling protein 7A, NKp80, cysteine ​​protease protein B, osteoadhesion, mid-term factor, calreticulin, osteoactivin, asparagine endopeptidase, TAZ, cathepsin L, RBP4, serine protease inhibitor A4, JAM-A, MCSF, LIMPII, OPG, IL-22, galactoglobulin-3, MOG, trypsin 3, SIRP α, cohesin-4, IGFBP-4, IL-1, R6 GSTM1, NUP85, LAMP2, transmembrane peptidase A, IL-1 F10, bIG-H3, GPR115, TGFb1, liver glycoside A4, CD109, serine protease inhibitor F1, IGFBP-6, HS3ST4, aminopeptidase LRAP, OPN, PAI-1, DAPP1, GDF-9, cathepsin B, IGFBP-2, brain signaling protein 6C, IGF-2, PDGF Rα, sorting protein, serine protease inhibitor B6, Dkk-3, CNTF, TSP-1, GM-CSF Ra, coagulation regulatory protein, endosaccharides, IGFBP-3, RGM-C, PF4, MIF, TGM4, periostealin, furin, TIMP-1, PAPP-A, dermal proteoglycans, PCK1, arylsulfatase A, CD99, CA2, PRDX4, transferrin, DCR3, GP73, LAIR2, ULBP-4, optical proteoglycans, TIMP-2, TFPI, SOX2, SLITRK5, FAPSpinal cord protein, ENPP-2, CD97, CTACK, integrin α1, EXTL3, IL-18 BPa, PD-L2, PSMA, IL-20 Ra, glyoxalase II, trypsin I, IGF-2R, ADAMTSL-1, erythropoietin, globulin D1, DNMT3A, BCL-2, CL-P1, liver glycoside-B3, FABP6, CHI3L1, FCRLS, TFF3, leptospirin, DPPII, cIAP-1, PDGF Rb, pentamericin 3, angiotensinogen, follicle-stimulating hormone, CFVII, persephin, TRAIL R1, THAP11, CD200, CLEC-2, AMIGO, IGFBP-5, PON1, SOX7, GALNT10, endothelin, granulosa protein precursor, PCSK2, GKN1, IL-18, enkephalin, stabilizer-2, IL-17 RD, albumin, follicle-stimulating protein 1, MMP-10, FKBP51, LRRC4, Pref-1, galactoglobin-1, troponin C, UNC5H3, FLRT2, CD314, brain signaling protein 6B, cytokeratin-4, CD27 ligand, IL-20 Rβ, brain signaling protein 6A, TSK, cytokeratin-8, CHST3, Mcl-1, DPPIV, SREC-II, norin, JAM-C, Bcl-10, Wnt-4, LSECtin, Kell, TNF RI, PTP1B, htPAPP-A, IDO, PDGF-CC, Glycopropyl peptide, Activator Protein A, TLR2, SCCA2, FABP1, eNOS, SHP-1, ICOS, C1qTNF9, MMP-1, TC-PTP, IL-24, gp130, C-myc, LILRB4, BMP-2, MIA, CD34, CD63, CD9, CD81, IFNab R2, Phosphatidylinositol Proteoglycan 2, MSP R, DSCAM, Membrane-type Serine Protease, KIR2DL3, CD30, Salivary Agglutinin-10, CLEC-1, TPP1, Ubiquitin+1, ANGPTL4, TWEAK R, Nestin-1, CD2, Kallikrein 1, TSLPR, LAMP1, TROY, VCAM-1, Salivary agglutinin-11, S100A1, PAR1, Thyroid peroxidase, Aminopeptidase P2, IL-1RI, ADAMS, OSM Rβ, Platelet-Reactive Protein-2, SMPD1, B2M, MFRP, LRP-6, ST3GAL1, NCAM-1 (CD56), Granulase B, Lipocontin, IL-22BP, TPST2, PD-ECGF, LH, LEDGF, Cyr61, ULBP-3, IFNb, THSD1, FGF-23, LAMA4Lipoprotein, AIF, SorCS2, SULT2A1, CD39L2, Insulin R, HIF-1 α, OX40 ligand, Pax3, UCH-L3, cMASP3, Langerin, Desmin, SOX9, ST6GAL1, MEP1B, CD99-L2, Convolutional protein A4, Brain signaling protein 4D, ROBO2, PDX-1, APRIL, Neural rank protein, cyclic transmembrane protein-2, EMMPRIN, activator protein RIB, neuroligand 2, epithelial regulatory protein, CASA, MMP-12, GALNT2, CEACAM-5, VEGF R1, DSPG3, SorCS1, Extracellular matrix protein-2, sFRP-3, p53, EphB3, NCK1, Brain signaling protein 7A, NKp80, Prolactin, Cysteine ​​protease protein B, Sirtuin 1, FGF-16, FGF R5, NQO-1, Brain signaling protein 6D, FGF-3, GATA-4, VAP-A, CHST2, Pregnancy-associated plasma protein-2, Cohesin-3, Serpentin-1, AKR1C4, Oligosin-2, Osteoadhesin, NKp44, Thyroglobulin, IL-21R, Chemokines, EphA1, CD48, MICB, FGF-5, TRANCE, CES2, ULBP-1, Integrin α 5. VAMP-2, FLRG, Ret metaphase factor, CD73, TRAP, proGRP, granzyme H, PRX2, p2'7, salivary lectin-6, dendritic cell-associated C-type lectin-1, CD51, Notch-1, calreticulin, DR3, DCTN1, CDC25B, bone activator, ACE, CA125, HAO-1, ​​PSMA1, FCRLB, BMP-9, CRIM1, LIF, SPINK1, EphB6, RGM-B, HS3ST1, ROR1, CMG-2, 4-1BB ligand, L1CAM-2, p63, cathepsin V, testosterone-2, phosphatidylinositol proteoglycan 5, CD6, salivary lectin-2, asparagine endopeptidase, PRELP, CES1, TAZ, NSE, TECK, HTRA2, HIF-1 β, TAFA1, podocyte protein, RalA, CRELD2, GRAP2, SP-D, BID, GFR α-2, Notch-3, VEGF R3, DLL4, TGFb2, LIGHT, XIAP, ST8SIA1, cathepsin L, 6-Ckine, MIS RII, kallikrein 5, TGM3, FCAR, contactin-2, CD83, IL-1R3, SALM4, GBA3, ROBO4, OSCAR, VEGF, IGSF3, disaccharide proteoglycan, neurodevelopmental factor, ILT4, uPAR, Axl, WIF-1IL-7 Rα, GPR56, CEACAM-3, MCEMP1, FABP2, plexin B3, MEPE, activator RIIA, ANG-2, Cochlin, progerin 1, NPTXR, SLAM, COMT, SPHK1, RBP4, stalkin-1, GUSB, nestin-2, IL-17F, SR-AI, TAFA2, N-cadherin, IL-17B, IL-17RC, MIP-3b, cysteine ​​protease C, cysteine ​​protease D, AMSH, FcERI, CLEC10A, HGF R, ANG-1, prolactin R, FGF-20, CD28, Nogo-A, HSD17B1, IL-19, intestinal peptidase, cathepsin E, TSLP, TCN2, GDF-15, epidermal morphogenetics, GRKS, PD-1, serine protease inhibitor A4, ADAM23, NOV, galactoglobulin-2, neuronal surface protein 3β, TLR3, Sirtuin2, Numb, IL-28 Rα, IL-33, Lin28, FCRL1, KLF4, NKp30, lymphocyte chemokine, cysteine ​​protease protein SN, JAM-A, calreticulin-2, ErbB4, BMP-8, IL-27 Ra, Fas, IL-4 Ra, kallikrein 14, extracellular matrix protein-3, Oligo2, kallikrein 12, CA13, IL-9, stalk protein-3, MPIF-1, cysteine ​​protease protein S, ADA, IL-2 Rb, GFR α-1, Smad4, ICAM-1, MEF2C, TREM-1, L-selectin, transmembrane serine protease, CD42b, MCSF, RANK, CHST4, CA8, FCRL3, ASAH2, CF XIV, PYY, HGF, I-TAC, brain signaling protein 4C, SorCS3, Tie-1, IL-31 RA, Arginase 1, POGLUT1, IL-1ra, Flatfoot protein, TIM-3, CREG, CD300f, uPA, EphA2, LLRTM4, LIMPII, Tenosynovin R, CPE, PECAM-1, DNAM-1, DKK-1, OPG, CPB1, TSH, MMP-2, Salivary lectin-9, ICAM-3, Cysteine ​​protease inhibitor SA, Galactohemagglutinin-4, Pepsinogen II, Desmosome core protein-3, Stalk protein-4, SCF, Serine protease inhibitor A5, PTH, FGF-19, MSP, IL-28A, FGF-12, METAP2, ASAHL, EDIL3, NTAL, EGF R, TAFAS, Galactohemagglutinin-9, vWF-A2, TACE, Activator protein RIM, Cathepsin S, LDL RBMPR-IA, OX40, IL-13 R2, B7-H4, MMP-13, ANGPTL7, TRAIL R4, IGSF4B, Sirtuin 5, PEAR1, SH2D1A, Cerberus 1, GDF-11, Nrf2, TROP-2, NUDTS, ROR2, EphB4, phosphatidylinositol proteoglycan 1, LAP (TGFb1), Gash, contactin-1, IL-27, UNC5H4, ICAM-2, MBL, HS3ST3B1, RCOR1, IL-10 Rb, XEDAR, IL-22, PILR-α, NRG1-131, FABP4, RGM-A, RELT, TrkC, CSa, SREC-I, neural epithelial stem cell protein, TPO, ErbB3, Kirrel3, FLRT1, galactoglobulin-3, CXCL16, JAM-B, DR6, Nogo receptor, TLR4, VEGF R2, Tie-2, IL-15 R, Caspr2, LTbR, LAMP, ALCAM, GLP-1, NG2, IL-22 Rα 1, AMIGO2, HCC-1, TFPI-2, ULBP-2, desmosome core protein 2, agglutinin, synaptic fusion protein 4, VAMP-1, stalkin-2, FGF-21, Flt-3, GFAP, TIM-1, inhibin A, cadherin-4, PIGF-2, neurogranulin, HE4, IL-23 R, galactoglobulin-7, GALNT3, GITR L, CD14, R-vertebral protein 2, CK19, cardiotrophin-1, TREML1, HAPLN1, CD27, ANG-4, salivary immunoglobulin-7, CD155, VEGF-C, TNF RII, PGRP-S, SDF-1a, PDGF-AB, GPVI, CD40, SCF R, platelet-reactive protein-5, IL-1 RII, neurofeedin-2, cadherin-13, E-selectin, GITR, WISP-1, renin, AgRP, MDL-1, ROBO3, RANTES, endothelial cell-specific molecules, granzyme, hCGb, mesothelin, TLR1, TRAIL, MOG, DDR1, NGF R, TRAIL R3, trypsin 3, ARSB, LIF Rα, BAFFR, CD157, granzyme A, 2B4, ESAM, IL-1 R4, CXCL14, IL-31, SIRP α, urinary modulatory proteins, CTRC, CEACAM-1, TARC, MIP-3a, SDF-1b, NKp46, MCP-3, IL-32 α, TGFb3, FOLR2, CD58, IL-23, CD36, TNFb, Shh-N, fibrinogen-1, Reg4ILT2, Mer, TREM-2, Flt-3L, CDS, IL-6, CD229, Insulin, Synaptic Fusion Protein 6, GRO, Bcl-w, Lipocrine-2, PDGF-AA, IL-2 Ra, Angiopoietin, LYVE-1, CD4, RAGE, CDNF, Short Proteoglycan, NAP-2, PU.1, EDAR, ADAMTS13, Kynureninase, PTH1R, IFN-γ R1, CrkL, B7-1, PARC, Draxin, VE-cadherin, Procalcitonin, SOX15, Kallikrein 11, BCMA, Dendritic Cell-Associated C-Lectin-2, EpCAM, HCC-4, TGFa, IP-10, BLAME, CILP-1, PIGF, LOX-1, MCP-2, Resistin, HVEM, ENPP-7, Cohesin-Glycan-4, IL-2 Rg, MICA, dopa decarboxylase, NPDC-1, MCP-4, EG-VEGF, glycoprotein V, brain signaling protein 4G, IL-12p40, total PSA, IL-15, MAP1D, C1q, TNF4, Dtk, endothelial glycoprotein, ENA-78, Reg3A, MIP-1b, FGF-17, IL-6R, IL-8, galactolectin-8, CA4, cysteine ​​protease protein EM, FUT8, B7-H 3. GCP-2, CD40L, MDC, 4-1BB, HO-1, SOST, S100A13, kallikrein 7 or IL-13, or a combination of two or more thereof; (ii) hsa-let-7a-5p, hsa-let-7b-5p, hsa-let-7c-5p, hsa-let-7d-3p, hsa-let-7e-5p, hsa-let-7g-5p, hsa-let-7i, hs a-let-7i-5p, hsa-miR-100-5p, hsa-miR-103a-3p, hsa-miR-106a-5p, hsa-miR-106b-5p, hsa-mir- 10b, hsa-miR-10b-5p, hsa-mir-1246, hsa-miR-1246, hsa-miR-125a-5p, hsa-miR-125b-5p, hsa-mi R-130a-3p, hsa-mir-130b, hsa-miR-130b-3p, hsa-miR-132-3p, hsa-miR-136-5p, hsa-miR-138-5p , hsa-miR-139-5p, hsa-mir-140, hsa-miR-140-3p, hsa-miR-145-5p, hsa-mir-146a, hsa-miR-146a- 5p, hsa-miR-148a-3p,hsa-miR-152-3p, hsa-miR-15a-5p, hsa-miR-15b-5p, hsa-mir-16-1, hsa-mir-16-2, hsa-miR-16-5p, hsa-miR-1'7-5p, hsa-miR-181a-5p, hsa-miR-191-5p, hsa-miR-193a-5p, hsa-miR-193b-3p, hsa-miR-19'7-3p, hsa-miR-199a-3p, hsa-miR-199a-5p, hsa-miR-199b-5p, hsa-miR-19a-3p, hsa-mi R-19b-3p, hsa-miR-20a-5p, hsa-mir-203a, hsa-miR-203a-3p, hsa-miR-214-3p, hsa-mir-21, hsa-miR-21-3p, hsa-miR-21-5p, hsa-mir-221, hsa-miR-221-3p, hsa-mir-222, hsa-miR-222-3p, hsa-miR-22-3p, hsa-miR-23a-3p, hsa-miR-23b-3p, hsa-mir-24-1, hsa-mir-24-2, hsa-miR-24-3p, hsa- mir-25, hsa-miR-25-3p, hsa-miR-26a-5p, hsa-miR-27a-3p, hsa-mir-27b, hsa-miR-27b-3p, hsa-miR-29a-3p, hsa-miR-29c-3p, hsa-miR-30a-5p, hsa-miR-30a-5p, hsa-miR-30b-5p, hsa-miR-30c-5p, hsa-mir-30d, hsa-miR-30d-5p, hsa-mir-30e, hsa-miR-30e-5p, hsa-miR-31-3p, hsa-miR-31-5p hsa-miR-320a hsa-miR-342-3p hsa-miR-345-5p hsa-miR-34a-5p hsa-miR-361-5p hsa-miR-376a-3p hsa-miR-376c-3p hsa-miR-423-3p hsa -miR-423-5p, hsa-miR-424-5p, hsa-miR-484, hsa-mir-486-1, hsa-mir-486-2, hsa-miR-486-5p, hsa-miR-570-3p, hsa-miR-574-3p, hsa-miR-663ahsa-miR-874-3p, hsa-mir-92a-1, hsa-mir-92a-2, hsa-miR-92a-3p, hsa-miR-92b-3p, hsa-mir-93, hsa-miR-93-5p, hsa-miR-940, hsa-miR-99a-5p or hsa-miR-99b-5p, or a combination of two or more thereof; or both (iii), (i), and (ii).

[0014] One aspect of this disclosure is a method for treating lumbar facet joint syndrome, the method comprising administering a therapeutic MSC secretory composition to the subject. Another aspect of this disclosure is a method for treating low back pain, the method comprising administering a therapeutic MSC secretory composition to the subject. Another aspect of this disclosure is a method for reducing symptoms associated with lumbar facet joint syndrome in a subject, the method comprising administering a therapeutic MSC secretory composition to the subject. Another aspect of this disclosure is a method for improving symptoms of lumbar facet joint syndrome selected from one or more of the following: pain, stiffness, range of motion, posture, general health, mood, social interaction, sleep and / or walking ability, and combinations thereof, the method comprising administering a therapeutic MSC secretory composition to the subject. In some embodiments, the extracellular vesicles in the therapeutic MSC secretory composition are CD63+CD9-CD81-. In some embodiments, the therapeutic MSC secretome comprises: (i) ferritin, NUP85, LAMP2, GPR115, serine protease inhibitor F1, OPN, PAI-1, DAPP1, cathepsin B, brain signaling protein 6C, PDGF Rα, sorting protein, serine protease inhibitor B6, Dkk-3, coagulation regulatory protein, PF4, MIF, periosteal protein, furin, TIMP-1, tectonic proteoglycan, PCK1, CD99, CD63, CD9, CD81, transferrin, DcR3, photoglucan, TIMP-2, SLITRK5, FAP, leptospirin, DPPII, cIAP-1, pentameric protein 3, lactone, enkephalin, albumin, galactolectin-1, UNC5H3, IL-20R β, SREC-II, JAM-C, TNFRI, htPAPP-A, eNOS, MSP R, TPP1, LAMP1, B2M, NCAM-1, HIF-1 α, ST6GAL1, CD99-L2, convolutional protein A4, EMMPRIN, p53, brain signaling protein 7A, NKp80, cysteine ​​apoproteinase B, osteoadhesion, mid-term factor, calreticulin, osteoactivin, asparagine endopeptidase, TAZ, cathepsin L, RBP4, serine protease inhibitor A4, JAM-A, MCSF, LIMPII, OPG, IL-22, galactolectin-3, MOG, trypsin 3, SIRP α, cohesin-4, IGFBP-4, IL-1, R6 GSTM1, NUP85, LAMP2, transmembrane peptidase A, IL-1 F10, bIG-H3, GPR115, TGFb1, liver glycoside A4, CD109, serine protease inhibitor F1, IGFBP-6, HS3ST4, aminopeptidase LRAP, OPN, PAI-1, DAPP1, GDF-9, cathepsin B,IGFBP-2, Brain signaling protein 6C, IGF-2, PDGF Rα, Sorting protein, Serine protease inhibitor B6, Dkk-3, CNTF, TSP-1, GM-CSF Ra, Coagulation regulatory protein, Endoglycosides, IGFBP-3, RGM-C, PF4, MIF, TGM4, Periostrin, Flintase, TIMP-1, PAPP-A, Glycerin proteoglycan, PCK1, Arylsulfatase A, CD99, CA2, PRDX4, Transferrin, DcR3, GP73, LAIR2, ULBP-4, Optical proteoglycan, TIMP-2, TFPI, SOX2, SLITRK5, FAP, Spinal cord protein, ENPP-2, CD97, CTACK, Integrin α1, EXTL3, IL-18, BPa, PD-L2, PSMA, IL-20 Ra, Glyoxalase II, Trypsin I, IGF-2R, ADAMTS L1-1, Erythropoietin, Convolutional D1, DNMT3A, BCL-2, CL-P1, Hepatocyte-B3, FABP6, CHI3L1, FCRLS, TFF3, Nephlebotomycin, DPPII, cIAP-1, PDGF Rb, Pentanoic Acid 3, Angiotensinogen, Follicle-Stapressin, CF VII, Persephin, TRAIL R1, THAP11, CD200, CLEC-2, AMIGO, IGFBP-5, PON1, SOX7, GALNT10, Lactone, Granulosin Progenitor, PCSK2, GKN1, IL-18, Enkephalin, Stabilin-2, IL-17 RD, albumin, follicle-stimulating protein 1, MMP-10, FKBP51, LRRC4, Pref-1, galactoglobin-1, troponin C, UNC5H3, FLRT2, CD314, brain signaling protein 6B, cytokinin-4, CD27 ligand, IL-20 Rβ, brain signaling protein 6A, TSK, cytokeratin-8, CHST3, Mcl-1, DPPIV, SREC-II, norin, JAM-C, Bcl-10, Wnt-4, LSECtin, Kell, TNF RI, PTP1B, htPAPP-A, IDO, PDGF-CC, Glycopropyl peptide, Activator Protein A, TLR2, SCCA2, FABP1, eNOS, SHP-1, ICOS, C1qTNF9, MMP-1, TC-PTP, IL-24, gp130, C-myc, LILRB4, BMP-2, MIA, CD34, CD63, CD9, CD81, IFNab R2, Phosphatidylinositol Proteoglycan 2, MSP R, DSCAM, Membrane-type Serine Protease, KIR2DL3, CD30, Salivary Agglutinin-10, CLEC-1, TPP1, Ubiquitin+1, ANGPTL4TWEAK R, Nestin-1, CD2, Kallikrein 1, TSLP R, LAMP1, TROY, VCAM-1, Salivary agglutinin-11, S100A1, PAR1, Thyroid peroxidase, Aminopeptidase P2, IL-1 RI, ADAMS, OSM R β, Platelet-Reactive Protein-2, SMPD1, B2M, MFRP, LRP-6, ST3GAL1, NCAM-1 (CD56), Granulase B, Lipocontin, IL-22BP, TPST2, PD-ECGF, LH, LEDGF, Cyr61, ULBP-3, IFNb, THSD1, FGF-23, LAMA4, Lipoprotein, AIF, SorCS2, SULT2A1, CD39L2, Insulin R, HIF-1 α, OX40 ligand, Pax3, UCH-L3, cMASP3, Langerin, desmin, SOX9, ST6GAL1, MEP1B, CD99-L2, conglomerate A4, brain signaling protein 4D, ROBO2, PDX-1, APRIL, neuronal rank protein, transmembrane protein-2 with ring structure, EMMPRIN, activating protein RIB, neuroligand 2, epithelial regulatory protein, CASA, MMP-12, GALNT2, CEACAM-5, VEGF R1, DSPG3, SorCS1, extracellular matrix protein-2, sFRP-3, p53, EphB3, NCK1, brain signaling protein 7A, NKp80, prolactin, cysteine ​​agonist protein B, Sirtuin 1, FGF-16, FGF R5, NQO-1, Brain signaling protein 6D, FGF-3, GATA-4, VAP-A, CHST2, Pregnancy-associated plasma protein-2, Cohesin-3, Serpentin-1, AKR1C4, Oligosin-2, Osteoadhesin, NKp44, Thyroglobulin, IL-21R, Chemokines, EphA1, CD48, MICB, FGF-5, TRANCE, CES2, ULBP-1, Integrin α 5. VAMP-2, FLRG, Ret metaphase factor, CD73, TRACP, proGRP, granzyme H, PRX2, p27, salivary lectin-6, dendritic cell-associated C-type lectin-1, CD51, Notch-1, calreticulin, DR3, DCTN1, CDC25B, bone activator, ACE, CA125, HAO-1, ​​PSMA1, FCRLB, BMP-9, CRIM1, LIF, SPINK1, EphB6, RGM-B, HS3ST1, ROR1, CMG-2, 4-1BB ligand, L1CAM-2, p63, cathepsin V, testosterone-2, phosphatidylinositol proteoglycan 5, CD6, salivary lectin-2, asparagine endopeptidase, PRELP, CES1, TAZ, NSETECK, HTRA2, HIF-1β, TAFA1, podocyte protein, RalA, CRELD2, GRAP2, SP-D, BID, GFR α-2, Notch-3, VEGF R3, DLL4, TGFb2, LIGHT, XIAP, ST8SIA1, cathepsin L, 6-Ckine, MIS RII, kallikrein 5, TGM3, FCAR, contactin-2, CD83, IL-1 R3, SALM4, GBA3, ROBO4, OSCAR, VEGF, IGSF3, disaccharide proteoglycan, neurodevelopmental factor, ILT4, uPAR, Axl, WIF-1, IL-7 R α, GPR56, CEACAM-3, MCEMP1, FABP2, plexin B3, MEPE, activator RIIA, ANG-2, Cochlin, presenilin 1, NPTXR, SLAM, COMT, SPHK1, RBP4, stalkin-1, GUSB, nestin-2, IL-17F, SR-AI, TAFA2, N-cadherin, IL-17B, IL-17RC, MIP-3b, cysteine ​​protease C, cysteine ​​protease D, AMSH, FcERI, CLEC10A, HGF R, ANG-1, prolactin R, FGF-20, CD28, Nogo-A, HSD17B1, IL-19, intestinal peptidase, cathepsin E, TSLP, TCN2, GDF-15, epidermal morphogenetics, GRKS, PD-1, serine protease inhibitor A4, ADAM23, NOV, galactoglobulin-2, neuronal surface protein 3β, TLR3, Sirtuin 2, Numb, IL-28 Rα, IL-33, Lin28, FCRL1, KLF4, NKp30, lymphocyte chemokine, cysteine ​​protease protein SN, JAM-A, calreticulin-2, ErbB4, BMP-8, IL-27 Ra, Fas, IL-4 Ra, kallikrein 14, extracellular matrix protein-3, Olig2, kallikrein 12, CA13, IL-9, stalk protein-3, MPIF-1, cysteine ​​protease protein S, ADA, IL-2 Rb, GFR α-1, Smad4, ICAM-1, MEF2C, TREM-1, L-selectin, transmembrane serine protease, CD42b, MCSF, RANK, CHST4, CA8, FCRL3, ASAH2, CF XIV, PYY, HGF, I-TAC, brain signaling protein 4C, SorCS3, Tie-1, IL-31RA, arginase 1, POGLUT1, IL-1ra, flatfoot protein, TIM-3, CREG, CD300f, uPA, EphA2, LLRTM4LIMPII, Tenosynovin R, CPE, PECAM-1, DNAM-1, DKK-1, OPG, CPB1, TSH, MMP-2, Salivary lectin-9, ICAM-3, Cysteine ​​protease inhibitor SA, Galactohemagglutinin-4, Pepsinogen II, Desmosome core protein-3, Stalk protein-4, SCF, Serine protease inhibitor A5, PTH, FGF-19, MSP, IL-28A, FGF-12, METAP2, ASAHL, EDIL3, NTAL, EGF R, TAFAS, Galactohemagglutinin-9, vWF-A2, TACE, Activator protein RIM, Cathepsin S, LDLR, BMPR-IA, OX40, IL-13 R2, B7-H4, MMP-13, ANGPTL7, TRAIL R4, IGSF4B, Sirtuin 5, PEAR1, SH2D1A, Cerberus 1. GDF-11, Nrf2, TROP-2, NUDTS, ROR2, EphB4, phosphatidylinositol proteoglycan 1, LAP (TGFb1), Gash, contactin-1, IL-27, UNC5H4, ICAM-2, MBL, HS3ST3B1, RCOR1, IL-10 Rb, XEDAR, IL-22, PILR-α, NRG1-131, FABP4, RGM-A, RELT, TrkC, CSa, SREC-I, neural epithelial stem cell protein, TPO, ErbB3, Kirrel3, FLRT1, galactolectin-3, CXCL16, JAM-B, DR6, Nogo receptor, TLR4, VEGFR2, Tie-2, IL-15 R, Caspr2, LTbR, LAMP, ALCAM, GLP-1, NG2, IL-22 R α 1. AMIGO2, HCC-1, TFPI-2, ULBP-2, desmosome core protein 2, agglutinin, synaptic fusion protein 4, VAMP-1, stalkin-2, FGF-21, Flt-3, GFAP, TIM-1, inhibin A, cadherin-4, PIGF-2, neurogranulin, HE4, IL-23R, galactolectin-7, GALNT3, GITR L, CD14, R-vertebral protein 2, CK19, cardiotrophin-1, TREML1, HAPLN1, CD27, ANG-4, salivary lectin-7, CD155, VEGF-C, TNF-α, PGRP-S, SDF-1α, PDGF-AB, GPVI, CD40, SCFR, platelet-reactive protein-5, IL-1 RII, neurotrophin-2, cadherin-13, E-selectin, GITR, WISP-1, renin, AgRP, MDL-1, ROBO3, RANTESEndothelial cell-specific molecules, granzyme-6, hCGb, mesothelin, TLR1, TRAIL, MOG, DDR1, NGF R, TRAIL R3, trypsin 3, ARSB, LIF Rα, BAFF R, CD157, granzyme A, 2B4, ESAM, IL-1 R4, CXCL14, IL-31, SIRP α, urinary modulatory proteins, CTRC, CEACAM-1, TARC, MIP-3a, SDF-1b, NKp46, MCP-3, IL-32 α, TGFb3, FOLR2, CD58, IL-23, CD36, TNFb, Shh-N, fibrinogen-1, Reg4, ILT2, Mer, TREM-2, Flt-3L, CDS, IL-6, CD229, insulin, synaptic fusion protein 6, GRO, Bcl-w, lipocalin-2, PDGF-AA, IL-2 Ra, angiopoietin, LYVE-1, CD4, RAGE, CDNF, short proteoglycans, NAP-2, PU.1, EDAR, ADAMTS13, kynurenase, PTH1R, IFN-γ R1, CrkL, B7-1, PARC, Draxin, VE-cadherin, procalcitonin, SOX15, kallikrein 11, BCMA, dendritic cell-associated C-lectin-2, EpCAM, HCC-4, TGFa, IP-10, BLAME, CILP-1, PIGF, LOX-1, MCP-2, resistin, HVEM, ENPP-7, cohesin-glycan-4, IL-2 Rg, MICA, dopa decarboxylase, NPDC-1, MCP-4, EG-VEGF, glycoprotein V, brain signaling protein 4G, IL-12p40, total PSA, IL-15, MAP1D, C1q, TNF4, Dtk, endothelial glycoprotein, ENA-78, Reg3A, MIP-1b, FGF-17, IL-6R, IL-8, galactolectin-8, CA4, cysteine ​​protease protein EM, FUT8, B7-H3, GCP-2, CD40L, MDC, 4-1BB, HO-1, SOST, S100A13, kallikrein 7 or IL -13 or combinations of two or more thereof; (ii) hsa-let-7a-5p, hsa-let-7b-5p, hsa-let-7c-5p, hsa-let-7d-3p, hsa-let-7e-5p, hsa-let-7g-5p, hsa-let-7i, hsa-let-7i-5p, hsa-miR-100-5p, hsa-miR-103a-3p, hsa-miR-106a-5p, hsa-miR-106b-5p, hsa-mir-10b, hsa-miR-10b-5p,hsa-mir-1246, hsa-miR-1246, hsa-miR-125a-5p, hsa-miR-125b-5p, hsa-miR-130a-3p, hsa-mir-130b, hsa-miR-130b-3p, hsa-miR-132-3p, hsa-miR-136-5p, hsa-miR-138-5p, hsa-miR-139-5p, hsa-mir-140, hsa-miR-140-3p, hsa-miR-145-5p, hsa-mir-146a, hsa-miR-146a- 5p, hsa-miR-148a-3p, hsa-miR-152-3p, hsa-miR-15a-5p, hsa-miR-15b-5p, hsa-mir-16-1, hsa-mir-16-2, hsa-miR-16-5p, hsa-miR-1'7-5p, hsa-miR-181a-5p, hsa-miR-191-5p, hsa-miR-193a-5p, hsa-miR-193b-3p, hsa-miR-1 9'7-3p、hsa-miR-199a-3p、hsa-miR-199a-5p、hsa-miR-199b-5p、hsa-miR-19a-3p、hsa-miR-19b-3p、hsa-miR-20a-5p、hsa-mir-203a、hsa-miR-203a-3p、hsa-miR-214-3p、hsa-mir-21、hsa-miR-21-3p、hsa-miR-21-5p、hsa-mir-2 21, hsa-miR-221-3p, hsa-mir-222, hsa-miR-222-3p, hsa-miR-22-3p, hsa-miR-23a-3p, hsa-miR-23b-3p, hsa-mir-24-1, hsa-mir-24-2, hsa-miR-24-3p, hsa-mir-25, hsa-miR-25-3p, hsa-miR-26a-5p, hsa-miR-27a-3p, hsa-mir -27b、hsa-miR-27b-3p、hsa-miR-29a-3p、hsa-miR-29c-3p、hsa-miR-30a-5p、hsa-miR-30a-5p、hsa-miR-30b-5p、h sa-miR-30c-5p、hsa-mir-30d、hsa-miR-30d-5p、hsa-mir-30e、hsa-miR-30e-5p、hsa-miR-31-3p、hsa-miR-31-5p、hsa-miR-320a, hsa-miR-342-3p, hsa-miR-345-5p, hsa-miR-34a-5p, hsa-miR-361-5p, hsa-miR-376a-3p, hsa-miR-376c-3 p, hsa-miR-423-3p, hsa-miR-423-5p, hsa-miR-424-5p, hsa-miR-484, hsa-mir-486-1, hsa-mir-486-2, hsa-miR-486-5p, hs a-miR-570-3p, hsa-miR-574-3p, hsa-miR-663a, hsa-miR-874-3p, hsa-mir-92a-1, hsa-mir-92a-2, hsa-miR-92a-3p, hsa-miR-92b-3p, hsa-mir-93, hsa-miR-93-5p, hsa-miR-940, hsa-miR-99a-5p or hsa-miR-99b-5p, or a combination of two or more thereof; or both (iii), (i) and (ii). In some embodiments, the therapeutic MSC secretome composition is prepared by a method comprising the following steps: (a) culturing bone marrow-derived MSCs under the following conditions to produce MSC conditioned medium: (i) oxygen partial pressure below 5%; and (ii) a medium with pH below 7; (b) harvesting the MSC conditioned medium; and (c) formulating the MSC conditioned medium to produce the therapeutic MSC secretome composition, wherein the therapeutic MSC secretome composition comprises proteins and extracellular vesicles produced by the bone marrow-derived MSCs in step (a). In some embodiments, the subject suffers from chronic pain. In some embodiments, the subject suffers from back pain. In some embodiments, the subject suffers from chronic low back pain. In some embodiments, the subject experiences improvement after treatment in one or more of the following skin characteristics: pain, stiffness, range of motion, posture, overall health, mood, social interaction, sleep and / or walking ability, and combinations thereof. In some embodiments, the composition comprises 0.5 mL of the therapeutic MSC secretome composition. In some embodiments, the composition is injected into the lumbar facet joint space.

[0015] One aspect of this disclosure is a method for treating a subject with lumbar facet joint syndrome, the method comprising administering to the subject a composition comprising a therapeutic mesenchymal stem cell (MSC) secretome composition containing extracellular vesicles (EVs), wherein the composition comprises 0.5 mL of the therapeutic MSC secretome composition.

[0016] One aspect of this disclosure is a method for treating lumbar facet joint syndrome in a subject, the method comprising administering to the subject a composition comprising a therapeutic mesenchymal stem cell (MSC) secretome composition containing extracellular vesicles (EVs), wherein the administration improves one or more of the following skin characteristics: pain, stiffness, range of motion, posture, general health, mood, social interaction, sleep and / or walking ability, and combinations thereof. In some embodiments, the administration results in improvement in one or more of a severity index, an interference index, and / or an Oswestry Disability Index (ODI). In some implementations, the subjects experienced 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%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46% of their scores after treatment. %, 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% or 100% improvement.In some implementations, the subjects experienced a severity index of 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%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, and 48% after treatment. 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%, or 100% improvement. In some implementations, the subject experiences an interference index of 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%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 4 9%, 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%, or 100% improvement.In some implementations, the subjects experienced 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%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 4 Improvements of 9%, 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%, or 100%. In some embodiments, the application results in improvements in one or more of the following: pain, stiffness, range of motion, posture, overall health, mood, social interaction, sleep, and / or walking ability. In some embodiments, the application results in improvements in functional capacity. In some embodiments, the application improves inflammation.

[0017] One aspect of this disclosure is the use of a composition comprising a therapeutic mesenchymal stem cell (MSC) secretome composition containing extracellular vesicles in lumbar facet joint syndrome in a subject, wherein at least 80% of the extracellular vesicles in the therapeutic MSC secretome composition are CD63+CD9-CD81-. Another aspect of this disclosure is the use of a composition comprising a therapeutic mesenchymal stem cell (MSC) secretome composition containing extracellular vesicles (EVs) in the treatment of lumbar facet joint syndrome in a subject in need, wherein the therapeutic mesenchymal stem cell (MSC) secretome composition comprises: (i) ferritin, NUP85, LAMP2, GPR115, serine protease inhibitor F1, OPN, PAI-1, DAPP1, cathepsin B, brain signaling protein 6C, PDGF R. α, Sorting protein, serine protease inhibitor B6, Dkk-3, coagulation regulator protein, PF4, MIF, periosteal protein, furin, TIMP-1, dermal proteoglycan, PCK1, CD99, CD63, CD9, CD81, transferrin, DcR3, photoglycan, TIMP-2, SLITRK5, FAP, leptospirin, DPPII, cIAP-1, pentameric protein 3, lactone, enkephalin, albumin, galactoglobin-1, UNC5H3, IL-20, β-reactive protein, SREC-II, JAM-C, TNF-α, htPAPP-A, eNOS, MSP, TPP1, LAMP1, B2M, NCAM-1, HIF-1 α, ST6GAL1, CD99-L2, conglomerate A4, EMMPRIN, p53, brain signaling protein 7A, NKp80, cysteine ​​protease protein B, osteoadhesion, mid-term factor, calreticulin, osteoactivin, asparagine endopeptidase, TAZ, cathepsin L, RBP4, serine protease inhibitor A4, JAM-A, MCSF, LIMPII, OPG, IL-22, galactoglobulin-3, MOG, trypsin 3, SIRP α, cohesin-4, IGFBP-4, IL-1, R6 GSTM1, NUP85, LAMP2, transmembrane peptidase A, IL-1 F10, bIG-H3, GPR115, TGFb1, liver glycoside-A4, CD109, serine protease inhibitor F1, IGFBP-6, HS3ST4, aminopeptidase LRAP, OPN, PAI-1, DAPP1, GDF-9, cathepsin B, IGFBP-2, brain signaling protein 6C, IGF-2, PDGF Rα, sorting protein, serine protease inhibitor B6, Dkk-3, CNTF, TSP-1, GM-CSF Ra, coagulation regulatory protein, endosaccharide, IGFBP-3, RGM-C, PF4, MIF, TGM4, periosteal protein, furin protease.TIMP-1, PAPP-A, Glycerin, PCK1, Arylsulfatase A, CD99, CA2, PRDX4, Transferrin, DcR3, GP73, LAIR2, ULBP-4, Optical Glycerin, TIMP-2, TFPI, SOX2, SLITRK5, FAP, Spinal Protein, ENPP-2, CD97, CTACK, Integrin α1, EXTL3, IL-18 BPa, PD-L2, PSMA, IL-20 Ra, Glyoxalase II, Trypsin I, IGF-2R, ADAMTSI-1, Erythropoietin, Convolutional Protein D1, DNMT3A, BCL-2, CL-P1, Hepatocyte Glycol-B3, FABP6, CHI3L1, FCRLS, TFF3, Neurosphingomyelin, DPPII, cIAP-1, PDGF Rb, Pentanoicin 3, Angiotensinogen, Follicle-Stapressin, CF VII, Persephin, TRAIL R1, THAP11, CD200, CLEC-2, AMIGO, IGFBP-5, PON1, SOX7, GALNT10, Lactopagin, granulosa protein precursor, PCSK2, GKN1, IL-18, Enkephalin, Stabilin-2, IL-17RD, Albumin, Follicle-stimulating protein 1, MMP-10, FKBP51, LRRC4, Pref-1, Galactoglobin-1, Troponin C, UNC5H3, FLRT2, CD314, Brain signaling protein 6B, cytokeratin-4, CD27 ligand, IL-20Rβ, Brain signaling protein 6A, TSK, Cytokeratin-8, CHST3, Mcl-1, DPPIV, SREC-II, Norlin, JAM-C, Bcl-10, Wnt-4, LSECtin, Kell, TNF RI, PTP1B, htPAPP-A, IDO, PDGF-CC, Glycopropyl peptide, Activator Protein A, TLR2, SCCA2, FABP1, eNOS, SHP-1, ICOS, C1qTNF9, MMP-1, TC-PTP, IL-24, gp130, C-myc, LILRB4, BMP-2, MIA, CD34, CD63, CD9, CD81, IFNab R2, Phosphatidylinositol Proteoglycan 2, MSP R, DSCAM, Membrane-type Serine Protease, KIR2DL3, CD30, Salivary Agglutinin-10, CLEC-1, TPP1, Ubiquitin+1, ANGPTL4, TWEAK R, Nestin-1, CD2, Kallikrein 1, TSLP R, LAMP1, TROY, VCAM-1, salivary immunoglobulin-11, S100A1, PAR1, thyroid peroxidase, aminopeptidase P2, IL-1 RI, ADAMS, OSM R β, thromboretin-2, SMPD1B2M, MFRP, LRP-6, ST3GAL1, NCAM-1 (CD56), Granulase B, Lipocontin, IL-22BP, TPST2, PD-ECGF, LH, LEDGF, Cyr61, ULBP-3, IFNb, THSD1, FGF-23, LAMA4, Lipoprotein, AIF, SorCS2, SULT2A1, CD39L2, Insulin R, HIF-1 α, OX40 ligand, Pax3, UCH-L3, cMASP3, Langerin, desmin, SOX9, ST6GAL1, MEP1B, CD99-L2, conglomerate A4, brain signaling protein 4D, ROBO2, PDX-1, APRIL, neuronal rank protein, transmembrane protein-2 with ring structure, EMMPRIN, activating protein RIB, neuroligand 2, epithelial regulatory protein, CASA, MMP-12, GALNT2, CEACAM-5, VEGF R1, DSPG3, SorCS1, extracellular matrix protein-2, sFRP-3, p53, EphB3, NCK1, brain signaling protein 7A, NKp80, prolactin, cysteine ​​agonist protein B, Sirtuin 1, FGF-16, FGF R5, NQO-1, Brain signaling protein 6D, FGF-3, GATA-4, VAP-A, CHST2, Pregnancy-associated plasma protein-2, Cohesin-3, Serpentin-1, AKR1C4, Oligosin-2, Osteoadhesin, NKp44, Thyroglobulin, IL-21R, Chemokines, EphA1, CD48, MICB, FGF-5, TRANCE, CES2, ULBP-1, Integrin α 5. VAMP-2, FLRG, Ret metaphase factor, CD73, TRAP, proGRP, granzyme H, PRX2, p2'7, salivary lectin-6, dendritic cell-associated C-type lectin-1, CD51, Notch-1, calreticulin, DR3, DCTN1, CDC25B, bone activator, ACE, CA125, HAO-1, ​​PSMA1, FCRLB, BMP-9, CRIM1, LIF, SPINK1, EphB6, RGM-B, HS3ST1, ROR1, CMG-2, 4-1BB ligand, L1CAM-2, p63, cathepsin V, testosterone-2, phosphatidylinositol proteoglycan 5, CD6, salivary lectin-2, asparagine endopeptidase, PRELP, CES1, TAZ, NSE, TECK, HTRA2, HIF-1 β, TAFA1, podocyte protein, RalA, CRELD2, GRAP2, SP-D, BID, GFR α-2, Notch-3, VEGF R3, DLL4, TGFb2, LIGHT, XIAP, ST8SIA1, cathepsin L,6Ckine, MIS RII, kallikrein 5, TGM3, FCAR, contactin-2, CD83, IL-1 R3, SALM4, GBA3, ROBO4, OSCAR, VEGF, IGS F3, disaccharide proteoglycan, neurodevelopmental factor, ILT4, uPAR, Axl, WIF-1, IL-7 Rα, GPR56, CEACAM-3, MCEMP1, FABP2, plexin B3, MEPE, activator RIIA, ANG-2, Cochlin, progerin 1, NPTXR, SLAM, COMT, SPHK1, RBP4, stalkin-1, GUSB, nestin-2, IL-17F, SR-AI, TAFA2, N-cadherin, IL-17B, IL-17RC, MIP-3b, cysteine ​​protease C, cysteine ​​protease D, AMSH, FcERI, CLEC10A, HGF R, ANG-1, prolactin R, FGF-20, CD28, Nogo-A, HSD17B1, IL-19, intestinal peptidase, cathepsin E, TSLP, TCN2, GDF-15, epidermal morphogenetics, GRKS, PD-1, serine protease inhibitor A4, ADAM23, NOV, galactoglobulin-2, neuronal surface protein 3β, TLR3, Sirtuin 2, Numb, IL-28 Rα, IL-33, Lin28, FCRL1, KLF4, NKp30, lymphocyte chemokine, cysteine ​​protease protein SN, JAM-A, calreticulin-2, ErbB4, BMP-8, IL-27 Ra, Fas, IL-4 Ra, kallikrein 14, extracellular matrix protein-3, Oligo2, kallikrein 12, CA13, IL-9, stalk protein-3, MPIF-1, cysteine ​​protease protein S, ADA, IL-2 Rb, GFRα-1, Smad4, ICAM-1, MEF2C, TREM-1, L-selectin, transmembrane serine protease, CD42b, MCSF, RANK, CHST4, CA8, FCRL3, ASAH2, CF XIV, PYY, HGF, I-TAC, Brain signaling protein 4C, SorCS3, Tie-1, IL-31RA, Arginase 1, POGLUT1, IL-1ra, Flatfoot protein, TIM-3, CREG, CD300f, uPA, EphA2, LLRTM4, LIMPII, Tenosynovin R, CPE, PECAM-1, DNAM-1, DKK-1, OPG, CPB1, TSH, MMP-2, Salivary lectin-9, ICAM-3, Cysteine ​​agglutinin SA, Galactohemagglutinin-4, Pepsinogen II, Desmosome core protein-3, Stalk protein-4, SCFSerine protease inhibitor A5, PTH, FGF-19, MSP, IL-28A, FGF-12, METAP2, ASAHL, EDIL3, NTAL, EGF R, TAFAS, galactoglobulin-9, vWF-A2, TACE, activator protein RIM, cathepsin S, LDLR, BMPR-IA, OX40, IL-13 R2, B7-H4, MMP-13, ANGPTL7, TRAIL R4, IGSF4B, Sirtuin 5, PEAR1, SH2D1A, Cerberus 1, GDF-11, Nrf2, TROP-2, NUDTS, ROR2, EphB4, phosphatidylinositol proteoglycan 1, LAP (TGFb1), Gash, contactin-1, IL-27, UNC5H4, ICAM-2, MBL, HS3ST3B1, RCOR1, IL-10 Rb, XEDAR, IL-22, PILR-α, NRG1-131, FABP4, RGM-A, RELT, TrkC, CSa, SREC-I, neural epithelial stem cell protein, TPO, ErbB3, Kirrel3, FLRT1, galactoglobin-3, CXCL16, JAM-B, DR6, Nogo receptor, TLR4, VEGFR2, Tie-2, IL-15R, Caspr2, LTbR, LAMP, ALCAM, GLP-1, NG2, IL-22Rα1, AMIGO2, HCC-1, TFPI-2, ULBP-2, desmosome core protein 2, agglutinin, synaptic fusion protein 4, VAMP-1, stalkin-2, FGF-21, Flt-3, GFAP, TIM-1, inhibin A, cadherin-4, P1GF-2, neurogranulin, HE4, IL-23 R, galactoglobulin-7, GALNT3, GITR L, CD14, R-vertebral protein 2, CK19, myocardial trophin-1, TREML1, HAPLN1, CD27, ANG-4, salivary immunoglobulin-7, CD155, VEGF-C, TNF RII, PGRP-S, SDF-1a, PDGF-AB, GPVI, CD40, SCFR, platelet-reactive protein-5, IL-1 RII, neurofeedin-2, cadherin-13, E-selectin, GITR, WISP-1, renin, AgRP, MDL-1, ROBO3, RANTES, endothelial cell-specific molecules, granzyme, hCGb, mesothelin, TLR1, TRAIL, MOG, DDR1, NGF R, TRAIL R3, trypsin 3, ARSB, LIF Rα, BAFF R, CD157, granzyme A, 2B4, ESAM, IL-1 R4, CXCL14IL-31, SIRP α, urinary modulatory proteins, CTRC, CEACAM-1, TARC, MIP-3a, SDF-1b, NKp46, MCP-3, IL-32 α, TGFb3, FOLR2, CD58, IL-23, CD36, TNFb, Shh-N, fibrinogen-1, Reg4, ILT2, Mer, TREM-2, Flt-3L, CDS, IL-6, CD229, insulin, synaptic fusion protein 6, GRO, Bcl-w, lipocalin-2, PDGF-AA, IL-2 Ra, angiopoietin, LYVE-1, CD4, RAGE, CDNF, short proteoglycans, NAP-2, PU.1, EDAR, ADAMTS13, kynurenin, PTH1R, IFN-γ R1, CrkL, B7-1, PARC, Draxin, VE-cadherin, procalcitonin, SOX15, kallikrein 11, BCMA, dendritic cell-associated C-lectin-2, EpCAM, HCC-4, TGFa, IP-10, BLAME, CILP-1, PIGF, LOX-1, MCP-2, resistin, HVEM, ENPP-7, cohesin-4, IL-2 Rg, MICA, dopa decarboxylase, NPDC-1, MCP-4, EG-VEGF, glycoprotein V, brain signaling protein 4G, IL-12p40, total PSA, IL-15, MAP1D, C1q, TNF4, Dtk, endothelial glycoprotein, ENA-78, Reg3A, MIP-1b, FGF-17, IL-6R, IL-8, galactoglobulin-8, CA4, cysteine ​​protease protein EM, FUT8, B7-H3, GCP-2, CD40L, MDC, 4-1BB, HO-1, SOST, S100A13, kallikrein 7 or IL-13 or a combination of two or more thereof; (ii) hsa-let-7a-5p, hsa-let-7b-5p, hsa-let-7c-5p , hsa-let-7d-3p, hsa-let-7e-5p, hsa-let-7g-5p, hsa-let-7i, hsa-let-7i-5p, hsa-miR-100-5p, hsa-miR-103a-3p, hsa-miR-106a-5p, hsa-miR-106b-5p, hsa-mir -10b, hsa-miR-10b-5p, hsa-mir-1246, hsa-miR-1246, hsa-miR-125a-5p, hsa-miR -125b-5p, hsa-miR-130a-3p, hsa-mir-130b, hsa-miR-130b-3p, hsa-miR-132-3p,hsa-miR-136-5p, hsa-miR-138-5p, hsa-miR-139-5p, hsa-mir-140, hsa-miR-140-3p, hsa-miR-145-5p, hsa-mir-146a, hsa-miR-146a- 5p, hsa-miR-148a-3p, hsa-miR-152-3p, hsa-miR-15a-5p, hsa-miR-15b-5p, hsa-mir-16-1, hsa-mir-16-2, hsa-miR-16-5p, hsa-miR-1'7-5p, hsa-miR-181a-5p, hsa-miR-191-5p, hsa-miR-193a-5p, hsa-miR-193b-3p, hsa-miR-19'7-3p, hsa-miR-199a-3p, hsa-miR -199a-5p, hsa-miR-199b-5p, hsa-miR-19a-3p, hsa-miR-19b-3p, hsa-miR-20a-5p, hsa-mir-203a, hsa-miR-203a-3p, hsa-miR-214-3p, hsa-mir-21, hsa-miR-21-3p, hsa-miR-21-5p, hsa-mir-221, hsa-miR-221-3p, hsa-mir-222, hsa-miR-222-3p, hsa-miR-22-3p, h sa-miR-23a-3p, hsa-miR-23b-3p, hsa-mir-24-1, hsa-mir-24-2, hsa-miR-24-3p, hsa-mir-25, hsa-miR-25-3p, hsa-miR-26a-5p, hsa-miR-27a-3p, hsa-mir-27b, hsa-miR-27b-3p, hsa-miR-29a-3p, hsa-miR-29c-3p, hsa-miR-30a-5p, hsa-miR-30a-5p, hsa-miR-30 b-5p、hsa-miR-30c-5p、hsa-mir-30d、hsa-miR-30d-5p、hsa-mir-30e、hsa-miR-30e-5p、hsa-miR-31-3p、hsa-miR-31-5p、hsa-miR-3 20a、hsa-miR-342-3p、hsa-miR-345-5p、hsa-miR-34a-5p、hsa-miR-361-5p、hsa-miR-376a-3p、hsa-miR-376c-3p、hsa-miR-423-3p、hsa-miR-423-5p, hsa-miR-424-5p, hsa-miR-484, hsa-mir-486-1, hsa-mir-486-2, hsa -miR-486-5p, hsa-miR-570-3p, hsa-miR-574-3p, hsa-miR-663a, hsa-miR-874-3p, hsa- The following are possible combinations of mir-92a-1, hsa-mir-92a-2, hsa-miR-92a-3p, hsa-miR-92b-3p, hsa-mir-93, hsa-miR-93-5p, hsa-miR-940, hsa-miR-99a-5p, or hsa-miR-99b-5p, or a combination of two or more thereof; or both (iii), (i), and (ii). Another aspect of this disclosure is the use of a composition comprising a therapeutic mesenchymal stem cell (MSC) secretory composition containing extracellular vesicles (EVs) in the treatment of lumbar facet joint syndrome, wherein the composition comprises 0.5 mL of the therapeutic MSC secretory composition. In some embodiments, the therapeutic MSC secretory composition is injected into the facet joint space. Attached Figure Description

[0018] The novel features of this disclosure are set forth in the appended claims. A better understanding of the features and advantages of this disclosure will be obtained by referring to the following detailed description and accompanying drawings, which illustrate illustrative embodiments utilizing the principles of this disclosure, in which: Figure 1 The mean patient progression following injection of the treatment product into the lumbar facet joint space is shown. The following are presented: Severity Index (101), a measure of pain severity, with lower scores being desirable; Interference Index (102), with lower scores indicating stronger function; Oswestry Disability Index (ODI) (103), with lower scores indicating stronger function. All paired t-tests at all time points showed p-values ​​<0.001 compared to baseline measurements.

[0019] Figure 2 A simplified pain index (BPI) severity graph is shown for subjects treated with the compositions of this disclosure.

[0020] Figure 3 A graph of BPI interference index is shown for subjects treated with the compositions of this disclosure.

[0021] Figure 4 An Oswestry Disorder Index graph is shown for subjects treated with the compositions of this disclosure.

[0022] Figure 5Transparent images show the therapeutic product injected into the epidural space in the neck (top 2 images) and waist (bottom 2 images). Detailed Implementation

[0023] Therapeutic Composition Extracellular vesicles (EVs) are membrane-bound globules containing proteins and RNA (exosomes are a subset of them). Exosomes are small (e.g., 30–170 nm) diameter lipid bilayer vesicles secreted by cells to initiate paracrine communication. Other EV populations originate directly from the plasma membrane or form during apoptosis (apoptotic bodies). This document discloses compositions containing therapeutically effective amounts of MSC secretory components (e.g., including but not limited to MSC growth factors, MSC exosomes, MSC extracts, and / or compositions containing extracellular vesicles).

[0024] The exemplary compositions described herein comprise therapeutic compositions comprising biomolecules (which may include proteins, lipids, and / or ribonucleic acid) secreted from mesenchymal lineage cells and / or extracellular vesicles containing biomolecules. In one aspect, the therapeutic composition comprises a therapeutically effective amount of a component secreted from MSCs (i.e., the MSC secretome), such as, but not limited to, MSC growth factors, MSC exosomes, MSC extracts, and / or compositions containing extracellular vesicles. In an exemplary embodiment, the MSC is bone marrow MSC. The MSC secretome can be purified or otherwise isolated from MSC growth and / or culture conditions. For example, the MSC secretome may comprise exosomes isolated from MSC cultures. Thus, references to the MSC secretome include purified secretome components, such as exosomes or extracellular vesicles. Purified secretome components may be therapeutic compositions. Partially purified secretome components may be therapeutic compositions. For example, a therapeutic composition may comprise extracellular vesicles from the MSC secretome and one or more growth factors. The therapeutic composition may comprise reconstructed extracellular vesicles, such as those reconstructed from lyophilized or otherwise powdered or dried compositions. The therapeutic composition may contain reconstructed extracellular vesicles and one or more growth factors, for example, reconstructed from a lyophilized or otherwise powdered or dried composition.

[0025] In some embodiments, the MSC secretome comprises an MSC growth factor composition. In some embodiments, the MSC secretome is an MSC growth factor composition. The MSC growth factor composition may comprise one or more growth factors secreted from MSCs. One or more of the one or more growth factors secreted from MSCs may be present in exosomes secreted from MSCs. One or more of the one or more growth factors secreted from MSCs may be present in extracellular vesicles secreted from MSCs. One or more of the one or more growth factors secreted from MSCs may not be present in exosomes or extracellular vesicles secreted from MSCs. In an exemplary embodiment, the MSC is a bone marrow MSC.

[0026] In some embodiments, the MSC secretome comprises an MSC exosome composition. In some embodiments, the MSC secretome is an MSC exosome composition. The MSC exosome composition may comprise one or more exosomes secreted from MSCs. MSC exosomes may comprise one or more biomolecules, such as peptides, polypeptides, proteins, siRNA, shRNA, and / or microRNAs (miRNAs). MSC exosomes may comprise growth factors. Growth factors may be present in one or more exosomes secreted from MSCs. Growth factors may not be present in one or more exosomes secreted from MSCs. MSC exosomes may comprise nucleic acids, such as miRNAs. Nucleic acids may be present in one or more exosomes secreted from MSCs. Nucleic acids may not be present in one or more exosomes secreted from MSCs. In an exemplary embodiment, the MSC is a bone marrow MSC.

[0027] In some embodiments, the MSC secretome comprises an MSC extracellular vesicle composition. In some embodiments, the MSC secretome is an MSC extracellular vesicle composition. The MSC extracellular vesicle composition may comprise one or more extracellular vesicles secreted from MSCs. The MSC extracellular vesicle composition may comprise one or more biomolecules, such as peptides, polypeptides, proteins, siRNA, shRNA, and / or microRNAs (miRNAs). MSC extracellular vesicles may contain growth factors. Growth factors may be present within one or more extracellular vesicles secreted from MSCs. Growth factors may not be present within one or more extracellular vesicles secreted from MSCs. MSC extracellular vesicles may contain nucleic acids, such as miRNAs. Nucleic acids may be present within one or more extracellular vesicles secreted from MSCs. Nucleic acids may not be present within one or more extracellular vesicles secreted from MSCs. In an exemplary embodiment, the MSC is a bone marrow MSC.

[0028] In some embodiments, the MSC secretome comprises an MSC extract composition. In an exemplary embodiment, the MSC is a bone marrow MSC. In some embodiments, the MSC secretome is an MSC extract composition. The MSC extract composition may comprise one or more biomolecules, such as peptides, polypeptides, proteins, siRNA, shRNA, and / or microRNAs (miRNAs). The MSC extract composition may comprise exosomes and one or more biomolecules, wherein the exosomes are secreted from MSCs and one or more biomolecules are secreted from MSCs. One or more of the one or more biomolecules may be present in the exosomes. One or more of the one or more biomolecules may not be present in the exosomes. The MSC extract composition may comprise extracellular vesicles and one or more biomolecules, wherein the extracellular vesicles are secreted from MSCs and one or more biomolecules are secreted from MSCs. One or more of the one or more biomolecules may be present within the extracellular vesicles. One or more of the one or more biomolecules may not be present in the extracellular vesicles. One of the one or more biomolecules may be a growth factor. One of the one or more biomolecules may be a nucleic acid, such as miRNA.

[0029] In some embodiments, the MSC secretome comprises an MSC growth factor composition and an MSC exosome composition. In an exemplary embodiment, the MSC is a bone marrow MSC. The MSC growth factor composition may comprise one or more growth factors secreted from MSCs. One or more of the one or more growth factors secreted from MSCs may be present in the MSC exosome composition. One or more of the one or more growth factors secreted from MSCs may not be present in the exosomes. The MSC exosome composition may comprise one or more exosomes secreted from MSCs. MSC exosomes may comprise one or more biomolecules, such as peptides, polypeptides, proteins, siRNA, shRNA, and / or microRNAs (miRNAs). One of the one or more biomolecules may be a nucleic acid, such as miRNA.

[0030] In some embodiments, the MSC secretory group comprises an MSC growth factor composition and an MSC extracellular vesicle composition. In an exemplary embodiment, the MSC is a bone marrow MSC. The MSC growth factor composition may comprise one or more growth factors secreted from MSCs. One or more of the one or more growth factors secreted from MSCs may be present in the MSC extracellular vesicle composition. One or more of the one or more growth factors secreted from MSCs may not be present in the extracellular vesicles. The MSC extracellular vesicle composition may comprise one or more extracellular vesicles secreted from MSCs. MSC extracellular vesicles may comprise one or more biomolecules, such as peptides, polypeptides, proteins, siRNA, shRNA, and / or microRNAs (miRNAs). One of the one or more biomolecules may be a nucleic acid, such as miRNA.

[0031] In some embodiments, the therapeutic composition (e.g., an MSC secretome composition) comprises one or more peptide biomolecules. At least one of the one or more peptide biomolecules may be a growth factor. For example, 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, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 or more proteins may be present in the MSC secretome. Non-restricted exemplary growth factors or growth factor-related proteins that may be present in the MSC secretome include: ferritin, NUP85, LAMP2, GPR115, serine protease inhibitor F1, OPN, PAI-1, DAPP1, cathepsin B, brain signaling protein 6C, PDGF Rα, sorting protein, serine protease inhibitor B6, Dkk-3, coagulation regulator protein, PF4, MIF, periostealin, furin, TIMP-1, gypsum proteoglycan, PCK1, CD99, CD63, CD9, CD81, transferrin, DcR3, photoglucan, TIMP-2, SLITRK5, FAP, leptospirin, DPPII, cIAP-1, pentamericin 3, lactone, enkephalin, albumin, galactolectin-1, UNC5H3, IL-20 Rβ, SREC-II, JAM-C, TNF. RI, htPAPP-A, eNOS, MSP R, TPP1, LAMP1, B2M, NCAM-1, HIF-1 α, ST6GAL1, CD99-L2, conglomerate A4, EMMPRIN, p53, brain signaling protein 7A, NKp80, cysteine ​​protease protein B, osteoadhesion, mid-term factor, calreticulin, osteoactivin, asparagine endopeptidase, TAZ, cathepsin L, RBP4, serine protease inhibitor A4, JAM-A, MCSF, LIMPII, OPG, IL-22, galactoglobulin-3, MOG, trypsin 3, SIRP α, and cohesin-glycan-4. Non-restricted exemplary proteins that may be present in the MSC secretome include: ferritin, IGFBP-4, IL-1 R6, GSTM1, NUP85, LAMP2, transmembrane peptidase A, IL-1 F10, bIG-H3, GPR115, TGFb1, hepatocyte glycoside A4, CD109, serine protease inhibitor F1, IGFBP-6, HS3ST4, aminopeptidase LRAP, OPN, PAI-1, DAPP1, GDF-9, cathepsin B, IGFBP-2, brain signaling protein 6C, IGF-2, and PDGF R.α, Sorting protein, Serine protease inhibitor B6, Dkk-3, CNTF, TSP-1, GM-CSF Ra, Coagulation regulator protein, Endoglycosides, IGFBP-3, RGM-C, PF4, MIF, TGM4, Periostrin, Flintase, TIMP-1, PAPP-A, Glycerin proteoglycan, PCK1, Arylsulfatase A, CD99, CA2, PRDX4, Transferrin, DcR3, GP73, LAIR2, ULBP-4, Optical proteoglycan, TIMP-2, TFPI, SOX2, SLITRK5, FAP, Spinal cord protein, ENPP-2, CD97, CTACK, Integrin α1, EXTL3, IL-18, BPa, PD-L2, PSMA, IL-20 Ra, Glyoxalase II, Trypsin I, IGF-2R, ADAMTS L1-1, Erythropoietin, Convolutional D1, DNMT3A, BCL-2, CL-P1, Hepatocyte-B3, FABP6, CHI3L1, FCRLS, TFF3, Nephlebotomycin, DPPII, cIAP-1, PDGF Rb, Pentanoic Acid 3, Angiotensinogen, Follicle-Stapressin, CF VII, Persephin, TRAIL R1, THAP11, CD200, CLEC-2, AMIGO, IGFBP-5, PON1, SOX7, GALNT10, Lactone, Granulosin Progenitor, PCSK2, GKN1, IL-18, Enkephalin, Stabilin-2, IL-17 RD, albumin, follicle-stimulating protein 1, MMP-10, FKBP51, LRRC4, Pref-1, galactoglobin-1, troponin C, UNC5H3, FLRT2, CD314, brain signaling protein 6B, cytokinin-4, CD27 ligand, IL-20 Rβ, brain signaling protein 6A, TSK, cytokeratin-8, CHST3, Mcl-1, DPPIV, SREC-II, norin, JAM-C, Bcl-10, Wnt-4, LSECtin, Kell, TNF RI, PTP1B, htPAPP-A, IDO, PDGF-CC, Glycopropyl peptide, Activator Protein A, TLR2, SCCA2, FABP1, eNOS, SHP-1, ICOS, C1qTNF9, MMP-1, TC-PTP, IL-24, gp130, C-myc, LILRB4, BMP-2, MIA, CD34, CD63, CD9, CD81, IFNab R2, Phosphatidylinositol Proteoglycan 2, MSP R, DSCAM, Membrane-type Serine Protease, KIR2DL3, CD30, Salivary Agglutinin-10, CLEC-1, TPP1, Ubiquitin+1, ANGPTL4, TWEAKR, Nestin-1, CD2, Kallikrein 1, TSLP R, LAMP1, TROY, VCAM-1, Salivary agglutinin-11, S100A1, PAR1, Thyroid peroxidase, Aminopeptidase P2, IL-1 RI, ADAMS, OSM R β, Platelet-Reactive Protein-2, SMPD1, B2M, MFRP, LRP-6, ST3GAL1, NCAM-1 (CD56), Granulase B, Lipocontin, IL-22BP, TPST2, PD-ECGF, LH, LEDGF, Cyr61, ULBP-3, IFNb, THSD1, FGF-23, LAMA4, Lipoprotein, AIF, SorCS2, SULT2A1, CD39L2, Insulin R, HIF-1 α, OX40 ligand, Pax3, UCH-L3, cMASP3, Langerin, desmin, SOX9, ST6GAL1, MEP1B, CD99-L2, conglomerate A4, brain signaling protein 4D, ROBO2, PDX-1, APRIL, neuronal rank protein, transmembrane protein-2 with ring structure, EMMPRIN, activating protein RIB, neuroligand 2, epithelial regulatory protein, CASA, MMP-12, GALNT2, CEACAM-5, VEGF R1, DSPG3, SorCS1, extracellular matrix protein-2, sFRP-3, p53, EphB3, NCK1, brain signaling protein 7A, NKp80, prolactin, cysteine ​​agonist protein B, Sirtuin 1, FGF-16, FGF R5, NQO-1, Brain signaling protein 6D, FGF-3, GATA-4, VAP-A, CHST2, Pregnancy-associated plasma protein-2, Cohesin-3, Serpentin-1, AKR1C4, Oligosin-2, Osteoadhesin, NKp44, Thyroglobulin, IL-21R, Chemokines, EphA1, CD48, MICB, FGF-5, TRANCE, CES2, ULBP-1, Integrin α5. VAMP-2, FLRG, Ret metaphase factor, CD73, TRAP, proGRP, granzyme H, PRX2, p2'7, salivary lectin-6, dendritic cell-associated C-type lectin-1, CD51, Notch-1, calreticulin, DR3, DCTN1, CDC25B, bone activator, ACE, CA125, HAO-1, ​​PSMA1, FCRLB, BMP-9, CRIM1, LIF, SPINK1, EphB6, RGM-B, HS3ST1, ROR1, CMG-2, 4-1BB ligand, L1CAM-2, p63, cathepsin V, testosterone-2, phosphatidylinositol proteoglycan 5, CD6, salivary lectin-2, asparagine endopeptidase, PRELP, CES1, TAZ, NSE, TECK, HTRA2, HIF-1 β, TAFA1, podocyte protein, RalA, CRELD2, GRAP2, SP-D, BID, GFRα-2, Notch-3, VEGF R3, DLL4, TGFb2, LIGHT, XIAP, ST8SIA1, cathepsin L, 6-Ckine, MIS RII, kallikrein 5, TGM3, FCAR, contactin-2, CD83, IL-1 R3, SALM4, GBA3, ROBO4, OSCAR, VEGF, IGSF3, disaccharide proteoglycan, neurodevelopmental factor, ILT4, uPAR, Axl, WIF-1, IL-7 R α, GPR56, CEACAM-3, MCEMP1, FABP2, plexin B3, MEPE, activator RIIA, ANG-2, Cochlin, presenilin 1, NPTXR, SLAM, COMT, SPHK1, RBP4, stalkin-1, GUSB, nestin-2, IL-17F, SR-AI, TAFA2, N-cadherin, IL-17B, IL-17RC, MIP-3b, cysteine ​​protease C, cysteine ​​protease D, AMSH, FcERI, CLEC10A, HGF R, ANG-1, prolactin R, FGF-20, CD28, Nogo-A, HSD17B1, IL-19, intestinal peptidase, cathepsin E, TSLP, TCN2, GDF-15, epidermal morphogenetics, GRKS, PD-1, serine protease inhibitor A4, ADAM23, NOV, galactoglobulin-2, neuronal surface protein 3β, TLR3, Sirtuin 2, Numb, IL-28 Rα, IL-33, Lin28, FCRL1, KLF4, NKp30, lymphocyte chemokine, cysteine ​​protease protein SN, JAM-A, calreticulin-2, ErbB4, BMP-8, IL-27 Ra, Fas, IL-4Ra, kallikrein 14, extracellular matrix protein-3, Oligo2, kallikrein 12, CA13, IL-9, stalk protein-3, MPIF-1, cysteine ​​protease protein S, ADA, IL-2 Rb, GFR α-1, Smad4, ICAM-1, MEF2C, TREM-1, L-selectin, transmembrane serine protease, CD42b, MCSF, RANK, CHST4, CA8, FCRL3, ASAH2, CF XIV, PYY, HGF, I-TAC, brain signaling protein 4C, SorCS3, Tie-1, IL-31 RA, Arginase 1, POGLUT1, IL-1ra, Flatfoot protein, TIM-3, CREG, CD300f, uPA, EphA2, LLRTM4, LIMPII, Tenosynovin R, CPE, PECAM-1, DNAM-1, DKK-1, OPG, CPB1, TSH, MMP-2, Salivary lectin-9, ICAM-3, Cysteine ​​protease inhibitor SA, Galactohemagglutinin-4, Pepsinogen II, Desmosome core protein-3, Stalk protein-4, SCF, Serine protease inhibitor A5, PTH, FGF-19, MSP, IL-28A, FGF-12, METAP2, ASAHL, EDIL3, NTAL, EGF R, TAFAS, Galactohemagglutinin-9, vWF-A2, TACE, Activator protein RIM, Cathepsin S, LDL R, BMPR-IA, OX40, IL-13 R2, B7-H4, MMP-13, ANGPTL7, TRAIL R4, IGSF4B, Sirtuin 5, PEAR1, SH2D1A, Cerberus1, GDF-11, Nrf2, TROP-2, NUDTS, ROR2, EphB4, phosphatidylinositol proteoglycan 1, LAP (TGFb1), Gash, contactin-1, IL-27, UNC5H4, ICAM-2, MBL, HS3ST3B1, RCOR1, IL-10 Rb, XEDAR, IL-22, PILR-α, NRG1-131, FABP4, RGM-A, RELT, TrkC, CSa, SREC-I, neural epithelial stem cell protein, TPO, ErbB3, Kirrel3, FLRT1, galactolectin-3, CXCL16, JAM-B, DR6, Nogo receptor, TLR4, VEGF R2, Tie-2, IL-15 R, Caspr2, LTbR, LAMP, ALCAM, GLP-1, NG2, IL-22 R α1. AMIGO2, HCC-1, TFPI-2, ULBP-2, desmosome core protein 2, agglutinin, synaptic fusion protein 4, VAMP-1, stalkin-2, FGF-21, Flt-3, GFAP, TIM-1, inhibin A, cadherin-4, PIGF-2, neurogranulin, HE4, IL-23R, galactolectin-7, GALNT3, GITR L, CD14, R-vertebral protein 2, CK19, cardiotrophin-1, TREML1, HAPLN1, CD27, ANG-4, salivary lectin-7, CD155, VEGF-C, TNF-α, PGRP-S, SDF-1α, PDGF-AB, GPVI, CD40, SCF-R, platelet-reactive protein-5, IL-1 RII, neurofeltin-2, cadherin-13, E-selectin, GITR, WISP-1, renin, AgRP, MDL-1, ROBO3, RANTES, endothelial cell-specific molecules, granzyme, hCGb, mesothelin, TLR1, TRAIL, MOG, DDR1, NGF R, TRAIL R3, trypsin 3, ARSB, LIF Rα, BAFF R, CD157, granzyme A, 2B4, ESAM, IL-1R4, CXCL14, IL-31, SIRP α, urinary modulatory proteins, CTRC, CEACAM-1, TARC, MIP-3a, SDF-1b, NKp46, MCP-3, IL-32 α, TGFb3 FOLR2, CD58, IL-23, CD36, TNFb, Shh-N, fibrinogen-1, Reg4, ILT2, Mer, TREM-2, Flt-3L, CDS, IL-6, CD229, Insulin, Synaptic Fusion Protein 6, GRO, Bcl-w, Lipocrine-2, PDGF-AA, IL-2 Ra, Angiopoietin, LYVE-1, CD4, RAGE, CDNF, Short Proteoglycan, NAP-2, PU.1, EDAR, ADAMTS13, Kynurenase, PTH1R, IFN-γ R1, CrkL, B7-1, PARC, Draxin, VE-cadherin, procalcitonin, SOX15, kallikrein 11, BCMA, dendritic cell-associated C-lectin-2, EpCAM, HCC-4, TGFa, IP-10, BLAME, CILP-1, PIGF, LOX-1, MCP-2, resistin, HVEM, ENPP-7, cohesin-4, IL-2Rg, MICA, dopa decarboxylase, NPDC-1, MCP-4, EG-VEGF, glycoprotein V, brain signaling protein 4G, IL-12p40, total PSA, IL-15, MAP1D, C1q, TNF4, Dtk, endothelial glycoprotein, ENA-78, Reg3A, MIP-1b, FGF-17, IL-6R, IL-8, galactolectin-8, CA4, cysteine ​​protease protein EM, FUT8, B7-H3, GCP-2, CD40L, MDC, 4-1BB, HO-1, SOST, S100A13, kallikrein 7, and IL-13.

[0032] In some embodiments, the therapeutic composition (e.g., an MSC secretome composition) comprises one or more nucleic acid biomolecules. At least one of the one or more nucleic acid biomolecules may be a miRNA. For example, 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, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 or more nucleic acid sequences may be present in the MSC secretome. Non-restricted example miRNAs that can be present in the MSC secretome include: hsa-let-7a-5p, hsa-let-7b-5p, hsa-let-7c-5p, hsa-let-7d-3p, hsa-let-7e-5p, hsa-let-7g-5p, hsa-let-7i, hsa-let-7i-5p, hsa-miR-100-5p, hsa-miR-103a-3p, hsa-miR-106a-5p, hsa-miR-106b-5p, hsa-mir-10b, hsa-miR-10b-5p, hs a-mir-1246, hsa-miR-1246, hsa-miR-125a-5p, hsa-miR-125b-5p, hsa-miR-130a-3p, hsa-mir-130b, hsa-miR-130b-3p, hsa-miR-132-3 p, hsa-miR-136-5p, hsa-miR-138-5p, hsa-miR-139-5p, hsa-mir-140, hsa-miR-140-3p, hsa-miR-145-5p, hsa-mir-146a, hsa-miR-146a- 5p, hsa-miR-148a-3p, hsa-miR-152-3p, hsa-miR-15a-5p, hsa-miR-15b-5p, hsa-mir-16-1 , hsa-mir-16-2, hsa-miR-16-5p, hsa-miR-1'7-5p, hsa-miR-181a-5p, hsa-miR-191-5p, hs a-miR-193a-5p, hsa-miR-193b-3p, hsa-miR-19'7-3p, hsa-miR-199a-3p, hsa-miR-199a-5 p, hsa-miR-199b-5p, hsa-miR-19a-3p, hsa-miR-19b-3p, hsa-miR-20a-5p, hsa-mir-203a,hsa-miR-203a-3p, hsa-miR-214-3p, hsa-mir-21, hsa-miR-21-3p, hsa-miR-21-5p, hsa-mir-221, hsa-miR-221-3p, hsa-mir-222, hsa-miR-222-3p, hsa-miR-22-3p, hsa-miR-23a-3p, hsa-miR-23b-3p, hsa-mir-24-1, hsa-mir-24-2, hsa-miR-24-3p, hsa-mir-25, hsa-miR-25-3p, hsa-miR-26a-5p, hsa-miR-27a-3p, hsa-mir-27b, hsa-miR-27b-3p, hsa-miR-29a-3p, hsa-miR-29c-3p, hsa-miR-30a-5p, hsa-miR-30a-5p, hsa-miR-30b-5p, hsa-miR-30c-5p, hsa-mir-30d, hsa-miR-30d-5p, hsa-mir-30e, hsa-miR-30e-5p, hsa-miR-31-3p, hsa-miR-31-5p, hsa-miR-320a, hsa-miR-342-3p, hsa-miR-345-5p, hsa-miR-34a-5p, hsa-miR-361-5p, hsa-miR-376a-3p, hsa-miR-376c-3p, hsa-miR-423-3p, hsa-miR-423-5p, hsa-miR-424-5p, hsa-miR-484, hsa-mir-486-1, hsa-mir-486-2, hsa-miR-486-5p, hsa-miR-570-3p, hsa-miR-574-3p, hsa-miR-663a, hsa-miR-874-3p, hsa-mir-92a-1, hsa-mir-92a-2, hsa-miR-92a-3p, hsa-miR-92b-3p, hsa-mir-93, hsa-miR-93-5p, hsa-miR-940, hsa-miR-99a-5p and hsa-miR-99b-5p.

[0033] Exemplary microRNAs that may be present in therapeutic compositions (e.g., MSC secretomes) include hsa-let-7a-5p, hsa-let-7b-5p, hsa-let-7c-5p, hsa-let-7g-5p, hsa-let-7i-5p, hsa-miR-214-3p, and hsa-miR-27a-3p, as well as combinations of two or more thereof, each of which has a binding site for TMPRSS2 in the mRNA.

[0034] In some embodiments, the therapeutic composition (e.g., MSC secretome) contains CD63 + CD9 - CD81 - Extracellular vesicles of the phenotype. In some embodiments, at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, or 95% of the extracellular vesicles in the therapeutic composition are CD63. + CD9 - CD81 - In some embodiments, at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, or 95% of the extracellular vesicles in the therapeutic composition are CD9+. - In some embodiments, at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, or 95% of the extracellular vesicles in the therapeutic composition are CD81. - In an exemplary implementation, the MSC is a bone marrow MSC.

[0035] In some embodiments, the MSCs cultured to produce the therapeutic composition have the ability to differentiate in vitro into three lineages: adipocytes, osteoblasts, and chondrocytes. In some embodiments, the MSCs are positive for CD73, CD105, CD166, and CD90, and negative for CD14, CD31, CD34, and CD45. In an exemplary embodiment, the MSCs are bone marrow MSCs.

[0036] The therapeutic compositions described herein may comprise one or more exosomes and one or more growth factors. The growth factors and / or exosomes may be heterologous or homologous. The growth factors and / or exosomes may be derived from any cells in the human body, such as ectoderm cells, endoderm cells, or mesodermal cells. For example, the therapeutic composition may comprise growth factors derived from mesenchymal stem cells (MSCs), MSC-derived exosomes, or both MSC-derived growth factors and exosomes. In some embodiments, the therapeutic composition comprises one or more components derived from the MSC secretome and additives of components not derived from the MSC secretome. In one aspect, this article discloses a therapeutic composition comprising MSC secretome and one or more additional additives, wherein the one or more additional additives comprise prostaglandin E2 (PGE2), transforming growth factor 131 (TGF-131), hepatocyte growth factor (HGF), stromal cell-derived factor-1 (SDF-1), nitric oxide, indoleamine 2,3-dioxygenase, interleukin-4 (IL-4), IL-6, interleukin-10 (IL-10), IL-1 receptor antagonist and soluble TNF-α receptor, insulin-like growth factor, fibroblasts Growth factors (FGFs) 1-23 (especially FGF1 and FGF2), bone morphogenetic protein (BMP) 1-15, epidermal growth factor (EGF), transforming growth factor-α (TGF-α) macrophage-stimulating protein (MSP), platelet-derived growth factor (PLGF), vascular endothelial growth factor (VEGF), macrophage colony-stimulating factor (M-CSF), insulin, granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), estrogen or thyroid hormone, or combinations of two or more thereof. Non-limiting examples of the selection of growth factors or growth factor proteins are shown in Table 1 below.

[0037] Table 1 Embodiments of the therapeutic compositions described herein may include proteins and microRNAs, some of which may be embedded in or surrounded by a lipid membrane to generate vesicles ranging in size from about >20 nm to about 200 nm. The number of vesicles in the composition may be about 1 million to about 100 billion vesicles / mL when in suspension, or about 10 million to about 1 trillion when formulated as a lyophilized powder. The vesicles may be extracellular vesicles. Extracellular vesicles may be components of the MSC secretome. The vesicles may be exosomes. Exosomes may be components of the MSC secretome.

[0038] mesenchymal stem cells The example therapeutic compositions described herein comprise MSC secretome compositions and / or components derived from mesenchymal stem cells (MSCs) (e.g., biomolecules such as nucleic acids like miRNAs, and peptides such as growth factors). In one aspect, this document discloses MSC secretome compositions (including, but not limited to, MSC growth factors, MSC exosomes, MSC extracts, and / or compositions comprising extracellular vesicles) for the treatment, inhibition, relief, reduction, improvement, and / or prevention of conditions such as, for example, lumbar facet joint syndrome.

[0039] MSCs are pluripotent cells capable of differentiating into multiple cell types, including myocytes, chondrocytes, adipocytes, and osteoblasts. These cells are typically found in the placenta, umbilical cord blood, adipose tissue, bone marrow, or amniotic fluid, including perivascular tissue. As used herein, “MSC” refers to non-terminally differentiated cells, including but not limited to pluripotent stem cells, pluripotent stromal cells, stromal vascular cells, pericytes, vascular pericytes, stromal cells, pluripotent cells, fibroblast-like cells derived from adipose tissue, stromal vascular fractions derived from adipose tissue, MSCs derived from bone marrow, fibroblast-like cells derived from bone marrow, stromal vascular fractions derived from bone marrow, MSCs derived from bone marrow, fibroblast-like cells derived from tissue, adult stem cells, adult stromal cells, keratinocytes, and / or melanocytes.

[0040] In some embodiments, the MSC secretome composition comprises MSC growth factors, MSC exosomes, extracellular vesicles, extracellular vesicle isolates (EVIPs), cell-free extracts of MSCs, or MSC lysates, or combinations of two or more thereof, obtained from MSCs. MSCs can be human MSCs, fibroblast-like cells, or non-human animal MSCs, including but not limited to MSCs from horses, cattle, pigs, sheep, non-human primates, dogs, cats, rabbits, rats, or mice. In some embodiments, MSCs can be derived from the patient to whom the composition will be applied (autologous) or from another individual (allogeneic). MSCs can be cultured and expanded to collect conditioned medium and / or increase the cell count of the lysates or used fresh before incorporation into the therapeutic composition of this disclosure.

[0041] MSC secretome compositions (including, but not limited to, MSC growth factors, MSC exosomes, MSC extracts and / or compositions containing extracellular vesicles) may contain about 0.00001 to about 20 wt.%, such as about 0.01 to about 10 wt.% of mesenchymal stem cell (MSC) extracts, MSC exosomes or MSC growth factor formulations.

[0042] The MSC secretome composition or its components can be obtained by culturing MSCs under normal hyperoxia conditions or under artificial wound healing conditions.

[0043] MSCs can be selectively stimulated to produce the MSC secretome compositions or components thereof disclosed herein. Stimulated MSCs can produce MSC growth factors, secretomes, cytokines, chemokines, mesenchymal stem cell proteins, peptides, glycosaminoglycans, extracellular matrix (ECM), proteoglycans, or extracellular vesicles (e.g., exosomes), or combinations of two or more thereof. MSC growth factors include, but are not limited to, prostaglandin E2 (PGE2), transforming growth factor 131 (TGF-131), hepatocyte growth factor (HGF), stromal cell-derived factor-1 (SDF-1), nitric oxide, indoleamine 2,3-dioxygenase, interleukin-4 (IL-4), IL-6, interleukin-10 (IL-10), IL-1 receptor antagonists and soluble TNF-α receptors, insulin-like growth factor, fibroblast growth factor (FGF) 1-23 (especially FGF1 and FGF2), bone morphogenetic protein (BMP) 1-15, epidermal growth factor (EGF), transforming growth factor-a (TGF-a), macrophage-stimulating protein (MSP), platelet-derived growth factor (PLGF), vascular endothelial growth factor (VEGF), macrophage colony-stimulating factor (M-CSF), insulin, granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), and hormones, including estrogen and thyroid hormones.

[0044] MSC culture can occur under wound healing and / or hypoxic conditions. Wound healing conditions can include approximately 1% to approximately 5% oxygen, reduced or absent serum, reduced glucose, or various combinations of these elements. Combined reduced nutrient and metabolite environments can trigger cultured cells to produce wound-healing and anti-inflammatory ECM proteins and growth factors to guide tissue healing. In one aspect, the MSC secretome composition comprises MSC growth factors, MSC exosomes, and / or MSC cell extracts or MSC lysates obtained from MSCs cultured under standard hyperoxia conditions (e.g., 21% oxygen) or under artificial wound healing conditions (e.g., such as 0.1% to approximately 5% oxygen).

[0045] Artificial wound healing conditions used to culture MSCs may include one or more of the following growth conditions: reduced glucose availability, reduced oxygen partial pressure, reduced pH, and increased temperature.

[0046] In some embodiments, glucose availability may be reduced relative to a normal control (e.g., 4.5 g / L). The glucose in modified culture media that reduce glucose without harming cells may be reduced by 0% to 50%, more preferably by about 5% to 40%. For example, MSC artificial wound healing culture conditions may include glucose reductions of about 5% to about 15%, about 10% to about 20%, about 15% to about 25%, about 20% to about 30%, or about 25% to about 35%. In some embodiments, glucose is present at a concentration of about 0.1, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, or 4.0 g / L, or at a concentration in the range of any two of these values. In some embodiments, glucose is present at a concentration of less than or no more than 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, or 4.5 g / L.

[0047] In some implementations, the oxygen partial pressure can be reduced to the oxygen level required for hypoxic conditions. Normal atmospheric oxygen is approximately 21%, and any reduction is considered hypoxic. Therefore, in one aspect, MSCs can be cultured at oxygen levels of 0.0% to 20.9%, from about 0.1% to about 0.5%, from about 0.1% to about 2.0%, from about 0.1% to about 5.0%, from about 0.5% to 5.0%, from about 1.0% to about 10%, from about 5.0% to about 10.0%, and from about 10.0% to about 15.0%. Hypoxic conditions can be one aspect of artificial wound healing conditions.When MSCs are cultured to produce a therapeutic secretory composition containing extracellular vesicles and / or growth factors secreted by MSCs, the oxygen partial pressure can be between about 0.5% and 20.5% oxygen, for example, such as 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4 5, 4.6, 4.7, 4.8, 4.9, 5, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10, 10.1, 10.2, 10.3, 10.4, 10.5, 10.6, 10.7, 10.8, 10.9, 11, 11.1, 11.2, 11.3, 11.4, 11.5, 11.6, 11.7, 11.8, 11.9, 12, 12.1, 12.2, 12.3, 12.4, 12.5, 12.6, 12.7, 12.8, 12.9, 13, 13.1, 13.2, 13.3, 13.4, 13.5, 13.6, 13.7, 13.8, 13.9, 14, 14.1, 14.2, 14.3, 14.4, 14.5, 14.6, 14.7, 14.8, 14.9, 15, 15.1, 15.2, 15.3, 15.4, 15 0.5, 15.6, 15.7, 15.8, 15.9, 16, 16.1, 16.2, 16.3, 16.4, 16.5, 16.6, 16.7, 16.8, 16.9, 17, 17.1, 17.2, 17.3, 17.4, 17.5, 17.6, 17.7, 17.8, 17.9, 18, 18.1, 18.2, 18.3, 18.4, 18.5, 18.6, 18.7, 18.8, 18.9, 19, 19.1, 19.2, 19.3, 19.4, 19.5, 19.6, 19.7, 19.8, 19.9, or 20.0% oxygen, or a range between any two of these values.

[0048] The pH value can also be lowered during MSC culture. The pH can be from about 6.0 to about 7.4, for example, from about 6.0 to about 6.4, from about 6.2 to about 6.4, from about 6.2 to about 6.6, from about 6.4 to about 6.6, from about 6.4 to about 6.8, or from about 6.6 to about 7.0, such as 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, or 7.4.

[0049] The temperature of the culture environment can be increased relative to the physiological homeostatic temperature (e.g., 37°C). In one aspect, the culture conditions for MSCs can include from about 35°C to about 39°C, from about 35°C to about 36°C, from about 36°C to about 37°C, from about 37°C to about 38°C, from about 38°C to about 39°C, and from about 39°C to about 40°C. In another aspect, the culture temperature can be 35.0, 35.1, 35.2, 35.3, 36.4, 35.5, 35.6, 35.7, 35.8, 35.9, 36.0, 36.1, 36.2, 36.3, 36.4, 36.5, 36.6, 36.7, 36.8, 36.9, 37.0, 37.1, 37.2, 37.3, 3... 7.4, 37.5, 37.6, 37.7, 37.8, 37.9, 38.0, 38.1, 38.2, 38.3, 38.4, 38.5, 38.6, 38.7, 38.8, 38.9, 39.0, 39.1, 39.2, 39.3, 39.4, 39.5, 39.6, 39.7, 39.8, 39.9 or 40.0℃.

[0050] In some embodiments, the culture medium is serum-free. In some embodiments, the serum-free culture medium contains platelet lysate. In some embodiments, the platelet lysate is human platelet lysate (HPL). In some embodiments, the serum-free culture medium contains at least 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20% HPL by volume, or any range between two of these values. In some embodiments, the culture medium contains from 8% to 12%, 5% to 15%, or 9% to 11% HPL by volume.

[0051] In one aspect, therapeutic compositions, such as MSC secretome compositions (including but not limited to MSC growth factors, MSC exosomes, MSC extracts, and / or compositions containing extracellular vesicles), contain additives. Additives may act as a protective coating. Additives may reduce the degradation of components within the composition, such as growth factors. Additives may be cryoprotectants. Cryoprotectants may be oligosaccharides. Additives may be polymers. Polymers include relatively high molecular weight organic compounds, natural or synthetic, whose structure may be represented by repeating small unit monomers. Non-limiting examples of polymers include polyethylene, rubber, and cellulose. Synthetic polymers are typically formed by the addition or condensation polymerization of monomers. The term "copolymer" may refer to a polymer formed from two or more different repeating units (monomer residues). For example, but not limited to, copolymers may be alternating copolymers, random copolymers, block copolymers, or graft copolymers. Polymers may be natural polymers, synthetic polymers, homopolymers, heteropolymers, or copolymers. In one aspect, polymers may comprise copolymers, block copolymers, diblock copolymers, and / or triblock copolymers. In one aspect, additives may comprise biocompatible polymers. In one aspect, biocompatible polymers are crosslinked. Biocompatible polymers include, but are not limited to, polysaccharides; hydrophilic peptides; polyamino acids, such as poly-L-glutamic acid (PGS), γ-polyglutamic acid, poly-L-aspartic acid, poly-L-serine, or poly-L-lysine; polyalkylene glycols and polyalkylene oxides, such as polyethylene glycol (PEG), polypropylene glycol (PPG), and polyethylene oxide (PEO); poly(oxyethylated polyols); poly(enols); polyvinylpyrrolidone; poly(hydroxyalkyl methacrylamide); poly(hydroxyalkyl methacrylate); polysaccharides; poly(hydroxy acids); poly(vinyl alcohol), polyhydroxy acids such as poly(lactic acid), poly(glycolic acid), and polylactic-glycolic acid copolymers; and polyhydroxyalkanoates. Esters such as poly(3-hydroxybutyrate) or poly(4-hydroxybutyrate); polycaprolactone; poly(orthoester); polyanhydride; poly(phosphazene); polylactide-caprolactone copolymer; polycarbonates such as tyrosine polycarbonate; polyamides (including synthetic and natural polyamides), peptides and poly(amino acids); polyesteramide; polyester; poly(p-dioxanone); poly(alkylene oxide); hydrophobic polyether; polyurethane; polyether ester; polyacetal; polycyanoacrylate; polyacrylate; polymethyl methacrylate; polysiloxane; poly(ethylene oxide) / poly(propylene oxide) copolymer; polyketide; polyphosphate; polyhydroxyvalerate; polyalkylene oxalate; polyalkylene succinate; poly(maleic acid) and its copolymers.Biocompatible polymers may also include polyamides, polycarbonates, polyalkylenes, polyalkylene glycols, polyalkylene oxides, polyalkylene terephthalates, polyvinyl alcohol (PVA), methacrylate PVA (m-PVA), polyethylene ethers, polyethylene esters, polyhalogenated polyethylene, polyvinylpyrrolidone, polyglycolic acid, polysiloxanes, polyurethanes and their copolymers, alkyl cellulose, hydroxyalkyl cellulose, cellulose ethers, cellulose esters, nitrocellulose, polymers of acrylates and methacrylates, methylcellulose, ethylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, hydroxybutyl methylcellulose, cellulose acetate, cellulose propionate, cellulose acetate butyrate, cellulose acetate phthalate, carboxyethylcellulose, cellulose triacetate, sodium cellulose sulfate, poly(methyl methacrylate), poly(ethyl methacrylate), poly(butyl methacrylate), and poly(isobutyl methacrylate). Poly(hexyl methacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), poly(octadecyl acrylate), polyethylene, polypropylene, poly(ethylene glycol), poly(ethylene oxide), poly(ethylene glycol terephthalate), poly(vinyl alcohol), poly(vinyl acetate, polyvinyl chloride, polystyrene, and polyvinylpyrrolidone), their derivatives, their linear and branched copolymers and block copolymers, and blends thereof. Exemplary biodegradable polymers include polyesters, poly(orthoesters), poly(ethyleneamine), poly(caprolactone), poly(hydroxybutyrate), poly(hydroxyvalerate), polyanhydride, poly(acrylic acid), polyglycolic acid, poly(glycolic acid), poly(urethane), polycarbonate, polyphosphate, polyphosphazene, their derivatives, their linear and branched copolymers and block copolymers, and mixtures thereof.

[0052] In some embodiments, the protective coating comprises a carbohydrate structure of monosaccharides and carbohydrate polymers (such as disaccharides or polysaccharides, including but not limited to non-reducing polysaccharides or disaccharides and any combination thereof). Examples of carbohydrates that can be used in the protective coating include glucose, aldoses (D-allose, D-agrose, D-mannose, etc.), glucopyranose, pentahydroxyhexanal, aD-glucopyranosyl-D-glucose, aD-glucopyranosyl-dihydrate, polymers of PD-glucopyranosyl units, PD-fructofuranosyl-aD-glucopyranoside (anhydrous / dihydrate), f3-D-galactopyranosyl-D-glucose, aD-glucopyranosyl-dihydrate, etc. Glycosyl-aD-glucopyranoside (anhydrous / dihydrate), galactose, pentose (ribose, xylose, lysose), dextrose, decahydrate, fructose, sucrose, lactose, maltose, trehalose, agarose, D-galactosyl-O-(1-4)-dehydrated-L-galactosyl, cellulose, polymers of PD-glucopyranoside units and starch, as well as polyols, polyols, sugar alcohols, erythritol, glycols, glycerol, xylitol and sorbitol.

[0053] In some embodiments, the protective coating contains a biocompatible and / or biodegradable polyester or polyanhydride, such as poly(lactic-co-glycolic acid), poly(glycolic acid), and poly(lactic-co-glycolic acid) copolymers. The particles may comprise one or more of the following polyesters: homopolymers comprising glycolic acid units (referred to herein as “PGA”), and lactic acid units (such as poly-L-lactic acid, poly-D-lactic acid, poly-D,L-lactic acid, poly-L-lactide, poly-D-lactide, and poly-D,L-lactide 5, collectively referred to herein as “PLA”), and caprolactone units (such as poly(e-caprolactone) (collectively referred to herein as “PCL”); and copolymers comprising lactic acid and glycolic acid units, such as various forms of polylactic-co-glycolic acid copolymers and polylactide-glycolic acid copolymers, characterized by a lactic acid:glycolic acid ratio, collectively referred to herein as “PLGA”; and polyacrylates and their derivatives. Exemplary polymers also include copolymers of polyethylene glycol (PEG) and the aforementioned polyesters, such as various forms of PLGA-PEG or PLA-PEG copolymers, collectively referred to herein as "PEGylated polymers". In some embodiments, the PEG region can be covalently associated with the polymer via a pyrolytic linker to create a "PEGylated polymer". In one aspect, the polymer comprises at least 60%, 65%, 70%, 75%, 80%, 85%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% acetal side groups.

[0054] The triblock copolymers disclosed herein include, for example, polyethylene glycol (PEG), polyvinyl acetate, polyvinyl alcohol, polyvinylpyrrolidone (PVP), polyethylene oxide (PEO), polyvinylpyrrolidone-vinyl acetate copolymer, polymethacrylate, polyoxyethylene alkyl ether, polyoxyethylene castor oil, polycaprolactam, polylactic acid, polyglycolic acid, poly(lactic-glycolic acid), polylactic-glycolic acid copolymer (PLGA), and cellulose derivatives such as hydroxymethyl cellulose and hydroxypropyl cellulose. Examples of diblock copolymers that can be used in the protective coatings disclosed herein include, for example, polyethylene glycol (PEG), polyvinyl acetate, polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), polyethylene oxide (PEO), polyvinylpyrrolidone-vinyl acetate copolymer, polymethacrylate, polyoxyethylene alkyl ether, polyoxyethylene castor oil, polycaprolactam, polylactic acid, polyglycolic acid, poly(lactic-glycolic acid), polylactic-glycolic acid copolymer (PLGA).

[0055] In one aspect, the protective coating comprises (i.e., encapsulated), and the encapsulated composition may further comprise lecithin or hydrolyzed lecithin as a carrier or as an encapsulating material. As used herein, lecithin and / or hydrolyzed lecithin coatings comprise coatings containing phosphatidylcholine, phosphatidylinositol, phosphatidylethanolamine, phosphatidylserine, and phosphatidic acid. The source of lecithin may be plant or animal.

[0056] In one aspect, any of the polymers, monosaccharides, disaccharides, or polysaccharides used to form the protective coating formed by placing the MSC additive in the encapsulation solution can be at an appropriate concentration for forming the protective coating. For example, the polymers, monosaccharides, disaccharides, or polysaccharides can be at any concentration between 0.01 mM and 10.0 M, such as from about 0.01 M to about 0.1 M, from about 0.1 mM to about 1.0 M, or from about 1.0 M to about 10.0 M.

[0057] In one aspect, the MSC secretome compositions disclosed herein (including, but not limited to, MSC growth factors, MSC exosomes, MSC extracts, and / or compositions comprising extracellular vesicles) may include any known ingredients commonly found in the pharmaceutical field, such as agents for combating free radicals; bactericides; isolating agents; preservatives; alkalizing or acidifying agents; fragrances; surfactants; fillers; natural products or extracts of natural products, such as aloe or green tea extracts; vitamins; or coloring materials. Other ingredients that may be combined with the powder may include antioxidants, which may be selected from a variety of antioxidants. Suitable antioxidants include vitamins such as vitamin C (L-ascorbic acid, magnesium ascorbate-2-phosphate, ascorbate palmitate, tetrahexyldecyl ascorbate), vitamin E (tocotrienols), vitamin A (retinol, retinal, retinoic acid, provitamin A carotenoids, such as β-carotene), N-acetylglucosamine, or other derivatives of glucosamine. Other components may include at least one essential fatty acid, such as S2-3, S2-6, and S2-9 polyunsaturated fatty acids, such as linoleic acid (LA), gamma-linolenic acid (GLA), alpha-linolenic acid (ALA), di-homo-gamma-linolenic acid (DGLA), and arachidonic acid (ARA). Fatty acids can be derived from a variety of sources, including evening primrose oil, blackcurrant oil, borage oil, or GLA-modified safflower seed oil. Other components may include a platelet-rich fibrin matrix, at least one component that supports ECM production and hyaluronic acid production, such as N-acetylglucosamine or other derivatives of glucosamine, ultra-low molecular weight (ULMW) hyaluronic acid, chondroitin sulfate, or keratin sulfate.

[0058] MSC secretome compositions can be produced by a method comprising culturing MSCs collected from donors under stimulating conditions; collecting the secretome and combining the secretome with an additive; and freezing the combination; wherein the combination is formulated into a therapeutic composition. The frozen combination may be a dry powder. The therapeutic composition may comprise a dry powder reconstituted into a delivery medium (e.g., saline) suitable for human administration. The therapeutic composition may comprise exosomes, peptides, proteins, cytokines, growth factors, extracellular matrix (ECM), proteoglycans, glycosaminoglycans, chemokines, or combinations of two or more thereof. MSCs may be bone marrow MSCs. MSCs may be human MSCs, animal MSCs, pluripotent stromal cells, fibroblasts, or fibroblast cells. MSC secretome compositions can be produced by a method comprising culturing MSCs collected from donors under stimulating conditions, lysing the MSCs to produce an extracted lysate, concentrating the extracted lysate, combining the extracted lysate with an additive, and freezing the mixture to produce a dry powder. In an exemplary embodiment, the additive is a sugar. In some embodiments, freezing includes lyophilization. The powder may contain a concentrated collection of analgesic MSC secretory components (e.g., exosomes, extracellular matrix) that are specific for anti-inflammatory purposes.

[0059] The method may also include filtration-sterilization, concentration, freezing, or freeze-drying of MSC culture media, for example, after culture under wound healing conditions. Furthermore, MSC culture media may be combined with a cryoprotectant and then frozen. The cryoprotectant may be an additive, such as oligosaccharides.

[0060] Lysis can be achieved by adding a hypotonic solution or by repeated freeze-thaw cycles that disrupt the cell membrane. Cells can lyse while attached to a culture surface or in suspension. Cells can be lysed by enzymatic release and / or by mechanical homogenization.

[0061] Stimulation conditions include stimulating MSCs to selectively secrete desired anti-inflammatory proteins, peptides, glycosaminoglycans, proteoglycans, exosomes, and / or secretomes. Stimulation can be achieved by adjusting cell growth conditions such as cell confluence, culture medium additives, nutrient additives, oxygen levels, culture duration under these conditions, cell passage number, or combinations thereof. Stimulation can include growth under wound healing conditions. Wound healing conditions can include approximately 1% to approximately 5% oxygen, reduced or absent serum, reduced glucose, or various combinations of these elements.

[0062] Delivery of drug carriers / drug products Therapeutic compositions, such as MSC secretome compositions, can be administered in vivo in pharmaceutically acceptable carriers. "Pharmaceutically acceptable" means that the material is not biologically or otherwise undesirable; that is, the material can be administered to the subject together with the nucleic acid or carrier without causing any undesirable biological effects or interacting harmfully with any of the other components of the pharmaceutical composition containing it. The carrier can be selected to minimize any degradation of the active ingredient and any adverse side effects on the subject. The composition can be administered parenterally (e.g., intravenously).

[0063] If the composition is used for parenteral administration, it is typically characterized by injection. Injectable formulations can be prepared in conventional forms, such as liquid solutions or suspensions, solid forms suitable for dissolving or suspending in a liquid prior to injection, or emulsions. Parenteral administration may involve the use of sustained-release or continuous-release systems to maintain a constant dose.

[0064] Preparations intended for parenteral administration may include sodium chloride solution.

[0065] Therapeutic uses This article describes a treatment approach for lumbar facet joint syndrome. The patient may suffer from pain associated with lumbar facet joint syndrome. The pain may be chronic. The pain may cause functional impairment. The patient may also have lumbar facet joint degeneration.

[0066] Lumbar facet joint syndrome can be diagnosed in a subject prior to treatment. As one example, the subject has undergone imaging studies. As another example, the subject has received a diagnostic nerve block. As yet another example, the subject has a diagnosis of degenerative facet joint low back pain for at least 6 months, involving degeneration of one, two, or three facet joint segments.

[0067] Treatment of lumbar facet joint syndrome can lead to improvement in symptoms experienced by the subject prior to treatment. Non-limiting examples include pain, stiffness, range of motion, posture, general health, mood, social interaction, sleep, and walking ability, as well as combinations of two or more of these.

[0068] Compared with before treatment, treatment of lumbar facet joint syndrome can lead to improvement in the functional mobility of the subjects.

[0069] Treatment of lumbar facet joint syndrome can lead to an improvement in the severity index. This improvement can be defined as 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%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, or 50% compared to before treatment. Improvements of 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%, or 100% were observed. Treatment of lumbar facet joint syndrome can lead to improvements in the interference index. The improvement can be 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%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, or 50% compared to before application. Improvements of 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%, or 100% were observed. Treatment of lumbar facet joint syndrome can lead to an improvement in the Oswestry Disability Index (ODI).The improvement can be 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%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, or 50% compared to before application. Improvements of 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%, or 100%.

[0070] Methods for treating lumbar facet joint syndrome may include administering to the subject a protein-containing composition, wherein the protein comprises one or more proteins selected from the following: ferritin, IGFBP-4 (insulin-like growth factor binding protein-4), IL-1 R6 (interleukin-1 receptor 6), LAMP2 (lysosome-associated membrane glycoprotein 2), bIG-H3 (transforming growth factor-β-inducible protein ig-h3), GPR115 (adhesion G protein-coupled receptor F4), CD63 antigen, CD109 antigen, serine protease inhibitor F1 (pigment epithelial-derived factor), IGFBP-6 (insulin-like growth factor binding protein-6), HS3ST4 (heparanol sulfate glucosamine 3-O-sulfotransferase 4), OPN (osteopontin), PAI-1 (plasminogen activator inhibitor-1 or sERPINE). 1) Cathepsin B, IGFBP-2 (insulin-like growth factor binding protein-2), brain signaling protein 6C, IGF-2 (insulin-like growth factor-2), sorting protein, serine protease inhibitor B6, Dkk-3 (Dickkopf-related protein 3), CNTF (ciliary neurotrophic factor), TSP-1 (thromboretin-1), GM-CSF Ra (granulocyte-macrophage colony-stimulating factor receptor subunit α), coagulation regulatory protein, endosaccharide, (podocyte protein-like protein 2), IGFBP-3 (insulin-like binding protein-3), RGM-C (hepcidin regulatory protein), PF4 (platelet factor 4), MIF (macrophage migration inhibitory factor), TGM4 (protein glutamine-γ-glutamyl transferase 4), periosteal protein, furin protease, TIMP-1 (MMP tissue inhibitor 1), gypsum proteoglycan, PCK1 (cytosol-type phosphoenolpyruvate carboxykinase), CD9 antigen, CD99 antigen, CA2 (carbonic anhydrase 2), PRDX4 (peroxide reductase-4), transferrin, DcR3 (tumor necrosis factor receptor superfamily member 6B), GP73 (Golgi membrane protein 1), CD81 antigen, luminescent proteoglycan, TIMP-2 (MMP tissue inhibitor 2), and the proteins listed in Table 1. The composition may have a volume of approximately 0.5 mL. The composition can be injected into the interarticular space of small joints.

[0071] A method for treating lumbar facet joint syndrome may include administering to the subject a composition comprising extracellular vesicles (EVs) containing one or more nucleic acids selected from the following: hsa-miR-125b-5p, hsa-miR-145-5p, hsa-miR-191-5p, hsa-miR-199a-3p, hsa-miR-21-5p, hsa-miR-221-3p, hsa-miR-222-3p, hsa-miR-222-3p, hsa-miR-22-3p, hsa- miR-23a-3p, hsa-miR-23b-3p, hsa-miR-27a-3p, hsa-miR-27b-3p, hsa-miR-29a-3p, hsa-miR-29c-3p, hsa-miR-31-5p, hsa-miR-320a, hsa-miR-34a-5p, hsa-miR-423-3p, hsa-miR-424-5p, and hsa-miR-940, and combinations of two or more thereof. In some methods, at least 80% of the EV is CD63. + CD9 - CD81 - The composition can have a volume of about 0.5 mL. The composition can have at least about 60 billion EVs. The composition can have an EV concentration of at least about 60 billion EVs / mL. The composition can be injected into the interarticular space of small joints.

[0072] Methods for treating lumbar facet joint syndrome may include administering to the subject a composition comprising extracellular vesicles (EVs), wherein the composition contains at least about 60 billion EVs. At least about 60 billion EVs can be from about 60 billion to about 80 billion EVs. At least about 60 billion EVs can be a composition containing at least about 60 billion EVs / mL. At least about 60 billion EVs can be a composition containing about 60 billion to 80 billion EVs / mL. In some methods, at least 80% of the EVs are CD63. + CD9 - CD81 - The composition can have a volume of about 0.5 mL. The composition can be injected into the interarticular space of small joints.

[0073] Methods for treating lumbar facet joint syndrome may include administering a composition comprising extracellular vesicles (EVs), wherein at least 80% of the EVs are CD63. + CD9 - CD81 -The composition can have a volume of about 0.5 mL. The composition can be injected into the interarticular space of small joints. The composition can have at least about 60 billion EVs. The composition can have an EV concentration of at least about 60 billion EVs / mL.

[0074] Methods for treating lumbar facet joint syndrome may include administering to the subject a composition comprising a protein and extracellular vesicles (EVs), wherein the protein comprises one or more proteins selected from the following: ferritin, IGFBP-4 (insulin-like growth factor binding protein-4), IL-1 R6 (interleukin-1 receptor 6), LAMP2 (lysosome-associated membrane glycoprotein 2), bIG-H3 (transforming growth factor-β inducible protein ig-h3), GPR115 (adhesion G protein-coupled receptor F4), CD109 antigen, serine protease inhibitor F1 (pigment epithelial-derived factor), IGFBP-6 (insulin-like growth factor binding protein-6), HS3ST4 (heparanol sulfate glucosamine 3-O-sulfotransferase 4), OPN (osteopontin), PAI-1 (plasminogen activator inhibitor-1 or sERPINE). 1) Cathepsin B, IGFBP-2 (insulin-like growth factor binding protein-2), brain signaling protein 6C, IGF-2 (insulin-like growth factor-2), sorting protein, serine protease inhibitor B6, Dkk-3 (Dickkopf-related protein 3), CNTF (ciliary neurotrophic factor), TSP-1 (thromboretin-1), GM-CSF Ra (granulocyte-macrophage colony-stimulating factor receptor subunit α), coagulation regulatory protein, endosaccharide, (podocyte protein-like protein 2) IGFBP-3 (insulin-like binding protein-3), RGM-C (hepcidin regulatory protein), PF4 (platelet factor 4), MIF (macrophage migration inhibitory factor), TGM4 (protein glutamine-γ-glutamyl transferase 4), periosteal protein, furin protease, TIMP-1 (MMP tissue inhibitor 1), gypsum proteoglycan, PCK1 (cytosol-type phosphoenolpyruvate carboxykinase), CD9 antigen, CD99 antigen, CA2 (carbonic anhydrase 2), PRDX4 (peroxide reductase-4), transferrin, DcR3 (tumor necrosis factor receptor superfamily member 6B), GP73 (Golgi membrane protein 1), CD81 antigen, luminescent proteoglycan, TIMP-2 (MMP tissue inhibitor 2), and the proteins listed in Table 1;Furthermore, the EV contains one or more nucleic acids selected from the following: hsa-miR-125b-5p, hsa-miR-145-5p, hsa-miR-191-5p, hsa-miR-199a-3p, hsa-miR-21-5p, hsa-miR-221-3p, hsa-miR-222-3p, hsa-miR-22-3p, hsa-miR-23a-3p, hsa-miR- The miRNA sequences are hsa-miR-23b-3p, hsa-miR-27a-3p, hsa-miR-27b-3p, hsa-miR-29a-3p, hsa-miR-29c-3p, hsa-miR-31-5p, hsa-miR-320a, hsa-miR-34a-5p, hsa-miR-423-3p, hsa-miR-424-5p, and hsa-miR-940, as well as combinations of two or more of them. The miRNA sequences are available from https: / / www.mirbase.org / . In some methods, at least 80% of the EVs are CD63; + CD9 - CD81 - The composition can have a volume of about 0.5 mL. The composition can be injected into the interarticular space of small joints. The composition can have at least about 60 billion EVs. The composition can have an EV concentration of at least about 60 billion EVs / mL.

[0075] The protein to be administered to a subject can be prepared by a method comprising: (a) culturing bone marrow-derived mesenchymal stem cells (MSCs) under the following conditions to produce an MSC conditioned medium: (i) an oxygen partial pressure below 5%; and (ii) a medium with a pH below 7; (b) harvesting the MSC conditioned medium; and (c) formulating the MSC conditioned medium to produce a composition comprising the protein produced from the bone marrow-derived MSCs in step (a), and the formulation comprising formulating the protein into a pharmaceutically acceptable formulation for injection into a subject. The medium may be serum-free. The medium may have a glucose concentration below 4.5 g / L or be glucose-free. The composition may have a volume of about 0.5 mL. The composition may be injected into the interarticular space of small joints. The composition may have at least about 60 billion EVs. The composition may have an EV concentration of at least about 60 billion EVs / mL.

[0076] The EVs administered to the subject can be prepared by a method comprising: (a) culturing bone marrow-derived mesenchymal stem cells (MSCs) under the following conditions to produce an MSC conditioned medium: (i) an oxygen partial pressure below 5%; and (ii) a medium with a pH below 7; (b) harvesting the MSC conditioned medium; and (c) preparing the MSC conditioned medium to produce a composition comprising the EVs produced from the bone marrow-derived MSCs in step (a), and the preparation comprising formulating the EVs into a pharmaceutically acceptable formulation for injection into the subject. The medium may be serum-free. The medium may have a glucose concentration below 4.5 g / L or be glucose-free. In some methods, at least 80% of the EVs are CD63. + CD9 - CD81 - The composition can have a volume of about 0.5 mL. The composition can be injected into the interarticular space of small joints. The composition can have at least about 60 billion EVs. The composition can have an EV concentration of at least about 60 billion EVs / mL.

[0077] A method for treating lumbar facet joint syndrome may include administering a protein-containing composition to the subject, the method comprising: (a) culturing bone marrow-derived mesenchymal stem cells (MSCs) to produce an MSC conditioned medium under the following conditions: (i) an oxygen partial pressure of less than 5%; and (ii) a pH of less than 7; (b) harvesting the MSC conditioned medium; and (c) preparing the MSC conditioned medium to produce a composition comprising the protein produced from the bone marrow-derived MSCs in step (a), and the preparation comprising formulating the protein into a pharmaceutically acceptable formulation for injection into the subject; and (d) administering the pharmaceutically acceptable formulation to the subject. The medium may be serum-free. The medium may have a glucose concentration of less than 4.5 g / L or may be glucose-free. The composition may have a volume of about 0.5 mL. The composition may be injected into the facet joint space. The composition may have at least about 60 billion EVs. The composition may have an EV concentration of at least about 60 billion EVs / mL.

[0078] A method for treating lumbar facet joint syndrome may include administering a composition containing EVs to the subject, the method comprising: (a) culturing bone marrow-derived mesenchymal stem cells (MSCs) to produce MSC conditioned medium under the following conditions: (i) oxygen partial pressure below 5%; and (ii) a medium with a pH below 7; (b) harvesting the MSC conditioned medium; and (c) preparing the MSC conditioned medium to produce a composition comprising EVs produced from bone marrow-derived MSCs in step (a), and the preparation comprising formulating the EVs into a pharmaceutically acceptable formulation for injection into the subject; and (d) administering the pharmaceutically acceptable formulation to the subject. The medium may be serum-free. The medium may have a glucose concentration below 4.5 g / L or be glucose-free. In some methods, at least 80% of the EVs are CD63. + CD9 - CD81 - The composition can have a volume of about 0.5 mL. The composition can be injected into the interarticular space of small joints. The composition can have at least about 60 billion EVs. The composition can have an EV concentration of at least about 60 billion EVs / mL.

[0079] A method for treating lumbar facet joint syndrome may include administering a composition comprising a protein and an EV to the subject, the method comprising: (a) culturing bone marrow-derived mesenchymal stem cells (MSCs) to produce an MSC conditioned medium under the following conditions: (i) an oxygen partial pressure of less than 5%; and (ii) a medium with a pH of less than 7; (b) harvesting the MSC conditioned medium; and (c) preparing the MSC conditioned medium to produce a composition comprising the protein and EV produced from the bone marrow-derived MSCs in step (a), and the preparation comprising formulating the protein and EV into a pharmaceutically acceptable formulation for injection into the subject; and (d) administering the pharmaceutically acceptable formulation to the subject. The medium may be serum-free. The medium may have a glucose concentration of less than 4.5 g / L or be glucose-free. In some methods, at least 80% of the EV is CD63. + CD9 - CD81 - The composition can have a volume of about 0.5 mL. The composition can be injected into the interarticular space of small joints. The composition can have at least about 60 billion EVs. The composition can have an EV concentration of at least about 60 billion EVs / mL.

[0080] In some embodiments, the therapeutic compositions described herein (such as MSC secretome compositions) comprise growth factors and / or exosomes. Growth factors and / or exosomes can induce cell proliferation and angiogenesis. The therapeutic compositions described herein may comprise mitogenic proteins such as transforming growth factor-α (TGF-α), TGF-β, hepatocyte growth factor (HGF), epidermal growth factor (EGF), basic fibroblast growth factor (FGF-2), and / or insulin-like growth factor-1 (IGF-1). These increase the division of fibroblasts, epithelial cells, and endothelial cells. The therapeutic compositions described herein may comprise vascular endothelial growth factor (VEGF), IGF-1, EGF, and / or angiopoietin-1, which recruit endothelial lineage cells and initiate vascularization. The therapeutic compositions described herein may comprise anti-inflammatory components. The therapeutic compositions described herein may comprise immunomodulatory components. Non-limiting exemplary anti-inflammatory proteins include prostaglandin 2, TGF-131, HGF, SDF-1, nitrous oxide, indoleamine 2,3-dioxygenase, IL-4, IL-10, IL-1 receptor antagonists, and soluble tumor necrosis factor-α receptors. The therapeutic compositions of this invention may contain components that inhibit the proliferation and function of inflammatory immune cells, including T cells, natural killer cells, B cells, monocytes, macrophages, and dendritic cells.

[0081] A chronic inflammatory environment is characterized by a persistent imbalance between helper T cell types and macrophage types. In some implementations, therapeutic compositions, such as MSC secretory compositions, indirectly promote the conversion of TH1 cells to TH2 cells by reducing INF-γ and increasing IL-4 and IL-10. The restored TH1 / TH2 balance can improve tissue regeneration in cartilage, muscle, and other soft tissues. The reduction of INF-γ and the secretion of IL-4 can promote the conversion of macrophages from M1 type (pro-inflammatory, anti-angiogenic, and tissue growth inhibitory) to M2 type (anti-inflammatory, pro-remodeling, and tissue healing) for healing and regeneration of bone, muscle, and nerves.

[0082] This article discloses a method of treatment using a composition containing extracellular vesicles (EVs) derived from bone marrow mesenchymal stem cells (MSCs). In some embodiments, the EVs are 30-150 nm in size, encapsulated by a biphospholipid membrane containing a large number of bioactive proteins, lipids, and nucleic acids (translatable mRNA and miRNA). In some embodiments, the EVs inhibit apoptosis and modulate immune responses. One aspect of the research disclosed herein is to determine the safety and evaluate the clinical efficacy of a single injection of bone marrow mesenchymal stem cell-derived EVs (bmMSC EVs, the therapeutic product) into the lumbar facet joint space.

[0083] In some embodiments, the EV in the product described herein contains immunomodulatory proteins that immediately contribute to stimulating the production of anti-inflammatory chemokines and cytokines. These anti-inflammatory proteins help reduce the inflammatory activity of leukocytes and synovial cells. Simultaneously, the mRNA and miRNA inclusions of the EV can be translated within target cells to inhibit pro-inflammatory responses. These effects coordinately produce a comprehensive healing response.

[0084] Treatment methods for lumbar facet joint syndrome In some embodiments, the therapeutic compositions disclosed herein (e.g., MSC secretory composition) are used in a method of treating a subject with lumbar facet joint syndrome. In some embodiments, the subject suffers from chronic pain. In some embodiments, the subject suffers from back pain. In some embodiments, the subject has a history of chronic low back pain. In some embodiments, the subject suffers from chronic low back pain causing functional impairment. In some embodiments, the subject suffers from lumbar facet joint degeneration. In some embodiments, the subject has undergone imaging examinations to confirm lumbar facet joint degeneration. In some embodiments, the subject has received diagnostic nerve blocks at the L4-5 or L5-S1 segments to confirm lumbar facet joint syndrome. In some embodiments, the subject does not suffer from one or more of the following: severe stenosis, cauda equina symptoms, and / or a multifactorial diagnosis of lumbar facet joint syndrome. In some embodiments, the subject has had a diagnosis of degenerative facet joint low back pain for at least 6 months. In some embodiments, the subject is receiving routine treatment and / or pharmacological treatment for a diagnosis of DFLBP. In some embodiments, the subject suffers from facet joint degeneration of one, two, or three segments, as determined by magnetic resonance imaging (MRI). In some implementations, the subject does not have any autoimmune diseases. In some implementations, the subject does not have radiographic evidence of spinal degeneration or spondylolisthesis. In some implementations, the subject does not have symptomatic stenosis or herniated discs. In some implementations, the subject does not have symptomatic discogenic pain. In some implementations, the subject does not exhibit one or more of the following: blood cachexia, platelet dysfunction, sepsis, fever, malignancy, and / or skin infection.

[0085] In some implementations, the subject's response to treatment is measured via outcome assessment. In some implementations, outcome assessment includes a severity index, an interference index, and / or the Oswestry Disability Index (ODI). In some implementations, the Brief Pain Scale (BPI) is used to assess the severity of the subject's pain. In some implementations, the BPI is used to calculate the severity index. In some implementations, the BPI is used to calculate the interference index. In some implementations, the interference index includes several items, including but not limited to general activities, mood, walking ability, normal work (including housework), relationships with others, sleep, and enjoyment of life. In some implementations, the severity index includes several items, including but not limited to the severity of pain, the impact of pain on daily functioning, the location of pain, analgesics used, and the degree of pain relief over the past 24 hours or past week. In some implementations, subjects experience 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%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, or 46% of one or more of the following scores after treatment: Severity Index, Interference Index, and / or ODI score. 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%, or 100% improvement.

[0086] In some implementations, a baseline assessment is obtained prior to treatment. In some implementations, one or more outcome assessments are obtained at least once. In some implementations, one or more outcome assessments are compared to one or more baseline assessments. In some implementations, assessments are performed at 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 24 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, and 10 days post-treatment. Outcome assessments can be obtained in 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or 1 year.

[0087] Any therapeutic composition described herein may be used in treatments disclosed herein. In some embodiments, the persistence of any symptom disclosed herein is chronic. In some embodiments, one or more of the symptoms disclosed herein persist for 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 2 years, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, 10 years, or longer.

[0088] In some embodiments, the treatment product is administered via injection. In some embodiments, the treatment product is administered into the lumbar facet joint space. In some embodiments, the treatment product is administered via intra-articular puncture. In some embodiments, the treatment product is administered into one or more facet joint spaces. In some embodiments, a single dose of 0.5 mL of the treatment product is administered. In some embodiments, subjects are monitored post-treatment for at least one week, at least two weeks, at least three weeks, at least four weeks, at least one month, at least two months, at least three months, at least four months, at least five months, at least six months, at least seven months, at least eight months, at least nine months, at least ten months, at least eleven months, or at least twelve months.

[0089] This article discloses a method for treating lumbar facet joint syndrome in a subject, the method comprising administering to the subject a composition comprising a therapeutic mesenchymal stem cell (MSC) secretory composition containing extracellular vesicles, wherein at least 80% of the extracellular vesicles in the therapeutic MSC secretory composition are CD63+CD9-CD81-.

[0090] This article discloses a method for treating lumbar facet joint syndrome in a subject, wherein the method includes administering to the subject a composition comprising a therapeutic mesenchymal stem cell (MSC) secretory composition containing extracellular vesicles, wherein the subject exhibits, after administration, one or more improvements in pain, stiffness, range of motion, posture, general health, mood, social interaction, sleep, and / or walking ability compared to before administration.

[0091] This article also discloses methods and compositions for treating lumbar facet joint syndrome in subjects, wherein the method includes administering a treatment composition to the subject, for example, an MSC secretome composition comprising any combination of proteins and / or miRNAs selected from: ferritin, NUP85, LAMP2, GPR115, serine protease inhibitor F1, OPN, PAI-1, DAPP1, cathepsin B, brain signaling protein 6C, PDGF Rα, sorting protein, serine protease inhibitor B6, Dkk-3, coagulation regulator protein, PF4, MIF, periosteal protein, furin, TIMP-1, trabeculin glycan, PCK1, CD99, CD63, CD9, CD81, transferrin, DcR3, photoglycan, TIMP-2, SLITRK5, FAP, leptospirin, DPPII, cIAP-1, pentameric protein 3, endothelin, enkephalinase, albumin, galactolectin-1, UNC5H3, IL-20. Rβ, SREC-II, JAM-C, TNF RI, htPAPP-A, eNOS, MSP R, TPP1, LAMP1, B2M, NCAM-1, HIF-1 α, ST6GAL1, CD99-L2, conglomerate A4, EMMPRIN, p53, brain signaling protein 7A, NKp80, cysteine ​​protease protein B, osteoadhesion, mid-term factor, calreticulin, osteoactivin, leguminase, TAZ, cathepsin L, RBP4, serine protease inhibitor A4, JAM-A, MCSF, LIMPII, OPG, IL-22, galactolectin-3, MOG, trypsin 3, SIRP α, syndecan-4, IGFBP-4, IL-1, R6 GSTM1, NUP85, LAMP2, transmembrane peptidase A, IL-1 F10, bIG-H3, GPR115, TGFb1, liver glycoside-A4, CD109, serine protease inhibitor F1, IGFBP-6, HS3ST4, aminopeptidase LRAP, OPN, PAI-1, DAPP1, GDF-9, cathepsin B, IGFBP-2, brain signaling protein 6C, IGF-2, PDGF Rα, sorting protein, serine protease inhibitor B6, Dkk-3, CNTF, TSP-1, GM-CSFRa, coagulation regulatory protein, endosaccharide, IGFBP-3, RGM-C, PF4, MIF, TGM4, periostealin, furin, TIMP-1, PAPP-A, dermal proteoglycan, PCK1, arylsulfatase A, CD99, CA2, PRDX4, transferrin, DcR3, GP73, LAIR2, ULBP-4, optical proteoglycan, TIMP-2.TFPI, SOX2, SLITRK5, FAP, spinal cord protein, ENPP-2, CD97, CTACK, integrin α1, EXTL3, IL-18 BPa, PD-L2, PSMA, IL-20 Ra, glyoxalase II, trypsin I, IGF-2R, ADAMTSL-1, erythropoietin, globulin D1, DNMT3A, BCL-2, CL-P1, hepatocyte glycoside B3, FABP6, CHI3L1, FCRLS, TFF3, leptospirin, DPPII, cIAP-1, PDGF Rb, pentamericin 3, angiotensinogen, follicle-stimulating hormone, CF VII, persephin, TRAIL R1, THAP11, CD200, CLEC-2, AMIGO, IGFBP-5, PON1, SOX7, GALNT10, endothelin, granulosa protein precursor, PCSK2, GKN1, IL-18, enkephalin, stabilizer-2, IL-17 RD, albumin, follicle-stimulating protein 1, MMP-10, FKBP51, LRRC4, Pref-1, galactoglobin-1, troponin C, UNC5H3, FLRT2, CD314, brain signaling protein 6B, cytokeratin-4, CD27 ligand, IL-20 Rβ, brain signaling protein 6A, TSK, cytokeratin-8, CHST3, Mcl-1, DPPIV, SREC-II, norin, JAM-C, Bcl-10, Wnt-4, LSECtin, Kell, TNF RI, PTP1B, htPAPP-A, IDO, PDGF-CC, Glycopropyl peptide, Activator Protein A, TLR2, SCCA2, FABP1, eNOS, SHP-1, ICOS, C1qTNF9, MMP-1, TC-PTP, IL-24, gp130, C-myc, LILRB4, BMP-2, MIA, CD34, CD63, CD9, CD81, IFNab R2, Phosphatidylinositol Proteoglycan 2, MSP R, DSCAM, Membrane-type Serine Protease, KIR2DL3, CD30, Salivary Agglutinin-10, CLEC-1, TPP1, Ubiquitin+1, ANGPTL4, TWEAK R, Nestin-1, CD2, Kallikrein 1, TSLP R, LAMP1, TROY, VCAM-1, salivary immunoglobulin-11, S100A1, PAR1, thyroid peroxidase, aminopeptidase P2, IL-1 RI, ADAMS, OSM R β, thromboretin-2, SMPD1, B2M, MFRP, LRP-6, ST3GAL1, NCAM-1 (CD56), granzyme B, lipoconazole, IL-22BP, TPST2, PD-ECGF, LH, LEDGF, Cyr61, ULBP-3IFNb, THSD1, FGF-23, LAMA4, lipoprotein, AIF, SorCS2, SULT2A1, CD39L2, insulin R, HIF-1 α, OX40 ligand, Pax3, UCH-L3, cMASP3, Langerin, desmin, SOX9, ST6GAL1, MEP1B, CD99-L2, plexin A4, brain signaling protein 4D, ROBO2, PDX-1, APRIL, neuronal rankin, transmembrane protein-2 with ring structure, EMMPRIN, activator protein RIB, neuroligand 2, epithelial regulatory protein, CASA, MMP-12, GALNT2, CEACAM-5, VEGF R1, DSPG3, SorCS1, extracellular matrix protein-2, sFRP-3, p53, EphB3, NCK1, brain signaling protein 7A, NKp80, prolactin, cysteine ​​agonist protein B, Sirtuin 1, FGF-16, FGF R5, NQO-1, brain signaling protein 6D, FGF-3, GATA-4, VAP-A, CHST2, pregnancy-associated plasma protein-2, cohesin-3, serrated protein 1, AKR1C4, olfactory mesrin-2, osteoadhesion, NKp44, thyroglobulin, IL-21R, chemokines, EphA1, CD48, MICB, FGF-5, TRANCE, CES2, ULBP-1, integrin α 5. VAMP-2, FLRG, Ret metaphase factor, CD73, TRAP, proGRP, granzyme H, PRX2, p2'7, salivary lectin-6, dendritic cell-associated C-type lectin-1, CD51, Notch-1, calreticulin, DR3, DCTN1, CDC25B, bone activator, ACE, CA125, HAO-1, ​​PSMA1, FCRLB, BMP-9, CRIM1, LIF, SPINK1, EphB6, RGM-B, HS3ST1, ROR1, CMG-2, 4-1BB ligand, L1CAM-2, p63, cathepsin V, testosterone-2, phosphatidylinositol proteoglycan 5, CD6, salivary lectin-2, asparagine endopeptidase, PRELP, CES1, TAZ, NSE, TECK, HTRA2, HIF-1 β, TAFA1, podocyte protein, RalA, CRELD2, GRAP2, SP-D, BID, GFR α-2, Notch-3, VEGF R3, DLL4, TGFb2, LIGHT, XIAP, ST8SIA1, cathepsin L, 6-Ckine, MIS RII, kallikrein 5, TGM3, FCAR, contactin-2, CD83, IL-1 R3, SALM4, GBA3, ROBO4, OSCAR, VEGF, IGSF3, disaccharide proteoglycansNeurodevelopmental factor, ILT4, uPAR, Axl, WIF-1, IL-7 Rα, GPR56, CEACAM-3, MCEMP1, FABP2, plexin B3, MEPE, activator RIIA, ANG-2, Cochlin, presenilin 1, NPTXR, SLAM, COMT, SPHK1, RBP4, stalkin-1, GUSB, nestin-2, IL-17F, SR-AI, TAFA2, N-cadherin, IL-17B, IL-17RC, MIP-3b, cysteine ​​absorptioprotein C, cysteine ​​absorptioprotein D, AMSH, FcERI, CLEC10A, HGF R, ANG-1, prolactin R, FGF-20, CD28, Nogo-A, HSD17B1, IL-19, intestinal peptidase, cathepsin E, TSLP, TCN2, GDF-15, epidermal morphogenetics, GRKS, PD-1, serine protease inhibitor A4, ADAM23, NOV, galactoglobulin-2, neuronal surface protein 3β, TLR3, Sirtuin 2, Numb, IL-28 Rα, IL-33, Lin28, FCRL1, KLF4, NKp30, lymphocyte chemokine, cysteine ​​protease protein SN, JAM-A, calreticulin-2, ErbB4, BMP-8, IL-27 Ra, Fas, IL-4 Ra, kallikrein 14, extracellular matrix protein-3, Oligo2, kallikrein 12, CA13, IL-9, stalk protein-3, MPIF-1, cysteine ​​protease protein S, ADA, IL-2 Rb, GFR α-1, Smad4, ICAM-1, MEF2C, TREM-1, L-selectin, transmembrane serine protease, CD42b, MCSF, RANK, CHST4, CA8, FCRL3, ASAH2, CF XIV, PYY, HGF, I-TAC, brain signaling protein 4C, SorCS3, Tie-1, IL-31 RA, Arginase 1, POGLUT1, IL-1ra, Flatfoot protein, TIM-3, CREG, CD300f, uPA, EphA2, LLRTM4, LIMPII, Tenosynovin R, CPE, PECAM-1, DNAM-1, DKK-1, OPG, CPB1, TSH, MMP-2, Salivary lectin-9, ICAM-3, Cysteine ​​protease inhibitor SA, Galactolectin-4, Pepsinogen II, Desmosome core protein-3, Stalk protein-4, SCF, Serine protease inhibitor A5, PTH, FGF-19, MSP, IL-28A, FGF-12, METAP2, ASAHL, EDIL3, NTAL, EGF R, TAFA5, Galactolectin-9, vWF-A2TACE, activator protein RUB, cathepsin S, LDL R, BMPR-IA, OX40, IL-3 R2, B7-H4, MMP-13, ANGPTL7, TRAIL R4, IGSF4B, Sirtuin 5, PEAR1, SH2D1A, Cerberus1, GDF-11, Nrf2, TROP-2, NUDT5, ROR2, EphB4, phosphatidylinositol proteoglycan 1, LAP (TGFb1), Gash, contactin-1, IL-27, UNC5H4, ICAM-2, MBL, HS3ST3B1, RCOR1, IL-10 Rb, XEDAR, IL-22, PILR-α, NRG1-bl, FABP4, RGM-A, RELT, TrkC, C5a, SREC-I, neural epithelial stem cell protein, TPO, ErbB3, Kirrel3, FLRT1, galactoglobin-3, CXCL16, JAM-B, DR6, Nogo receptor, TLR4, VEGF R2, Tie-2, IL-15 R, Caspr2, LTbR, LAMP, ALCAM, GLP-1, NG2, IL-22 R α1, AMIGO2, HCC-1, TFPI-2, ULBP-2, desmosome core protein 2, agglutinin, synaptic fusion protein 4, VAMP-1, stalkin-2, FGF-21, Flt-3, GFAP, TIM-1, inhibin A, cadherin-4, P1GF-2, neurogranulin, HE4, IL-23 R, galactoglobulin-7, GALNT3, GITR L, CD14, R-vertebral protein 2, CK19, cardiotrophin-1, TREML1, HAPLN1, CD27, ANG-4, salivary immunoglobulin-7, CD155, VEGF-C, TNF-RH, PGRP-S, SDF-1a, PDGF-AB, GPVI, CD40, SCF R, platelet-reactive protein-5, IL-1 MI, neurofeedin-2, cadherin-13, E-selectin, GITR, WISP-1, renin, AgRP, MDL-1, ROBO3, RANTES, endothelial cell-specific molecules, granzyme, hCGb, mesothelin, TLR1, TRAIL, MOG, DDR1, NGF R, TRAIL R3, trypsin 3, ARSB, LIF Rα, BAFF R, CD157, granzyme A, 2B4, ESAM, IL-1 R4, CXCL14, IL-31, SIRP α, urinary modulatory proteins, CTRC, CEACAM-1, TARC, MIP-3a, SDF-1b, NKp46, MCP-3, IL-32 α, TGFb3, FOLR2, CD58, IL-23, CD36TNFb, Shh-N, Fibrin-1, Reg4, ILT2, Mer, TREM-2, Flt-3L, CDS, IL-6, CD229, Insulin, Synaptic Fusion Protein 6, GRO, Bcl-w, Lipocrine-2, PDGF-AA, IL-2 Ra, Angiopoietin, LYVE-1, CD4, RAGE, CDNF, Short Proteoglycan, NAP-2, PU.1, EDAR, ADAMTS13, Kynurenase, PTH1R, IFN-γ R1, CrkL, B7-1, PARC, Draxin, VE-cadherin, procalcitonin, SOX15, kallikrein 11, BCMA, dendritic cell-associated C-lectin-2, EpCAM, HCC-4, TGFa, IP-10, BLAME, CILP-1, PIGF, LOX-1, MCP-2, resistin, HVEM, ENPP-7, cohesin-glycan-4, IL-2, Rg, MICA, dopa decarboxylase, NPDC-1, MCP-4, EG-VEGF, glycoprotein V, brain signaling protein 4G, IL-12p40, total PSA, IL-15, MAP1D, C1q, TNF4, Dtk, endothelial glycoprotein, ENA-78, Reg3A, MIP- lb, FGF-17, IL-6R, IL-8, galactolectin-8, CA4, cysteine ​​protease protein EM, FUT8, B7-H3, GCP-2, CD40L, MDC, 4-1BB, HO-1, SOST, S100A13, kallikrein 7, IL-13, hsa-let-7a-5p, hsa-let-7b-5p, hsa-let-7c-5p, hsa-let-7d-3p, hsa-let-7e-5p, hsa-let-7g-5p, hsa-let-7i, hsa-let-7i-5p, hsa-miR-100-5p, hsa-miR-103a-3p, hsa-miR-106a-5p, hsa -miR-106b-5p, hsa-mir-10b, hsa-miR-10b-5p, hsa-mir-1246, hsa-miR-1246, hsa-miR-125a-5p, hsa-miR-125b-5p, hsa-miR-130a-3p, hsa-mir-130b, hsa-miR- 130b-3p, hsa-miR-132-3p, hsa-miR-136-5p, hsa-miR-138-5p, hsa-miR-139-5p, hsa-mir-140, hsa-miR-140-3p, hsa-miR-145-5p, hsa-mir-146a, hsa-miR-146a- 5p.hsa-miR-148a-3p, hsa-miR-152-3p, hsa-miR-15a-5p, hsa-miR-15b-5p, hsa-mir-16-1, hsa-mir-16-2, hsa-miR-16-5p, hsa-miR-1'7-5p, hsa-miR-181a-5p, hsa-miR-191-5p, hsa-miR-193a-5p, hsa-miR-193b-3p, hsa-miR-19'7-3p, hsa-miR-199a-3p, hsa-miR-199a-5p, hsa-miR-199b-5p, hsa-mi R-19a-3p, hsa-miR-19b-3p, hsa-miR-20a-5p, hsa-mir-203a, hsa-miR-203a-3p, hsa-miR-214-3p, hsa-mir-21, hsa-miR-21-3p, hsa-miR-21-5p, hsa-mir-221, hsa-miR-221-3p, hsa-mir-222, hsa-miR-222-3p, hsa-miR-22-3p, hsa-miR-23a-3p, hsa-miR-23b-3p, hsa-mir-24-1, hsa-mir-24-2, hsa- miR-24-3p, hsa-mir-25, hsa-miR-25-3p, hsa-miR-26a-5p, hsa-miR-27a-3p, hsa-mir-27b, hsa-miR-27b-3p, hsa-miR-29a-3p, hsa-miR-29c-3p, hsa-miR-30a-5p, hsa-miR-30a-5p, hsa-miR-30b-5p, hsa-miR-30c-5p, hsa-mir-30d, hsa-miR-30d-5p, hsa-mir-30e, hsa-miR-30e-5p, hsa-miR-31-3p hsa-miR-31-5p hsa-miR-320a hsa-miR-342-3p hsa-miR-345-5p hsa-miR-34a-5p hsa-miR-361-5p hsa-miR-376a-3p hsa-miR-376c-3p hsa-m iR-423-3p, hsa-miR-423-5p, hsa-miR-424-5p, hsa-miR-484, hsa-mir-486-1, hsa-mir-486-2, hsa-miR-486-5p, hsa-miR-570-3p, hsa-miR-574-3phsa-miR-663a, hsa-miR-874-3p, hsa-mir-92a-1, hsa-mir-92a-2, hsa-miR-92a-3p, hsa-m iR-92b-3p, hsa-mir-93, hsa-miR-93-5p, hsa-miR-940, hsa-miR-99a-5p and hsa-miR-99b-5p. ,

[0092] In some embodiments, the object to be treated with the therapeutic products and methods described herein may include any object suffering from or diagnosed with lumbar facet joint syndrome. In some embodiments, the object may include mammals. In some embodiments, the object may include humans. In some embodiments, the object may include non-human mammals. Non-limiting examples of non-human mammals may include non-human primates such as chimpanzees and other ape and monkey species; farm animals such as cattle, horses, sheep, goats, and pigs; domesticated animals such as rabbits, dogs, and cats; and laboratory animals including rodents such as mice, rats, and guinea pigs.

[0093] Non-restrictive numbering implementation plan 1. A method for treating lumbar facet joint syndrome in a subject, the method comprising administering to the subject a composition comprising a therapeutic mesenchymal stem cell (MSC) secretome composition, said therapeutic MSC secretome composition being prepared by a method comprising: (a) Culture bone marrow-derived MSCs under the following conditions to produce MSC conditioned medium: (i) Oxygen partial pressure below 5%; and (ii) Culture media with a pH below 7; (b) Harvest the MSC conditioned medium; and (c) Prepare the MSC conditioned medium to produce the therapeutic MSC secretome composition, wherein the therapeutic MSC secretome composition comprises proteins and extracellular vesicles produced by the bone marrow-derived MSCs in step (a).

[0094] 2. The method as described in implementation scheme 1, wherein the subject suffers from chronic pain.

[0095] 3. The method as described in implementation scheme 1 or 2, wherein the subject suffers from back pain.

[0096] 4. The method as described in any one of embodiments 1 to 3, wherein the subject suffers from chronic low back pain.

[0097] 5. The method as described in implementation scheme 4, wherein the chronic low back pain causes functional impairment.

[0098] 6. The method as described in any one of embodiments 5, wherein the subject suffers from lumbar facet joint degeneration.

[0099] 7. The method as described in any one of embodiments 1 to 6, wherein the subject has undergone imaging examinations and / or diagnostic nerve blocks to confirm lumbar facet joint syndrome.

[0100] 8. The method of any one of embodiments 1 to 7, wherein the subject experiences improvement in one or more of the following symptoms after treatment: pain, stiffness, range of motion, posture, general health, mood, social interaction, sleep and / or walking ability, and combinations thereof.

[0101] 9. The method of any one of embodiments 1 to 8, wherein the dose of the therapeutic MSC secretome composition administered to the subject is 600-800 billion extracellular vesicles / mL.

[0102] 10. The method of any one of embodiments 1 to 9, wherein the culture medium is serum-free.

[0103] 11. The method of any one of embodiments 1 to 10, wherein the culture medium has a glucose concentration of less than 4.5 g / L.

[0104] 12. The method according to any one of embodiments 1 to 11, wherein at least 80% of the extracellular vesicles in the therapeutic MSC secretome composition are CD63. + CD9 - CD81 - .

[0105] 13. The method according to any one of embodiments 1 to 12, wherein the therapeutic MSC secretome composition comprises one or more of the following proteins: ferritin, NUP85, LAMP2, GPR115, serine protease inhibitor F1, OPN, PAI-1, DAPP1, cathepsin B, brain signaling protein 6C, PDGF Rα, sorting protein, serine protease inhibitor B6, Dkk-3, coagulation regulatory protein, PF4, MIF, periosteal protein, furin, TIMP-1, gypsum proteoglycan, PCK1, CD99, CD63, CD9, CD81, transferrin, DcR3, photoglucan, TIMP-2, SLITRK5, FAP, leptospirin, DPPII, cIAP-1, pentameric protein 3, lactone, enkephalin, albumin, galactolectin-1, UNC5H3, IL-20 Rβ, SREC-II, JAM-C, TNF. RI, htPAPP-A, eNOS, MSP R, TPP1, LAMP1, B2M, NCAM-1, HIF-1 α, ST6GAL1, CD99-L2, convolutional protein A4, EMMPRIN, p53, brain signaling protein 7A, NKp80, cysteine ​​protease protein B, osteoadhesion, mid-term factor, calreticulin, osteoactivin, asparagine endopeptidase, TAZ, cathepsin L, RBP4, serine protease inhibitor A4, JAM-A, MCSF, LIMPII, OPG, IL-22, galactolectin-3, MOG, trypsin 3, SIRP α, cohesin-4, IGFBP-4, IL-1, R6 GSTM1, NUP85, LAMP2, transmembrane peptidase A, IL-1 F10, bIG-H3, GPR115, TGFb1, liver glycoside A4, CD109, serine protease inhibitor F1, IGFBP-6, HS3ST4, aminopeptidase LRAP, OPN, PAI-1, DAPP1, GDF-9, cathepsin B, IGFBP-2, brain signaling protein 6C, IGF-2, PDGFR α, sorting protein, serine protease inhibitor B6, Dkk-3, CNTF, TSP-1, GM-CSF Ra, coagulation regulatory protein, endosaccharides, IGFBP-3, RGM-C, PF4, MIF, TGM4, periosteal protein, furin, TIMP-1, PAPP-A, dermal proteoglycan, PCK1, arylsulfatase A, CD99, CA2, PRDX4, transferrin, DcR3, GP73, LAIR2, ULBP-4, optical proteoglycan, TIMP-2, TFPI, SOX2, SLITRK5, FAP, spinal cord protein, ENPP-2, CD97, CTACK, integrin α1, EXTL3, IL-18BPa, PD-L2, PSMA, IL-20 Ra, Glyoxalase II, Trypsin I, IGF-2R, ADAMTS L1-1, Erythropoietin, Convolutional D1, DNMT3A, BCL-2, CL-P1, Hepatocyte Glycol-B3, FABP6, CHI3L1, FCRLS, TFF3, Nephlebotomycin, DPPII, cIAP-1, PDGF Rb, Pentanoic Acid 3, Angiotensinogen, Follicle-Stapressin, CF VII, Persephin, TRAIL R1, THAP11, CD200, CLEC-2, AMIGO, IGFBP-5, PON1, SOX7, GALNT10, Lactone, Granulosin Progenitor, PCSK2, GKN1, IL-18, Enkephalin, Stabilin-2, IL-17 RD, albumin, follicle-stimulating protein 1, MMP-10, FKBP51, LRRC4, Pref-1, galactoglobin-1, troponin C, UNC5H3, FLRT2, CD314, brain signaling protein 6B, cytokinin-4, CD27 ligand, IL-20 Rβ, brain signaling protein 6A, TSK, cytokeratin-8, CHST3, Mcl-1, DPPIV, SREC-II, norin, JAM-C, Bcl-10, Wnt-4, LSECtin, Kell, TNF RI, PTP1B, htPAPP-A, IDO, PDGF-CC, Glycopropyl peptide, Activator Protein A, TLR2, SCCA2, FABP1, eNOS, SHP-1, ICOS, C1qTNF9, MMP-1, TC-PTP, IL-24, gp130, C-myc, LILRB4, BMP-2, MIA, CD34, CD63, CD9, CD81, IFNab R2, Phosphatidylinositol Proteoglycan 2, MSP R, DSCAM, Membrane-type Serine Protease, KIR2DL3, CD30, Salivary Agglutinin-10, CLEC-1, TPP1, Ubiquitin+1, ANGPTL4, TWEAK R, Nestin-1, CD2, Kallikrein 1, TSLPR, LAMP1, TROY, VCAM-1, Salivary agglutinin-11, S100A1, PAR1, Thyroid peroxidase, Aminopeptidase P2, IL-1RI, ADAMS, OSM Rβ, Platelet-Reactive Protein-2, SMPD1, B2M, MFRP, LRP-6, ST3GAL1, NCAM-1 (CD56), Granulase B, Lipocontin, IL-22BP, TPST2, PD-ECGF, LH, LEDGF, Cyr61, ULBP-3, IFNb, THSD1, FGF-23, LAMA4, Lipoprotein, AIF, SorCS2, SULT2A1, CD39L2, Insulin R, HIF-1α, OX40 ligand, Pax3, UCH-L3, cMASP3, Langerin, desmin, SOX9, ST6GAL1, MEP1B, CD99-L2, conglomerate A4, brain signaling protein 4D, ROBO2, PDX-1, APRIL, neuronal rank protein, transmembrane protein-2 with ring structure, EMMPRIN, activating protein RIB, neuroligand 2, epithelial regulatory protein, CASA, MMP-12, GALNT2, CEACAM-5, VEGF R1, DSPG3, SorCS1, extracellular matrix protein-2, sFRP-3, p53, EphB3, NCK1, brain signaling protein 7A, NKp80, prolactin, cysteine ​​agonist protein B, Sirtuin 1, FGF-16, FGF R5, NQO-1, Brain signaling protein 6D, FGF-3, GATA-4, V'PA, CHST2, Pregnancy-associated plasma protein-2, Cohesin-3, Serpentin-1, AKR1C4, Oligosin-2, Osteoadhesin, NKp44, Thyroglobulin, IL-21R, Chemokines, EphA1, CD48, MICB, FGF-5, TRANCE, CES2, ULBP-1, Integrin α 5. VAMP-2, FLRG, Ret metaphase factor, CD73, TRAP, proGRP, granzyme H, PRX2, p2'7, salivary lectin-6, dendritic cell-associated C-type lectin-1, CD51, Notch-1, calreticulin, DR3, DCTN1, CDC25B, bone activator, ACE, CA125, HAO-1, ​​PSMA1, FCRLB, BMP-9, CRIM1, LIF, SPINK1, EphB6, RGM-B, HS3ST1, ROR1, CMG-2, 4-1BB ligand, L1CAM-2, p63, cathepsin V, testosterone-2, phosphatidylinositol proteoglycan 5, CD6, salivary lectin-2, asparagine endopeptidase, PRELP, CES1, TAZ, NSE, TECK, HTRA2, HIF-1 β, TAFA1, podocyte protein, RalA, CRELD2, GRAP2, SP-D, BID, GFR α-2, Notch-3, VEGF R3, DLL4, TGFb2, LIGHT, XIAP, ST8SIA1, cathepsin L, 6-Ckine, MIS RII, kallikrein 5, TGM3, FCAR, contactin-2, CD83, IL-1R3, SALM4, GBA3, ROBO4, OSCAR, VEGF, IGSF3, disaccharide proteoglycan, neurodevelopmental factor, ILT4, uPAR, Axl, WIF-1, IL-7 Rα, GPR56, CEACAM-3, MCEMP1, FABP2, plexin B3, MEPE, activator RIIA, ANG-2, Cochlin, presenilin 1, NPTXR, SLAM, COMT, SPHK1, RBP4, stalkin-1, GUSB, nestin-2, IL-17F, SR-AI, TAFA2, N-cadherin, IL-17B, IL-17RC, MIP-3b, cysteine ​​protease C, cysteine ​​protease D, AMSH, FcERI, CLEC10A, HGF R, ANG-1, prolactin R, FGF-20, CD28, Nogo-A, HSD17B1, IL-19, intestinal peptidase, cathepsin E, TSLP, TCN2, GDF-15, epidermal morphogenetics, GRKS, PD-1, serine protease inhibitor A4, ADAM23, NOV, galactoglobulin-2, neuronal surface protein 3β, TLR3, Sirtuin2, Numb, IL-28 Rα, IL-33, Lin28, FCRL1, KLF4, NKp30, lymphocyte chemokine, cysteine ​​protease protein SN, JAM-A, calreticulin-2, ErbB4, BMP-8, IL-27 Ra, Fas, IL-4 Ra, kallikrein 14, extracellular matrix protein-3, Oligo2, kallikrein 12, CA13, IL-9, stalk protein-3, MPIF-1, cysteine ​​protease protein S, ADA, IL-2 Rb, GFR α-1, Smad4, ICAM-1, MEF2C, TREM-1, L-selectin, transmembrane serine protease, CD42b, MCSF, RANK, CHST4, CA8, FCRL3, ASAH2, CF XIV, PYY, HGF, I-TAC, brain signaling protein 4C, SorCS3, Tie-1, IL-31 RA, Arginase 1, POGLUT1, IL-1ra, Flatfoot protein, TIM-3, CREG, CD300f, uPA, EphA2, LLRTM4, LIMPII, Tenosynovin R, CPE, PECAM-1, DNAM-1, DKK-1, OPG, CPB1, TSH, MMP-2, Salivary lectin-9, ICAM-3, Cysteine ​​protease inhibitor SA, Galactohemagglutinin-4, Pepsinogen II, Desmosome core protein-3, Stalk protein-4, SCF, Serine protease inhibitor A5, PTH, FGF-19, MSP, IL-28A, FGF-12, METAP2, ASAHL, EDIL3, NTAL, EGF R, TAFAS, Galactohemagglutinin-9, vWF-A2, TACE, Activator protein RIM, Cathepsin S, LDLR, BMPR-IA, OX40, IL-13 R2, B7-H4, MMP-13, ANGPTL7, TRAIL R4, IGSF4B, Sirtuin 5, PEAR1, SH2D1A, Cerberus 1, GDF-11, Nrf2, TROP-2, NUDTS, ROR2, EphB4, phosphatidylinositol proteoglycan 1, LAP (TGFb1), Gash, contactin-1, IL-27, UNC5H4, ICAM-2, MBL, HS3ST3B1, RCOR1, IL-10 Rb, XEDAR, IL-22, PILR-α, NRG1-131, FABP4, RGM-A, RELT, TrkC, CSa, SREC-I, neural epithelial stem cell protein, TPO, ErbB3, Kirrel3, FLRT1, galactoglobulin-3, CXCL16, JAM-B, DR6, Nogo receptor, TLR4, VEGF R2, Tie-2, IL-15 R, Caspr2, LTbR, LAMP, ALCAM, GLP-1, NG2, IL-22 Rα 1, AMIGO2, HCC-1, TFPI-2, ULBP-2, desmosome core protein 2, agglutinin, synaptic fusion protein 4, VAMP-1, stalkin-2, FGF-21, Flt-3, GFAP, TIM-1, inhibin A, cadherin-4, PIGF-2, neurogranulin, HE4, IL-23 R, galactoglobulin-7, GALNT3, GITR L, CD14, R-vertebral protein 2, CK19, cardiotrophin-1, TREML1, HAPLN1, CD27, ANG-4, salivary immunoglobulin-7, CD155, VEGF-C, TNF RII, PGRP-S, SDF-1a, PDGF-AB, GPVI, CD40, SCF R, platelet-reactive protein-5, IL-1 RII, neurofeedin-2, cadherin-13, E-selectin, GITR, WISP-1, renin, AgRP, MDL-1, ROBO3, RANTES, endothelial cell-specific molecules, granzyme, hCGb, mesothelin, TLR1, TRAIL, MOG, DDR1, NGF R, TRAIL R3, trypsin 3, ARSB, LIF Rα, BAFFR, CD157, granzyme A, 2B4, ESAM, IL-1 R4, CXCL14, IL-31, SIRP α, urinary modulating protein, CTRC, CEACAM-1, TARC, MIP-3a, SDF-1b, NKp46, MCP-3, IL-32 α, TGFb3FOLR2, CD58, IL-23, CD36, TNFb, Shh-N, fibrinogen-1, Reg4, ILT2, Mer, TREM-2, Flt-3L, CDS, IL-6, CD229, Insulin, Synaptic Fusion Protein 6, GRO, Bcl-w, Lipocrine-2, PDGF-AA, IL-2 Ra, Angiopoietin, LYVE-1, CD4, RAGE, CDNF, Short Proteoglycan, NAP-2, PU.1, EDAR, ADAMTS13, Kynurenase, PTH1R, IFN-γ R1, CrkL, B7-1, PARC, Draxin, VE-cadherin, procalcitonin, SOX15, kallikrein 11, BCMA, dendritic cell-associated C-lectin-2, EpCAM, HCC-4, TGFa, IP-10, BLAME, CILP-1, PIGF, LOX-1, MCP-2, resistin, HVEM, ENPP-7, cohesin-4, IL-2 Rg, MICA, dopa decarboxylase, NPDC-1, MCP-4, EG-VEGF, glycoprotein V, brain signaling protein 4G, IL-12p40, total PSA, IL-15, MAP1D, C1q, TNF4, Dtk, endothelial glycoprotein, ENA-78, Reg3A, MIP-1b, FGF-17, IL-6R, IL-8, galactolectin-8, CA4, cysteine ​​protease protein EM, FUT8, B7-H3, GCP-2, CD40L, MDC, 4-1BB, HO-1, SOST, S100A13, kallikrein 7 or IL-13.

[0106] 14. The method according to any one of embodiments 1 to 13, wherein the therapeutic MSC secretome composition comprises one or more of the following nucleic acids: hsa-let-7a-5p, hsa-let-7b-5p, hsa-let-7c-5p, hsa-let-7d-3p, hsa-let-7e-5p, hsa-let-7g-5p, hsa-let-7i, hsa-let-7i-5p, hsa-miR-100-5p, hsa-miR-103a-3p, hsa-miR-106a-5p, hsa-miR-106b-5p, hsa-mir-10b, hsa-mi R-10b-5p, hsa-mir-1246, hsa-miR-1246, hsa-miR-125a-5p, hsa-miR-125b-5p, hsa-miR-130a-3p, hsa-mir-130b, hsa-miR-130b-3p, hsa-miR- 132-3p, hsa-miR-136-5p, hsa-miR-138-5p, hsa-miR-139-5p, hsa-mir-140, hsa-miR-140-3p, hsa-miR-145-5p, hsa-mir-146a, hsa-miR-146a- 5p, hsa-miR-148a-3p, hsa-miR-152-3p, hsa-miR-15a-5p, hsa-miR-15b-5p, hsa-mir-16-1, hsa-mir-16-2, hsa-miR-16-5p, hsa-miR-1'7-5p, hsa-miR-1 81a-5p, hsa-miR-191-5p, hsa-miR-193a-5p, hsa-miR-193b-3p, hsa-miR-19'7-3p, hsa-miR-199a-3p, hsa-miR-199a-5p, hsa-miR-199b-5p, hsa-miR-19 a-3p, hsa-miR-19b-3p, hsa-miR-20a-5p, hsa-mir-203a, hsa-miR-203a-3p, hsa-miR-214-3p, hsa-mir-21, hsa-miR-21-3p, hsa-miR-21-5p, hsa-mir-22 1. hsa-miR-221-3p, hsa-mir-222, hsa-miR-222-3p, hsa-miR-22-3p, hsa-miR-23a-3p, hsa-miR-23b-3p, hsa-mir-24-1, hsa-mir-24-2, hsa-miR-24-3p,hsa-mir-25, hsa-miR-25-3p, hsa-miR-26a-5p, hsa-miR-27a-3p, hsa-mir-27b, hsa-miR-27b-3 p, hsa-miR-29a-3p, hsa-miR-29c-3p, hsa-miR-30a-5p, hsa-miR-30a-5p, hsa-miR-30b-5p, hsa -miR-30c-5p, hsa-mir-30d, hsa-miR-30d-5p, hsa-mir-30e, hsa-miR-30e-5p, hsa-miR-31-3p, hsa-miR-31-5p, hsa-miR-320a, hsa-miR-342-3p, hsa-miR-345-5p, hsa-miR-34a-5p, hsa-miR-3 61-5p, hsa-miR-376a-3p, hsa-miR-376c-3p, hsa-miR-423-3p, hsa-miR-423-5p, hsa-miR-424- 5p, hsa-miR-484, hsa-mir-486-1, hsa-mir-486-2, hsa-miR-486-5p, hsa-miR-570-3p, hsa-miR -574-3p, hsa-miR-663a, hsa-miR-874-3p, hsa-mir-92a-1, hsa-mir-92a-2, hsa-miR-92a-3p, h sa-miR-92b-3p, hsa-mir-93, hsa-miR-93-5p, hsa-miR-940, hsa-miR-99a-5p or hsa-miR-99b-5p. ,

[0107] 15. A method for treating a subject with lumbar facet joint syndrome, the method comprising administering to the subject a composition comprising a therapeutic MSC secretome composition containing extracellular vesicles, wherein at least 80% of the extracellular vesicles in the therapeutic MSC secretome composition are CD63. + CD9 - CD81 - .

[0108] 16. The method of embodiment 15, wherein the therapeutic MSC secretome composition further comprises one or more of the following proteins: ferritin, NUP85, LAMP2, GPR115, serine protease inhibitor F1, OPN, PAI-1, DAPP1, cathepsin B, brain signaling protein 6C, PDGF Rα, sorting protein, serine protease inhibitor B6, Dkk-3, coagulation regulatory protein, PF4, MIF, periosteal protein, furin, TIMP-1, tectonic proteoglycan, PCK1, CD99, CD63, CD9, CD81, transferrin, DcR3, luciferin, TIMP-2, SLITRK5, FAP, leptospirin, DPPII, cIAP-1, pentameric protein 3, lactone, enkephalin, albumin, galactolectin-1, UNC5H3, IL-20 Rβ, SREC-II, JAM-C, TNF. RI, htPAPP-A, eNOS, MSP R, TPP1, LAMP1, B2M, NCAM-1, HIF-1 α, ST6GAL1, CD99-L2, convolutional protein A4, EMMPRIN, p53, brain signaling protein 7A, NKp80, cysteine ​​protease protein B, osteoadhesion, mid-term factor, calreticulin, osteoactivin, asparagine endopeptidase, TAZ, cathepsin L, RBP4, serine protease inhibitor A4, JAM-A, MCSF, LIMPII, OPG, IL-22, galactolectin-3, MOG, trypsin 3, SIRP α, cohesin-4, IGFBP-4, IL-1, R6 GSTM1, NUP85, LAMP2, transmembrane peptidase A, IL-1 F10, bIG-H3, GPR115, TGFb1, liver glycoside A4, CD109, serine protease inhibitor F1, IGFBP-6, HS3ST4, aminopeptidase LRAP, OPN, PAI-1, DAPP1, GDF-9, cathepsin B, IGFBP-2, brain signaling protein 6C, IGF-2, PDGFR α, sorting protein, serine protease inhibitor B6, Dkk-3, CNTF, TSP-1, GM-CSF Ra, coagulation regulatory protein, endosaccharides, IGFBP-3, RGM-C, PF4, MIF, TGM4, periosteal protein, furin, TIMP-1, PAPP-A, dermal proteoglycan, PCK1, arylsulfatase A, CD99, CA2, PRDX4, transferrin, DcR3, GP73, LAIR2, ULBP-4, optical proteoglycan, TIMP-2, TFPI, SOX2, SLITRK5, FAP, spinal cord protein, ENPP-2, CD97, CTACK, integrin α1, EXTL3, IL-18BPa, PD-L2, PSMA, IL-20 Ra, Glyoxalase II, Trypsin I, IGF-2R, ADAMTS L1-1, Erythropoietin, Convolutional D1, DNMT3A, BCL-2, CL-P1, Hepatocyte Glycol-B3, FABP6, CHI3L1, FCRLS, TFF3, Nephlebotomycin, DPPII, cIAP-1, PDGF Rb, Pentanoic Acid 3, Angiotensinogen, Follicle-Stapressin, CF VII, Persephin, TRAIL R1, THAP11, CD200, CLEC-2, AMIGO, IGFBP-5, PON1, SOX7, GALNT10, Lactone, Granulosin Progenitor, PCSK2, GKN1, IL-18, Enkephalin, Stabilin-2, IL-17 RD, albumin, follicle-stimulating protein 1, MMP-10, FKBP51, LRRC4, Pref-1, galactoglobin-1, troponin C, UNC5H3, FLRT2, CD314, brain signaling protein 6B, cytokinin-4, CD27 ligand, IL-20 Rβ, brain signaling protein 6A, TSK, cytokeratin-8, CHST3, Mcl-1, DPPIV, SREC-II, norin, JAM-C, Bcl-10, Wnt-4, LSECtin, Kell, TNF RI, PTP1B, htPAPP-A, IDO, PDGF-CC, Glycopropyl peptide, Activator Protein A, TLR2, SCCA2, FABP1, eNOS, SHP-1, ICOS, C1qTNF9, MMP-1, TC-PTP, IL-24, gp130, C-myc, LILRB4, BMP-2, MIA, CD34, CD63, CD9, CD81, IFNab R2, Phosphatidylinositol Proteoglycan 2, MSP R, DSCAM, Membrane-type Serine Protease, KIR2DL3, CD30, Salivary Agglutinin-10, CLEC-1, TPP1, Ubiquitin+1, ANGPTL4, TWEAK R, Nestin-1, CD2, Kallikrein 1, TSLPR, LAMP1, TROY, VCAM-1, Salivary agglutinin-11, S100A1, PAR1, Thyroid peroxidase, Aminopeptidase P2, IL-1RI, ADAMS, OSM Rβ, Platelet-Reactive Protein-2, SMPD1, B2M, MFRP, LRP-6, ST3GAL1, NCAM-1 (CD56), Granulase B, Lipocontin, IL-22BP, TPST2, PD-ECGF, LH, LEDGF, Cyr61, ULBP-3, IFNb, THSD1, FGF-23, LAMA4, Lipoprotein, AIF, SorCS2, SULT2A1, CD39L2, Insulin R, HIF-1α, OX40 ligand, Pax3, UCH-L3, cMASP3, Langerin, desmin, SOX9, ST6GAL1, MEP1B, CD99-L2, conglomerate A4, brain signaling protein 4D, ROBO2, PDX-1, APRIL, Ne'rturin, transmembrane protein-2 with ring structure, EMMPRIN, activating protein RIB, neuroligand 2, epithelial regulatory protein, CASA, MMP-12, GALNT2, CEACAM-5, VEGF R1, DSPG3, SorCS1, extracellular matrix protein-2, sFRP-3, p53, EphB3, NCK1, brain signaling protein 7A, NKp80, prolactin, cysteine ​​agonist protein B, Sirtuin 1, FGF-16, FGF R5, NQO-1, Brain signaling protein 6D, FGF-3, GATA-4, VAP-A, CHST2, Pregnancy-associated plasma protein-2, Cohesin-3, Serpentin-1, AKR1C4, Oligosin-2, Osteoadhesin, NKp44, Thyroglobulin, IL-21R, Chemokines, EphA1, CD48, MICB, FGF-5, TRANCE, CES2, ULBP-1, Integrin α 5. VAMP-2, FLRG, Ret metaphase factor, CD73, TRAP, proGRP, granzyme H, PRX2, p2'7, salivary lectin-6, dendritic cell-associated C-type lectin-1, CD51, Notch-1, calreticulin, DR3, DCTN1, CDC25B, bone activator, ACE, CA125, HAO-1, ​​PSMA1, FCRLB, BMP-9, CRIM1, LIF, SPINK1, EphB6, RGM-B, HS3ST1, ROR1, CMG-2, 4-1BB ligand, L1CAM-2, p63, cathepsin V, testosterone-2, phosphatidylinositol proteoglycan 5, CD6, salivary lectin-2, asparagine endopeptidase, PRELP, CES1, TAZ, NSE, TECK, HTRA2, HIF-1 β, TAFA1, podocyte protein, RalA, CRELD2, GRAP2, SP-D, BID, GFR α-2, Notch-3, VEGF R3, DLL4, TGFb2, LIGHT, XIAP, ST8SIA1, cathepsin L, 6-Ckine, MIS RII, kallikrein 5, TGM3, FCAR, contactin-2, CD83, IL-1R3, SALM4, GBA3, ROBO4, OSCAR, VEGF, IGSF3, disaccharide proteoglycan, neurodevelopmental factor, ILT4, uPAR, Axl, WIF-1, IL-7 Rα, GPR56, CEACAM-3, MCEMP1, FABP2, plexin B3, MEPE, activator RIIA, ANG-2, Cochlin, presenilin 1, NPTXR, SLAM, COMT, SPHK1, RBP4, stalkin-1, GUSB, nestin-2, IL-17F, SR-AI, TAFA2, N-cadherin, IL-17B, IL-17RC, MIP-3b, cysteine ​​protease C, cysteine ​​protease D, AMSH, FcERI, CLEC10A, HGF R, ANG-1, prolactin R, FGF-20, CD28, Nogo-A, HSD17B1, IL-19, intestinal peptidase, cathepsin E, TSLP, TCN2, GDF-15, epidermal morphogenetics, GRKS, PD-1, serine protease inhibitor A4, ADAM23, NOV, galactoglobulin-2, neuronal surface protein 3β, TLR3, Sirtuin2, Numb, IL-28 Rα, IL-33, Lin28, FCRL1, KLF4, NKp30, lymphocyte chemokine, cysteine ​​protease protein SN, JAM-A, calreticulin-2, ErbB4, BMP-8, IL-27 Ra, Fas, IL-4 Ra, kallikrein 14, extracellular matrix protein-3, Oligo2, kallikrein 12, CA13, IL-9, stalk protein-3, MPIF-1, cysteine ​​protease protein S, ADA, IL-2 Rb, GFR α-1, Smad4, ICAM-1, MEF2C, TREM-1, L-selectin, transmembrane serine protease, CD42b, MCSF, RANK, CHST4, CA8, FCRL3, ASAH2, CF XIV, PYY, HGF, I-TAC, brain signaling protein 4C, SorCS3, Tie-1, IL-31 RA, Arginase 1, POGLUT1, IL-1ra, Flatfoot protein, TIM-3, CREG, CD300f, uPA, EphA2, LLRTM4, LIMPII, Tenosynovin R, CPE, PECAM-1, DNAM-1, DKK-1, OPG, CPB1, TSH, MMP-2, Salivary lectin-9, ICAM-3, Cysteine ​​protease inhibitor SA, Galactohemagglutinin-4, Pepsinogen II, Desmosome core protein-3, Stalk protein-4, SCF, Serine protease inhibitor A5, PTH, FGF-19, MSP, IL-28A, FGF-12, METAP2, ASAHL, EDIL3, NTAL, EGF R, TAFAS, Galactohemagglutinin-9, vWF-A2, TACE, Activator protein RIM, Cathepsin S, LDLR, BMPR-IA, OX40, IL-13 R2, B7-H4, MMP-13, ANGPTL7, TRAIL R4, IGSF4B, Sirtuin 5, PEAR1, SH2D1A, Cerberus 1, GDF-11, Nrf2, TROP-2, NUDTS, ROR2, EphB4, phosphatidylinositol proteoglycan 1, LAP (TGFb1), Gash, contactin-1, IL-27, UNC5H4, ICAM-2, MBL, HS3ST3B1, RCOR1, IL-10 Rb, XEDAR, IL-22, PILR-α, NRG1-131, FABP4, RGM-A, RELT, TrkC, CSa, SREC-I, neural epithelial stem cell protein, TPO, ErbB3, Kirrel3, FLRT1, galactoglobulin-3, CXCL16, JAM-B, DR6, Nogo receptor, TLR4, VEGF R2, Tie-2, IL-15 R, Caspr2, LTbR, LAMP, ALCAM, GLP-1, NG2, IL-22 Rα 1, AMIGO2, HCC-1, TFPI-2, ULBP-2, desmosome core protein 2, agglutinin, synaptic fusion protein 4, VAMP-1, stalkin-2, FGF-21, Flt-3, GFAP, TIM-1, inhibin A, cadherin-4, PIGF-2, neurogranulin, HE4, IL-23 R, galactoglobulin-7, GALNT3, GITR L, CD14, R-vertebral protein 2, CK19, cardiotrophin-1, TREML1, HAPLN1, CD27, ANG-4, salivary immunoglobulin-7, CD155, VEGF-C, TNF RII, PGRP-S, SDF-1a, PDGF-AB, GPVI, CD40, SCF R, platelet-reactive protein-5, IL-1 RII, neurofeedin-2, cadherin-13, E-selectin, GITR, WISP-1, renin, AgRP, MDL-1, ROBO3, RANTES, endothelial cell-specific molecules, granzyme, hCGb, mesothelin, TLR1, TRAIL, MOG, DDR1, NGF R, TRAIL R3, trypsin 3, ARSB, LIF Rα, BAFFR, CD157, granzyme A, 2B4, ESAM, IL-1 R4, CXCL14, IL-31, SIRP α, urinary modulating protein, CTRC, CEACAM-1, TARC, MIP-3a, SDF-1b, NKp46, MCP-3, IL-32 α, TGFb3FOLR2, CD58, IL-23, CD36, TNFb, Shh-N, fibrinogen-1, Reg4, ILT2, Mer, TREM-2, Flt-3L, CDS, IL-6, CD229, Insulin, Synaptic Fusion Protein 6, GRO, Bcl-w, Lipocrine-2, PDGF-AA, IL-2 Ra, Angiopoietin, LYVE-1, CD4, RAGE, CDNF, Short Proteoglycan, NAP-2, PU.1, EDAR, ADAMTS13, Kynurenase, PTH1R, IFN-γ R1, CrkL, B7-1, PARC, Draxin, VE-cadherin, procalcitonin, SOX15, kallikrein 11, BCMA, dendritic cell-associated C-lectin-2, EpCAM, HCC-4, TGFa, IP-10, BLAME, CILP-1, PIGF, LOX-1, MCP-2, resistin, HVEM, ENPP-7, cohesin-4, IL-2 Rg, MICA, dopa decarboxylase, NPDC-1, MCP-4, EG-VEGF, glycoprotein V, brain signaling protein 4G, IL-12p40, total PSA, IL-15, MAP1D, C1q, TNF4, Dtk, endothelial glycoprotein, ENA-78, Reg3A, MIP-1b, FGF-17, IL-6R, IL-8, galactolectin-8, CA4, cysteine ​​protease protein EM, FUT8, B7-H3, GCP-2, CD40L, MDC, 4-1BB, HO-1, SOST, S100A13, kallikrein 7 or IL-13.

[0109] 17. The method according to embodiment 15 or 16, wherein the extracellular vesicles comprise one or more of the following nucleic acids: hsa-let-7a-5p, hsa-let-7b-5p, hsa-let-7c-5p, hsa-let-7d-3p, hsa-let-7e-5p, hsa-let-7g-5p, hsa-let-7i, hsa-let-7i-5p, hsa-miR-100-5p, hsa-miR-103a-3p, hsa-miR-106a-5p, hsa-miR-106b-5p, hsa-mir-10b, hsa-miR-10b-5p, hsa-mir-1246, hsa-miR-1246, hsa-miR-125a-5p, hsa-miR-125b-5p, hsa-miR-130a-3p, hsa-mir-130b, hsa-miR-130b-3p, hsa-miR-132-3p, hsa-miR-136-5p, hsa-miR-138-5p, hsa-miR-139-5p, hsa-mir-140, hsa-miR-140-3p, hsa-miR-145-5p, hsa-mir-146a, hsa-miR-146a-5p, hsa-miR-148a-3p, hsa-miR-152-3p, hsa-miR-15a-5p, hsa-miR-15b-5p, hsa-mir-16-1, hsa-mir-16-2, hsa-miR-16-5p, hsa-miR-1’7-5p, hsa-miR-181a-5p, hsa-miR-191-5p, hsa-miR-193a-5p, hsa-miR-193b-3p, hsa-miR-19’7-3p, hsa-miR-199a-3p, hsa-miR-199a-5p, hsa-miR-199b-5p, hsa-miR-19a-3p, hsa-miR-19b-3p, hsa-miR-20a-5p, hsa-mir-203a, hsa-miR-203a-3p, hsa-miR-214-3p, hsa-mir-21, hsa-miR-21-3p, hsa-miR-21-5p, hsa-mir-221, hsa-miR-221-3p, hsa-mir-222, hsa-miR-222-3p, hsa-miR-22-3p, hsa-miR-23a-3p, hsa-miR-23b-3p, hsa-mir-24-1, hsa-mir-24-2, hsa-miR-24-3p, hsa-mir-25,hsa-miR-25-3p, hsa-miR-26a-5p, hsa-miR-27a-3p, hsa-mir-27b, hsa-miR-27b-3p, hsa-miR -29a-3p, hsa-miR-29c-3p, hsa-miR-30a-5p, hsa-miR-30a-5p, hsa-miR-30b-5p, hsa-miR-30c -5p, hsa-mir-30d, hsa-miR-30d-5p, hsa-mir-30e, hsa-miR-30e-5p, hsa-miR-31-3p, hsa-miR -31-5p, hsa-miR-320a, hsa-miR-342-3p, hsa-miR-345-5p, hsa-miR-34a-5p, hsa-miR-361-5p , hsa-miR-376a-3p, hsa-miR-376c-3p, hsa-miR-423-3p, hsa-miR-423-5p, hsa-miR-424-5p, h sa-miR-484, hsa-mir-486-1, hsa-mir-486-2, hsa-miR-486-5p, hsa-miR-570-3p, hsa-miR-57 4-3p, hsa-miR-663a, hsa-miR-874-3p, hsa-mir-92a-1, hsa-mir-92a-2, hsa-miR-92a-3p, hsa -miR-92b-3p, hsa-mir-93, hsa-miR-93-5p, hsa-miR-940, hsa-miR-99a-5p or hsa-miR-99b-5p. ,

[0110] 18. The method as described in any one of embodiments 15 to 17, wherein the subject suffers from chronic pain.

[0111] 19. The method as described in any one of embodiments 15 to 18, wherein the subject suffers from back pain.

[0112] 20. The method as described in any one of embodiments 15 to 19, wherein the subject suffers from chronic low back pain.

[0113] 21. The method as described in embodiment 20, wherein the chronic low back pain causes functional impairment.

[0114] 22. The method as described in any one of embodiments 15 to 21, wherein the subject suffers from lumbar facet joint degeneration.

[0115] 23. The method as described in embodiment 22, wherein the subject has undergone imaging examinations and / or diagnostic nerve blocks to confirm lumbar facet joint syndrome.

[0116] 24. The method of any one of embodiments 15 to 23, wherein the subject has a diagnosis of degenerative facet joint low back pain for at least 6 months, involving one, two, or three segments of facet joint degeneration.

[0117] 25. The method as described in any one of embodiments 15 to 24, wherein the subject experiences improvement in one or more of the following symptoms after treatment: pain, stiffness, range of motion, posture, general health, mood, social interaction, sleep and / or walking ability, and combinations thereof.

[0118] 26. A method for treating lumbar facet joint syndrome in a subject, the method comprising administering to the subject a composition comprising a therapeutic mesenchymal stem cell (MSC) secretome composition containing extracellular vesicles (EVs), wherein the therapeutic MSC secretome comprises: (i) ferritin, NUP85, LAMP2, GPR115, serine protease inhibitor F1, OPN, PAI-1, DAPP1, cathepsin B, brain signaling protein 6C, PDGF R α, Sorting protein, Serine protease inhibitor B6, Dkk-3, Coagulation regulator protein, PF4, MIF, Periostrin, Flin protease, TIMP-1, Gynostemma pentaglycoside, PCK1, CD99, CD63, CD9, CD81, Transferrin, DcR3, Optical proteoglycan, TIMP-2, SLITRK5, FAP, Neurosphingomyelin, DPPII, cIAP-1, Pentanoic acid 3, Lactopeptidase, Enkephalin, Albumin, Galactoglobin-1, UNC5H3, IL-20 Rβ, SREC-II, JAM-C, TNF-α, htPAPP-A, eNOS, MSP-R, TPP1, LAMP1, B2M, NCAM-1, HIF-1 α, ST6GAL1, CD99-L2, conglomerate A4, EMMPRIN, p53, brain signaling protein 7A, NKp80, cysteine ​​protease protein B, osteoadhesion, mid-term factor, calreticulin, osteoactivin, asparagine endopeptidase, TAZ, cathepsin L, RBP4, serine protease inhibitor A4, JAM-A, MCSF, LIMPII, OPG, IL-22, galactoglobulin-3, MOG, trypsin 3, SIRP α, cohesin-4, IGFBP-4, IL-1, R6 GSTM1, NUP85, LAMP2, transmembrane peptidase A, IL-1 F10, bIG-H3, GPR115, TGFb1, liver glycoside A4, CD109, serine protease inhibitor F1, IGFBP-6, HS3ST4, aminopeptidase LRAP, OPN, PAI-1, DAPP1, GDF-9, cathepsin B, IGFBP-2, brain signaling protein 6C, IGF-2, PDGFR α, sorting protein, serine protease inhibitor B6, Dkk-3, CNTF, TSP-1, GM-CSF Ra, coagulation regulatory protein, endosaccharides, IGFBP-3, RGM-C, PF4, MIF, TGM4, periosteal protein, furin protease, TIMP-1, PAPP-A, dermal proteoglycans, PCK1, arylsulfatase A, CD99, CA2, PRDX4, transferrin, DcR3, GP73, LAIR2, ULBP-4, optical proteoglycans, TIMP-2, TFPI, SOX2, SLITRK5, FAP, spinal proteinENPP-2, CD97, CTACK, integrin α1, EXTL3, IL-18, BPa, PD-L2, PSMA, IL-20 Ra, glyoxalase II, trypsin I, IGF-2R, ADAMTSL-1, erythropoietin, plexin D1, DNMT3A, BCL-2, CL-P1, hepatocyte glycoside-B3, FABP6, CHI3L1, FCRLS, TFF3, leptospirin, DPPII, cIAP-1, PDGF Rb, pentameric protein 3, angiotensinogen, follicle-stimulating hormone, CF VII, persephin, TRAIL R1, THAP11, CD200, CLEC-2, AMIGO, IGFBP-5, PON1, SOX7, GALNT10, endothelin, granulosin precursor, PCSK2, GKN1, IL-18, enkephalin, stabilizer-2, IL-17 RD, albumin, follicle-stimulating protein 1, MMP-10, FKBP51, LRRC4, Pref-1, galactoglobin-1, troponin C, UNC5H3, FLRT2, CD314, brain signaling protein 6B, cytokinin-4, CD27 ligand, IL-20 Rβ, brain signaling protein 6A, TSK, cytokeratin-8, CHST3, Mcl-1, DPPIV, SREC-II, norin, JAM-C, Bcl-10, Wnt-4, LSECtin, Kell, TNF RI, PTP1B, htPAPP-A, IDO, PDGF-CC, Glycopropyl peptide, Activator Protein A, TLR2, SCCA2, FABP1, eNOS, SHP-1, ICOS, C1qTNF9, MMP-1, TC-PTP, IL-24, gp130, C-myc, LILRB4, BMP-2, MIA, CD34, CD63, CD9, CD81, IFNab R2, Phosphatidylinositol Proteoglycan 2, MSP R, DSCAM, Membrane-type Serine Protease, KIR2DL3, CD30, Salivary Agglutinin-10, CLEC-1, TPP1, Ubiquitin+1, ANGPTL4, TWEAK R, Nestin-1, CD2, Kallikrein 1, TSLPR, LAMP1, TROY, VCAM-1, Salivary agglutinin-11, S100A1, PAR1, Thyroid peroxidase, Aminopeptidase P2, IL-1RI, ADAMS, OSM Rβ, Platelet-Reactive Protein-2, SMPD1, B2M, MFRP, LRP-6, ST3GAL1, NCAM-1 (CD56), Granulase B, Lipocontin, IL-22BP, TPST2, PD-ECGF, LH, LEDGF, Cyr61, ULBP-3, IFNb, THSD1, FGF-23, LAMA4, LipoproteinAIF, SorCS2, SULT2A1, CD39L2, Insulin R, HIF-1 α, OX40 ligand, Pax3, UCH-L3, cMASP3, Langerin, Desmin, SOX9, ST6GAL1, MEP1B, CD99-L2, Convolutional protein A4, Brain signaling protein 4D, ROBO2, PDX-1, APRIL, Neural rank protein, cyclic transmembrane protein-2, EMMPRIN, activator protein RIB, neuroligand 2, epithelial regulatory protein, CASA, MMP-12, GALNT2, CEACAM-5, VEGF R1, DSPG3, SorCS1, Extracellular matrix protein-2, sFRP-3, p53, EphB3, NCK1, Brain signaling protein 7A, NKp80, Prolactin, Cysteine ​​protease protein B, Sirtuin 1, FGF-16, FGF R5, NQO-1, Brain signaling protein 6D, FGF-3, GATA-4, VAP-A, CHST2, Pregnancy-associated plasma protein-2, Cohesin-3, Serpentin-1, AKR1C4, Oligosin-2, Osteoadhesin, NKp44, Thyroglobulin, IL-21R, Chemokines, EphA1, CD48, MICB, FGF-5, TRANCE, CES2, ULBP-1, Integrin α 5. VAMP-2, FLRG, Ret metaphase factor, CD73, TRAP, proGRP, granzyme H, PRX2, p2'7, salivary lectin-6, dendritic cell-associated C-type lectin-1, CD51, Notch-1, calreticulin, DR3, DCTN1, CDC25B, bone activator, ACE, CA125, HAO-1, ​​PSMA1, FCRLB, BMP-9, CRIM1, LIF, SPINK1, EphB6, RGM-B, HS3ST1, ROR1, CMG-2, 4-1BB ligand, L1CAM-2, p63, cathepsin V, testosterone-2, phosphatidylinositol proteoglycan 5, CD6, salivary lectin-2, asparagine endopeptidase, PRELP, CES1, TAZ, NSE, TECK, HTRA2, HIF-1 β, TAFA1, podocyte protein, RalA, CRELD2, GRAP2, SP-D, BID, GFR α-2, Notch-3, VEGF R3, DLL4, TGFb2, LIGHT, XIAP, ST8SIA1, cathepsin L, 6-Ckine, MIS RII, kallikrein 5, TGM3, FCAR, contactin-2, CD83, IL-1R3, SALM4, GBA3, ROBO4, OSCAR, VEGF, IGSF3, disaccharide proteoglycan, neurodevelopmental factor, ILT4, uPAR, Axl, WIF-1IL-7 Rα, GPR56, CEACAM-3, MCEMP1, FABP2, plexin B3, MEPE, activator RIIA, ANG-2, Cochlin, progerin 1, NPTXR, SLAM, COMT, SPHK1, RBP4, stalkin-1, GUSB, nestin-2, IL-17F, SR-AI, TAFA2, N-cadherin, IL-17B, IL-17RC, MIP-3b, cysteine ​​protease C, cysteine ​​protease D, AMSH, FcERI, CLEC10A, HGF R, ANG-1, prolactin R, FGF-20, CD28, Nogo-A, HSD17B1, IL-19, intestinal peptidase, cathepsin E, TSLP, TCN2, GDF-15, epidermal morphogenetics, GRKS, PD-1, serine protease inhibitor A4, ADAM23, NOV, galactoglobulin-2, neuronal surface protein 3β, TLR3, Sirtuin2, Numb, IL-28 Rα, IL-33, Lin28, FCRL1, KLF4, NKp30, lymphocyte chemokine, cysteine ​​protease protein SN, JAM-A, calreticulin-2, ErbB4, BMP-8, IL-27 Ra, Fas, IL-4 Ra, kallikrein 14, extracellular matrix protein-3, Oligo2, kallikrein 12, CA13, IL-9, stalk protein-3, MPIF-1, cysteine ​​protease protein S, ADA, IL-2 Rb, GFR α-1, Smad4, ICAM-1, MEF2C, TREM-1, L-selectin, transmembrane serine protease, CD42b, MCSF, RANK, CHST4, CA8, FCRL3, ASAH2, CF XIV, PYY, HGF, I-TAC, brain signaling protein 4C, SorCS3, Tie-1, IL-31 RA, Arginase 1, POGLUT1, IL-1ra, Flatfoot protein, TIM-3, CREG, CD300f, uPA, EphA2, LLRTM4, LIMPII, Tenosynovin R, CPE, PECAM-1, DNAM-1, DKK-1, OPG, CPB1, TSH, MMP-2, Salivary lectin-9, ICAM-3, Cysteine ​​protease inhibitor SA, Galactohemagglutinin-4, Pepsinogen II, Desmosome core protein-3, Stalk protein-4, SCF, Serine protease inhibitor A5, PTH, FGF-19, MSP, IL-28A, FGF-12, METAP2, ASAHL, EDIL3, NTAL, EGF R, TAFAS, Galactohemagglutinin-9, vWF-A2, TACE, Activator protein RIM, Cathepsin S, LDL RBMPR-IA, OX40, IL-13 R2, B7-H4, MMP-13, ANGPTL7, TRAIL R4, IGSF4B, Sirtuin 5, PEAR1, SH2D1A, Cerberus 1, GDF-11, Nrf2, TROP-2, NUDTS, ROR2, EphB4, phosphatidylinositol proteoglycan 1, LAP (TGFb1), Gash, contactin-1, IL-27, UNC5H4, ICAM-2, MBL, HS3ST3B1, RCOR1, IL-10 Rb, XEDAR, IL-22, PILR-α, NRG1-131, FABP4, RGM-A, RELT, TrkC, CSa, SREC-I, neural epithelial stem cell protein, TPO, ErbB3, Kirrel3, FLRT1, galactoglobulin-3, CXCL16, JAM-B, DR6, Nogo receptor, TLR4, VEGF R2, Tie-2, IL-15 R, Caspr2, LTbR, LAMP, ALCAM, GLP-1, NG2, IL-22 Rα 1, AMIGO2, HCC-1, TFPI-2, ULBP-2, desmosome core protein 2, agglutinin, synaptic fusion protein 4, VAMP-1, stalkin-2, FGF-21, Flt-3, GFAP, TIM-1, inhibin A, cadherin-4, PIGF-2, neurogranulin, HE4, IL-23 R, galactoglobulin-7, GALNT3, GITR L, CD14, R-vertebral protein 2, CK19, cardiotrophin-1, TREML1, HAPLN1, CD27, ANG-4, salivary immunoglobulin-7, CD155, VEGF-C, TNF RII, PGRP-S, SDF-1a, PDGF-AB, GPVI, CD40, SCF R, platelet-reactive protein-5, IL-1 RII, neurofeedin-2, cadherin-13, E-selectin, GITR, WISP-1, renin, AgRP, MDL-1, ROBO3, RANTES, endothelial cell-specific molecules, granzyme, hCGb, mesothelin, TLR1, TRAIL, MOG, DDR1, NGF R, TRAIL R3, trypsin 3, ARSB, LIF Rα, BAFFR, CD157, granzyme A, 2B4, ESAM, IL-1 R4, CXCL14, IL-31, SIRP α, urinary modulatory proteins, CTRC, CEACAM-1, TARC, MIP-3a, SDF-1b, NKp46, MCP-3, IL-32 α, TGFb3, FOLR2, CD58, IL-23, CD36, TNFb, Shh-N, fibrinogen-1, Reg4ILT2, Mer, TREM-2, Flt-3L, CDS, IL-6, CD229, Insulin, Synaptic Fusion Protein 6, GRO, Bcl-w, Lipocrine-2, PDGF-AA, IL-2 Ra, Angiopoietin, LYVE-1, CD4, RAGE, CDNF, Short Proteoglycan, NAP-2, PU.1, EDAR, ADAMTS13, Kynureninase, PTH1R, IFN-γ R1, CrkL, B7-1, PARC, Draxin, VE-cadherin, Procalcitonin, SOX15, Kallikrein 11, BCMA, Dendritic Cell-Associated C-Lectin-2, EpCAM, HCC-4, TGFa, IP-10, BLAME, CILP-1, PIGF, LOX-1, MCP-2, Resistin, HVEM, ENPP-7, Cohesin-Glycan-4, IL-2 Rg, MICA, dopa decarboxylase, NPDC-1, MCP-4, EG-VEGF, glycoprotein V, brain signaling protein 4G, IL-12p40, total PSA, IL-15, MAP1D, C1q, TNF4, Dtk, endothelial glycoprotein, ENA-78, Reg3A, MIP-1b, FGF-17, IL-6R, IL-8, galactolectin-8, CA4, cysteine ​​protease protein EM, FUT8, B7-H 3. GCP-2, CD40L, MDC, 4-1BB, HO-1, SOST, S100A13, kallikrein 7 or IL-13, or a combination of two or more thereof; (ii) hsa-let-7a-5p, hsa-let-7b-5p, hsa-let-7c-5p, hsa-let-7d-3p, hsa-let-7e-5p, hsa-let-7g-5p, hsa-let-7i, hs a-let-7i-5p, hsa-miR-100-5p, hsa-miR-103a-3p, hsa-miR-106a-5p, hsa-miR-106b-5p, hsa-mir- 10b, hsa-miR-10b-5p, hsa-mir-1246, hsa-miR-1246, hsa-miR-125a-5p, hsa-miR-125b-5p, hsa-mi R-130a-3p, hsa-mir-130b, hsa-miR-130b-3p, hsa-miR-132-3p, hsa-miR-136-5p, hsa-miR-138-5p , hsa-miR-139-5p, hsa-mir-140, hsa-miR-140-3p, hsa-miR-145-5p, hsa-mir-146a, hsa-miR-146a- 5p, hsa-miR-148a-3p,hsa-miR-152-3p, hsa-miR-15a-5p, hsa-miR-15b-5p, hsa-mir-16-1, hsa-mir-16-2, hsa-miR-16-5p, hsa-miR-1'7-5p, hsa-miR-181a-5p, hsa-miR-191-5p, hsa-miR-193a-5p, hsa-miR-193b-3p, hsa-miR-19'7-3p, hsa-miR-199a-3p, hsa-miR-199a-5p, hsa-miR-199b-5p, hsa-miR-19a-3p, hsa-mi R-19b-3p, hsa-miR-20a-5p, hsa-mir-203a, hsa-miR-203a-3p, hsa-miR-214-3p, hsa-mir-21, hsa-miR-21-3p, hsa-miR-21-5p, hsa-mir-221, hsa-miR-221-3p, hsa-mir-222, hsa-miR-222-3p, hsa-miR-22-3p, hsa-miR-23a-3p, hsa-miR-23b-3p, hsa-mir-24-1, hsa-mir-24-2, hsa-miR-24-3p, hsa- mir-25, hsa-miR-25-3p, hsa-miR-26a-5p, hsa-miR-27a-3p, hsa-mir-27b, hsa-miR-27b-3p, hsa-miR-29a-3p, hsa-miR-29c-3p, hsa-miR-30a-5p, hsa-miR-30a-5p, hsa-miR-30b-5p, hsa-miR-30c-5p, hsa-mir-30d, hsa-miR-30d-5p, hsa-mir-30e, hsa-miR-30e-5p, hsa-miR-31-3p, hsa-miR-31-5p hsa-miR-320a hsa-miR-342-3p hsa-miR-345-5p hsa-miR-34a-5p hsa-miR-361-5p hsa-miR-376a-3p hsa-miR-376c-3p hsa-miR-423-3p hsa -miR-423-5p, hsa-miR-424-5p, hsa-miR-484, hsa-mir-486-1, hsa-mir-486-2, hsa-miR-486-5p, hsa-miR-570-3p, hsa-miR-574-3p, hsa-miR-663ahsa-miR-874-3p, hsa-mir-92a-1, hsa-mir-92a-2, hsa-miR-92a-3p, hsa-miR-92b-3p, hsa-mir-93, hsa-miR-93-5p, hsa-miR-940, hsa-miR-99a-5p or hsa-miR-99b-5p, or a combination of two or more thereof; or both (iii), (i), and (ii).

[0119] 27. A method for treating lumbar facet joint syndrome, the method comprising administering a therapeutic MSC secretory group composition to the subject.

[0120] 28. A method for treating low back pain, the method comprising administering a therapeutic MSC secretion group composition to the subject.

[0121] 29. A method for reducing symptoms associated with lumbar facet joint syndrome in a subject, the method comprising administering a therapeutic MSC secretome composition to the subject.

[0122] 30. A method for improving symptoms of lumbar facet joint syndrome selected from one or more of the following: pain, stiffness, range of motion, posture, general health, mood, social interaction, sleep and / or walking ability, and combinations thereof, said method comprising administering a therapeutic MSC secretory group composition to said subject.

[0123] 31. The method of any one of embodiments 27-30, wherein the extracellular vesicles in the therapeutic MSC secretome composition are CD63+CD9-CD81-.

[0124] 32. The method of any one of embodiments 27-31, wherein the therapeutic MSC secretory group comprises (i) ferritin, NUP85, LAMP2, GPR115, serine protease inhibitor F1, OPN, PAI-1, DAPP1, cathepsin B, brain signaling protein 6C, PDGF Rα, sorting protein, serine protease inhibitor B6, Dkk-3, coagulation regulator protein, PF4, MIF, periosteal protein, furin, TIMP-1, gypsum proteoglycan, PCK1, CD99, CD63, CD9, CD81, transferrin, DcR3, luciferin, TIMP-2, SLITRK5, FAP, sphingomyelin, DPPII, cIAP-1, pentameric protein 3, lactone, enkephalin, albumin, galactolectin-1, UNC5H3, IL-20 Rβ, SREC-II, JAM-C, TNF. RI, htPAPP-A, eNOS, MSP R, TPP1, LAMP1, B2M, NCAM-1, HIF-1 α, ST6GAL1, CD99-L2, convolutional protein A4, EMMPRIN, p53, brain signaling protein 7A, NKp80, cysteine ​​protease protein B, osteoadhesion, mid-term factor, calreticulin, osteoactivin, asparagine endopeptidase, TAZ, cathepsin L, RBP4, serine protease inhibitor A4, JAM-A, MCSF, LIMPII, OPG, IL-22, galactolectin-3, MOG, trypsin 3, SIRP α, cohesin-4, IGFBP-4, IL-1, R6 GSTM1, NUP85, LAMP2, transmembrane peptidase A, IL-1 F10, bIG-H3, GPR115, TGFb1, liver glycoside A4, CD109, serine protease inhibitor F1, IGFBP-6, HS3ST4, aminopeptidase LRAP, OPN, PAI-1, DAPP1, GDF-9, cathepsin B, IGFBP-2, brain signaling protein 6C, IGF-2, PDGF Rα, sorting protein, serine protease inhibitor B6, Dkk-3, CNTF, TSP-1, GM-CSF Ra, coagulation regulatory protein, endosaccharides, IGFBP-3, RGM-C, PF4, MIF, TGM4, periostealin, furin, TIMP-1, PAPP-A, dermal proteoglycans, PCK1, arylsulfatase A, CD99, CA2, PRDX4, transferrin, DCR3, GP73, LAIR2, ULBP-4, luminous proteoglycans, TIMP-2, TFPI, SOX2, SLITRK5, FAP, spinal cord protein, ENPP-2, CD97, CTACK, integrin α1, EXTL3, IL-18, BPa, PD-L2, PSMAIL-20 Ra, Glyoxalase II, Trypsin I, IGF-2R, ADAMTS L1-1, Erythropoietin, Convolutional D1, DNMT3A, BCL-2, CL-P1, Hepatocyte Glycol-B3, FABP6, CHI3L1, FCRLS, TFF3, Sphingomyelin, DPPII, cIAP-1, PDGF Rb, Pentanoic Acid 3, Angiotensinogen, Follicle-Stapressin, CF VII, Persephin, TRAIL R1, THAP11, CD200, CLEC-2, AMIGO, IGFBP-5, PON1, SOX7, GALNT10, Lactone, Granulosin Progenitor, PCSK2, GKN1, IL-18, Enkephalin, Stabilin-2, IL-17 RD, albumin, follicle-stimulating protein 1, MMP-10, FKBP51, LRRC4, Pref-1, galactoglobin-1, troponin C, UNC5H3, FLRT2, CD314, brain signaling protein 6B, cytokinin-4, CD27 ligand, IL-20 Rβ, brain signaling protein 6A, TSK, cytokeratin-8, CHST3, Mcl-1, DPPIV, SREC-II, norin, JAM-C, Bcl-10, Wnt-4, LSECtin, Kell, TNF RI, PTP1B, htPAPP-A, IDO, PDGF-CC, Glycopropyl peptide, Activator Protein A, TLR2, SCCA2, FABP1, eNOS, SHP-1, ICOS, C1qTNF9, MMP-1, TC-PTP, IL-24, gp130, C-myc, LILRB4, BMP-2, MIA, CD34, CD63, CD9, CD81, IFNab R2, Phosphatidylinositol Proteoglycan 2, MSP R, DSCAM, Membrane-type Serine Protease, KIR2DL3, CD30, Salivary Agglutinin-10, CLEC-1, TPP1, Ubiquitin+1, ANGPTL4, TWEAK R, Nestin-1, CD2, Kallikrein 1, TSLP R, LAMP1, TROY, VCAM-1, salivary immunoglobulin-11, S100A1, PAR1, thyroid peroxidase, aminopeptidase P2, IL-1 RI, ADAMS, OSM R β, platelet-reactive protein-2, SMPD1, B2M, MFRP, LRP-6, ST3GAL1, NCAM-1 (CD56), granzyme B, lipoconazole, IL-22BP, TPST2, PD-ECGF, LH, LEDGF, Cyr61, ULBP-3, IFNb, THSD1, FGF-23, LAMA4, lipoprotein, AIF, SorCS2, SULT2A1, CD39L2, insulin R, HIF-1 α, OX40 ligandPax3, UCH-L3, cMASP3, Langerin, desmin, SOX9, ST6GAL1, MEP1B, CD99-L2, conglomerate A4, brain signaling protein 4D, ROBO2, PDX-1, APRIL, neuronal rankin, transmembrane protein-2 with ring structure, EMMPRIN, activator protein RIB, neuroligand 2, epithelial regulatory protein, CASA, MMP-12, GALNT2, CEACAM-5, VEGF R1, DSPG3, SorCS1, extracellular matrix protein-2, sFRP-3, p53, EphB3, NCK1, brain signaling protein 7A, NKp80, prolactin, cysteine ​​agonist protein B, Sirtuin 1, FGF-16, FGF R5, NQO-1, Brain signaling protein 6D, FGF-3, GATA-4, VAP-A, CHST2, Pregnancy-associated plasma protein-2, Cohesin-3, Serpentin-1, AKR1C4, Oligosin-2, Osteoadhesin, NKp44, Thyroglobulin, IL-21R, Chemokines, EphA1, CD48, MICB, FGF-5, TRANCE, CES2, ULBP-1, Integrin α 5. VAMP-2, FLRG, Ret metaphase factor, CD73, TRAP, proGRP, granzyme H, PRX2, p27, salivary lectin-6, dendritic cell-associated C-type lectin-1, CD51, Notch-1, calreticulin, DR3, DCTN1, CDC25B, bone activator, ACE, CA125, HAO-1, ​​PSMA1, FCRLB, BMP-9, CRIM1, LIF, SPINK1, EphB6, RGM-B, HS3ST1, ROR1, CMG-2, 4-1BB ligand, L1CAM-2, p63, cathepsin V, testosterone-2, phosphatidylinositol proteoglycan 5, CD6, salivary lectin-2, asparagine endopeptidase, PRELP, CES1, TAZ, NSE, TECK, HTRA2, HIF-1 β, TAFA1, podocyte protein, RalA, CRELD2, GRAP2, SP-D, BID, GFR α-2, Notch-3, VEGF R3, DLL4, TGFb2, LIGHT, XIAP, ST8SIA1, cathepsin L, 6-Ckine, MIS RII, kallikrein 5, TGM3, FCAR, contactin-2, CD83, IL-1 R3, SALM4, GBA3, ROBO4, OSCAR, VEGF, IGSF3, disaccharide proteoglycan, neurodevelopmental factor, ILT4, uPAR, Axl, WIF-1, IL-7 Rα, GPR56, CEACAM-3, MCEMP1, FABP2, conglomerate B3, MEPEActivating proteins RIIA, ANG-2, Cochlin, presenilin 1, NPTXR, SLAM, COMT, SPHK1, RBP4, stalkin-1, GUSB, nestin-2, IL-17F, SR-AI, TAFA2, N-cadherin, IL-17B, IL-17RC, MIP-3b, cysteine ​​absorptase C, cysteine ​​absorptase D, AMSH, FcERI, CLEC10A, HGF R, ANG-1, prolactin R, FGF-20, CD28, Nogo-A, HSD17B1, IL-19, intestinal peptidase, cathepsin E, TSLP, TCN2, GDF-15, epidermal morphogenetics, GRKS, PD-1, serine protease inhibitor A4, ADAM23, NOV, galactolectin-2, neuronal surface protein 3β, TLR3, Sirtuin 2, Numb, IL-28 Rα, IL-33, Lin28, FCRL1, KLF4, NKp30, lymphocyte chemokines, cysteine ​​protease protein SN, JAM-A, calreticulin-2, ErbB4, BMP-8, IL-27 Ra, Fas, IL-4 Ra, kallikrein 14, extracellular matrix protein-3, Olig2, kallikrein 12, CA13, IL-9, stalkin-3, MPIF-1, cysteine ​​protease protein S, ADA, IL-2 Rb, GFR α-1, Smad4, ICAM-1, MEF2C, TREM-1, L-selectin, transmembrane serine protease, CD42b, MCSF, RANK, CHST4, CA8, FCRL3, ASAH2, CF XIV, PYY, HGF, I-TAC, Brain signaling protein 4C, SorCS3, Tie-1, IL-31RA, Arginase 1, POGLUT1, IL-1ra, Flatfoot protein, TIM-3, CREG, CD300f, uPA, EphA2, LLRTM4, LIMPII, Tenosynovin R, CPE, PECAM-1, DNAM-1, DKK-1, OPG, CPB1, TSH, MMP-2, Salivary lectin-9, ICAM-3, Cysteine ​​protease inhibitor SA, Galactohemagglutinin-4, Pepsinogen II, Desmosome core protein-3, Stalk protein-4, SCF, Serine protease inhibitor A5, PTH, FGF-19, MSP, IL-28A, FGF-12, METAP2, ASAHL, EDIL3, NTAL, EGF R, TAFAS, galactoglobulin-9, vWF-A2, TACE, activator protein RIM, cathepsin S, LDLR, BMPR-IA, OX40, IL-13 R2, B7-H4, MMP-13, ANGPTL7, TRAIL R4IGSF4B, Sirtuin 5, PEAR1, SH2D1A, Cerberus 1, GDF-11, Nrf2, TROP-2, NUDTS, ROR2, EphB4, phosphatidylinositol proteoglycan 1, LAP (TGFb1), Gash, contactin-1, IL-27, UNC5H4, ICAM-2, MBL, HS3ST3B1, RCOR1, IL-10, Rb, XEDAR, IL-22, PILR-α, NRG1-131, FABP4, RGM-A, RELT, TrkC, CSa, SREC-I, neural epithelial stem cell protein, TPO, ErbB3, Kirrel3, FLRT1, galactolectin-3, CXCL16, JAM-B, DR6, Nogo receptor, TLR4, VEGFR2, Tie-2, IL-15 R, Caspr2, LTbR, LAMP, ALCAM, GLP-1, NG2, IL-22, Rα1, AMIGO2, HCC-1, TFPI-2, ULBP-2, desmosome core protein 2, agglutinin, synaptic fusion protein 4, VAMP-1, stalkin-2, FGF-21, Flt-3, GFAP, TIM-1, inhibin A, cadherin-4, PIGF-2, neurogranulin, HE4, IL-23, R, galactolectin-7, GALNT3, GITR L, CD14, R-vertebral protein 2, CK19, cardiotrophin-1, TREML1, HAPLN1, CD27, ANG-4, salivary lectin-7, CD155, VEGF-C, TNF-α, PGRP-S, SDF-1α, PDGF-AB, GPVI, CD40, SCFR, platelet-reactive protein-5, IL-1 RII, neurofeltin-2, cadherin-13, E-selectin, GITR, WISP-1, renin, AgRP, MDL-1, ROBO3, RANTES, endothelial cell-specific molecules, granzyme, hCGb, mesothelin, TLR1, TRAIL, MOG, DDR1, NGF R, TRAIL R3, trypsin 3, ARSB, LIF Rα, BAFF R, CD157, granzyme A, 2B4, ESAM, IL-1 R4, CXCL14, IL-31, SIRP α, urinary modulatory proteins, CTRC, CEACAM-1, TARC, MIP-3a, SDF-1b, NKp46, MCP-3, IL-32 α, TGFb3 FOLR2, CD58, IL-23, CD36, TNFb, Shh-N, fibrin-1, Reg4, ILT2, Mer, TREM-2, Flt-3L, CDS, IL-6, CD229, insulin, synaptic fusion protein 6GRO, Bcl-w, lipocalin-2, PDGF-AA, IL-2 Ra, angiopoietin, LYVE-1, CD4, RAGE, CDNF, short proteoglycan, NAP-2, PU.1, EDAR, ADAMTS13, kynurenase, PTH1R, IFN-γ R1, CrkL, B7-1, PARC, Draxin, VE-cadherin, procalcitonin, SOX15, kallikrein 11, BCMA, dendritic cell-associated C-lectin-2, EpCAM, HCC-4, TGFa, IP-10, BLAME, CILP-1, PIGF, LOX-1, MCP-2, resistin, HVEM, ENPP-7, cohesin-glycan-4, IL-2 Rg, MICA, dopa decarboxylase, NPDC-1, MCP-4, EG-VEGF, glycoprotein V, brain signaling protein 4G, IL-12p40, total PSA, IL-15, MAP1D, C1q, TNF4, Dtk, endothelial glycoprotein, ENA-78, Reg3A, MIP-1b, FGF-17, IL-6R, IL-8, galactoglobulin-8, CA4, cysteine ​​protease protein EM, FUT8, B7-H3, GCP-2, CD40L, MDC, 4-1BB, HO-1, SOST, S100A13, kallikrein 7 or IL-13 or a combination of two or more of these; (ii) hsa-let-7a-5p, hsa-let-7b-5p, hsa-let-7c-5p, hsa-let-7d-3p, hsa-let-7e-5p, hsa-let-7g-5p, hsa-let-7i, hsa-let-7i -5p, hsa-miR-100-5p, hsa-miR-103a-3p, hsa-miR-106a-5p, hsa-miR-106b-5p, hsa-mir-10b, hsa-miR-10b-5p, hsa-mir-1246, h sa-miR-1246, hsa-miR-125a-5p, hsa-miR-125b-5p, hsa-miR-130a-3p, hsa-mir-130b, hsa-miR-130b-3p, hsa-miR-132-3p, hsa- miR-136-5p, hsa-miR-138-5p, hsa-miR-139-5p, hsa-mir-140, hsa-miR-140-3p, hsa-miR-145-5p, hsa-mir-146a, hsa-miR-146a- 5p, hsa-miR-148a-3p, hsa-miR-152-3p, hsa-miR-15a-5p, hsa-miR-15b-5p,hsa-mir-16-1, hsa-mir-16-2, hsa-miR-16-5p, hsa-miR-1'7-5p, hsa-miR-181a-5p, hsa-miR-191-5p, hsa-miR-193a-5p, hsa-miR-193b-3p, hsa-miR-19'7-3p, hsa-miR-199a-3p, hsa-miR-199a-5p, hsa-miR-199b-5p, hsa-miR-19a-3p, hsa-miR-19b-3p, hsa-miR-20a-5p, hsa-mir-203a, hsa-miR- 203a-3p, hsa-miR-214-3p, hsa-mir-21, hsa-miR-21-3p, hsa-miR-21-5p, hsa-mir-221, hsa-miR-221-3p, hsa-mir-222, hsa-miR-222-3p, hsa-miR-22-3p, hsa-miR-23a-3p, hsa-miR-23b-3p, hsa-mir-24-1, hsa-mir-24-2, hsa-miR-24-3p, hsa-mir-25, hsa-miR-25-3p, hsa-miR-26a-5p, hsa-miR- 27a-3p、hsa-mir-27b、hsa-miR-27b-3p、hsa-miR-29a-3p、hsa-miR-29c-3 p、hsa-miR-30a-5p、hsa-miR-30a-5p、hsa-miR-30b-5p、hsa-miR-30c-5p、 hsa-mir-30d、hsa-miR-30d-5p、hsa-mir-30e、hsa-miR-30e-5p、hsa-miR- 31-3p、hsa-miR-31-5p、hsa-miR-320a、hsa-miR-342-3p、hsa-miR-345-5p hsa-miR-34a-5p hsa-miR-361-5p hsa-miR-376a-3p hsa-miR-376c-3p hsa-miR-423-3p hsa-miR-423-5p hsa-miR-424-5p hsa-miR-484 hsa- mir-486-1, hsa-mir-486-2, hsa-miR-486-5p, hsa-miR-570-3p, hsa-miR-574-3p, hsa-miR-663a, hsa-miR-874-3p, hsa-mir-92a-1, hsa-mir-92a-2hsa-miR-92a-3p, hsa-miR-92b-3p, hsa-mir-93, hsa-miR-93-5p, hsa-miR-940, hsa-miR-99a-5p or hsa-miR-99b-5p, or a combination of two or more thereof; or both (iii), (i), and (ii).

[0125] 33. The method of any one of embodiments 27-32, wherein the therapeutic MSC secretome composition is prepared by a method comprising the steps of: (a) culturing bone marrow-derived MSCs to produce MSC conditioned medium under the following conditions: (i) oxygen partial pressure below 5%; and (ii) a medium with pH below 7; (b) harvesting the MSC conditioned medium; and (c) formulating the MSC conditioned medium to produce the therapeutic MSC secretome composition, wherein the therapeutic MSC secretome composition comprises proteins and extracellular vesicles produced by the bone marrow-derived MSCs in step (a).

[0126] 34. The method as described in any one of embodiments 27-33, wherein the subject suffers from chronic pain.

[0127] 35. The method of any one of embodiments 27-34, wherein the subject suffers from back pain.

[0128] 36. The method as described in any one of embodiments 27-35, wherein the subject suffers from chronic low back pain.

[0129] 37. The method of any one of embodiments 27-36, wherein the subject experiences improvement in one or more of the following skin characteristics after treatment: pain, stiffness, range of motion, posture, overall health, mood, social interaction, sleep and / or walking ability, and combinations thereof.

[0130] 38. The method of any one of embodiments 1-37, wherein the composition comprises 0.5 mL of the therapeutic MSC secretion group composition.

[0131] 39. The method of embodiment 38, wherein the composition is injected into the facet joint space of the lumbar spine.

[0132] 40. A method for treating a subject with lumbar facet joint syndrome, the method comprising administering to the subject a composition comprising a therapeutic mesenchymal stem cell (MSC) secretory composition containing extracellular vesicles (EVs), wherein the composition comprises 0.5 mL of the therapeutic MSC secretory composition.

[0133] 41. A method for treating a subject with lumbar facet joint syndrome, the method comprising administering to the subject a composition comprising a therapeutic mesenchymal stem cell (MSC) secretome composition containing extracellular vesicles (EVs), wherein the administration improves one or more of the following skin characteristics: pain, stiffness, range of motion, posture, general health, mood, social interaction, sleep and / or walking ability, and combinations thereof.

[0134] 42. The method of any one of embodiments 1-41, wherein the application results in an improvement in one or more of the severity index, interference index and / or Oswestry Disability Index (ODI).

[0135] 43. The method of embodiment 42, wherein the subject experiences 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%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, or 45% of one or more of the following scores after treatment: Severity Index, Interference Index, and / or ODI score. 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%, or 100% improvement.

[0136] 44. The method of embodiment 42, wherein the subject experiences a severity index of 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%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 4 Improvements of 8%, 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%, or 100%.

[0137] 45. The method of embodiment 42, wherein the subject experiences an interference index of 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%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48% after treatment. %, 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% or 100% improvement.

[0138] 46. ​​The method of embodiment 42, wherein the subject experiences an ODI score of 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%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, or 48% after treatment. %, 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% or 100% improvement.

[0139] 47. The method of any one of embodiments 1-46, wherein the application results in one or more improvements in: pain, stiffness, range of motion, posture, overall health, mood, social interaction, sleep, and / or walking ability.

[0140] 48. The method of any one of embodiments 1-47, wherein the application results in an improvement in functional capability.

[0141] 49. The method of any one of embodiments 1-48, wherein the application improves inflammation.

[0142] 50. Use of a composition comprising a therapeutic mesenchymal stem cell (MSC) secretome composition containing extracellular vesicles in lumbar facet joint syndrome in a subject of treatment, wherein at least 80% of the extracellular vesicles in the therapeutic MSC secretome composition are CD63. + CD9 - CD81 - .

[0143] 51. Use of a composition comprising a therapeutic mesenchymal stem cell (MSC) secretome composition containing extracellular vesicles (EVs) for the treatment of lumbar facet joint syndrome in subjects of need, wherein the therapeutic mesenchymal stem cell (MSC) secretome composition comprises: (i) ferritin, NUP85, LAMP2, GPR115, serine protease inhibitor F1, OPN, PAI-1, DAPP1, cathepsin B, brain signaling protein 6C, PDGF R α, Sorting protein, serine protease inhibitor B6, Dkk-3, coagulation regulator protein, PF4, MIF, periosteal protein, furin, TIMP-1, dermal proteoglycan, PCK1, CD99, CD63, CD9, CD81, transferrin, DcR3, photoglycan, TIMP-2, SLITRK5, FAP, leptospirin, DPPII, cIAP-1, pentameric protein 3, lactone, enkephalin, albumin, galactoglobin-1, UNC5H3, IL-20, β-reactive protein, SREC-II, JAM-C, TNF-α, htPAPP-A, eNOS, MSP, TPP1, LAMP1, B2M, NCAM-1, HIF-1 α, ST6GAL1, CD99-L2, conglomerate A4, EMMPRIN, p53, brain signaling protein 7A, NKp80, cysteine ​​protease protein B, osteoadhesion, mid-term factor, calreticulin, osteoactivin, asparagine endopeptidase, TAZ, cathepsin L, RBP4, serine protease inhibitor A4, JAM-A, MCSF, LIMPII, OPG, IL-22, galactoglobulin-3, MOG, trypsin 3, SIRP α, cohesin-4, IGFBP-4, IL-1, R6 GSTM1, NUP85, LAMP2, transmembrane peptidase A, IL-1 F10, bIG-H3, GPR115, TGFb1, liver glycoside A4, CD109, serine protease inhibitor F1, IGFBP-6, HS3ST4, aminopeptidase LRAP, OPN, PAI-1, DAPP1, GDF-9, cathepsin B, IGFBP-2, brain signaling protein 6C, IGF-2, PDGFR α, sorting protein, serine protease inhibitor B6, Dkk-3, CNTF, TSP-1, GM-CSF Ra, coagulation regulatory protein, endosaccharides, IGFBP-3, RGM-C, PF4, MIF, TGM4, periosteal protein, furin protease, TIMP-1, PAPP-A, dermal proteoglycans, PCK1, arylsulfatase A, CD99, CA2, PRDX4, transferrin, DcR3, GP73, LAIR2, ULBP-4, optical proteoglycans, TIMP-2, TFPI, SOX2, SLITRK5, FAP, spinal proteinENPP-2, CD97, CTACK, integrin α1, EXTL3, IL-18, BPa, PD-L2, PSMA, IL-20 Ra, glyoxalase II, trypsin I, IGF-2R, ADAMTSL-1, erythropoietin, plexin D1, DNMT3A, BCL-2, CL-P1, hepatocyte glycoside-B3, FABP6, CHI3L1, FCRLS, TFF3, leptospirin, DPPII, cIAP-1, PDGF Rb, pentameric protein 3, angiotensinogen, follicle-stimulating hormone, CF VII, persephin, TRAIL R1, THAP11, CD200, CLEC-2, AMIGO, IGFBP-5, PON1, SOX7, GALNT10, endothelin, granulosin precursor, PCSK2, GKN1, IL-18, enkephalin, stabilizer-2, IL-17 RD, albumin, follicle-stimulating protein 1, MMP-10, FKBP51, LRRC4, Pref-1, galactoglobin-1, troponin C, UNC5H3, FLRT2, CD314, brain signaling protein 6B, cytokinin-4, CD27 ligand, IL-20 Rβ, brain signaling protein 6A, TSK, cytokeratin-8, CHST3, Mcl-1, DPPIV, SREC-II, No'rin, JAM-C, Bcl-10, Wnt-4, LSECtin, Kell, TNF RI, PTP1B, htPAPP-A, IDO, PDGF-CC, Glycopropyl peptide, Activator Protein A, TLR2, SCCA2, FABP1, eNOS, SHP-1, ICOS, C1qTNF9, MMP-1, TC-PTP, IL-24, gp130, C-myc, LILRB4, BMP-2, MIA, CD34, CD63, CD9, CD81, IFNab R2, Phosphatidylinositol Proteoglycan 2, MSP R, DSCAM, Membrane-type Serine Protease, KIR2DL3, CD30, Salivary Agglutinin-10, CLEC-1, TPP1, Ubiquitin+1, ANGPTL4, TWEAK R, Nestin-1, CD2, Kallikrein 1, TSLPR, LAMP1, TROY, VCAM-1, Salivary agglutinin-11, S100A1, PAR1, Thyroid peroxidase, Aminopeptidase P2, IL-1RI, ADAMS, OSM Rβ, Platelet-Reactive Protein-2, SMPD1, B2M, MFRP, LRP-6, ST3GAL1, NCAM-1 (CD56), Granulase B, Lipocontin, IL-22BP, TPST2, PD-ECGF, LH, LEDGF, Cyr61, ULBP-3, IFNb, THSD1, FGF-23, LAMA4Lipoprotein, AIF, SorCS2, SULT2A1, CD39L2, Insulin R, HIF-1 α, OX40 ligand, Pax3, UCH-L3, cMASP3, Langerin, Desmin, SOX9, ST6GAL1, MEP1B, CD99-L2, Convolutional protein A4, Brain signaling protein 4D, ROBO2, PDX-1, APRIL, Neural rank protein, cyclic transmembrane protein-2, EMMPRIN, activator protein RIB, neuroligand 2, epithelial regulatory protein, CASA, MMP-12, GALNT2, CEACAM-5, VEGF R1, DSPG3, SorCS1, Extracellular matrix protein-2, sFRP-3, p53, EphB3, NCK1, Brain signaling protein 7A, NKp80, Prolactin, Cysteine ​​protease protein B, Sirtuin 1, FGF-16, FGF R5, NQO-1, Brain signaling protein 6D, FGF-3, GATA-4, VAP-A, CHST2, Pregnancy-associated plasma protein-2, Cohesin-3, Serpentin-1, AKR1C4, Oligosin-2, Osteoadhesin, NKp44, Thyroglobulin, IL-21R, Chemokines, EphA1, CD48, MICB, FGF-5, TRANCE, CES2, ULBP-1, Integrin α 5. VAMP-2, FLRG, Ret metaphase factor, CD73, TRAP, proGRP, granzyme H, PRX2, p2'7, salivary lectin-6, dendritic cell-associated C-type lectin-1, CD51, Notch-1, calreticulin, DR3, DCTN1, CDC25B, bone activator, ACE, CA125, HAO-1, ​​PSMA1, FCRLB, BMP-9, CRIM1, LIF, SPINK1, EphB6, RGM-B, HS3ST1, ROR1, CMG-2, 4-1BB ligand, L1CAM-2, p63, cathepsin V, testosterone-2, phosphatidylinositol proteoglycan 5, CD6, salivary lectin-2, asparagine endopeptidase, PRELP, CES1, TAZ, NSE, TECK, HTRA2, HIF-1 β, TAFA1, podocyte protein, RalA, CRELD2, GRAP2, SP-D, BID, GFR α-2, Notch-3, VEGF R3, DLL4, TGFb2, LIGHT, XIAP, ST8SIA1, cathepsin L, 6-Ckine, MIS RII, kallikrein 5, TGM3, FCAR, contactin-2, CD83, IL-1R3, SALM4, GBA3, ROBO4, OSCAR, VEGF, IGSF3, disaccharide proteoglycan, neurodevelopmental factor, ILT4, uPAR, Axl, WIF-1IL-7 Rα, GPR56, CEACAM-3, MCEMP1, FABP2, plexin B3, MEPE, activator RIIA, ANG-2, Cochlin, progerin 1, NPTXR, SLAM, COMT, SPHK1, RBP4, stalkin-1, GUSB, nestin-2, IL-17F, SR-AI, TAFA2, N-cadherin, IL-17B, IL-17RC, MIP-3b, cysteine ​​protease C, cysteine ​​protease D, AMSH, FcERI, CLEC10A, HGF R, ANG-1, prolactin R, FGF-20, CD28, Nogo-A, HSD17B1, IL-19, intestinal peptidase, cathepsin E, TSLP, TCN2, GDF-15, epidermal morphogenetics, GRKS, PD-1, serine protease inhibitor A4, ADAM23, NOV, galactoglobulin-2, neuronal surface protein 3β, TLR3, Sirtuin2, Numb, IL-28 Rα, IL-33, Lin28, FCRL1, KLF4, NKp30, lymphocyte chemokine, cysteine ​​protease protein SN, JAM-A, calreticulin-2, ErbB4, BMP-8, IL-27 Ra, Fas, IL-4 Ra, kallikrein 14, extracellular matrix protein-3, Oligo2, kallikrein 12, CA13, IL-9, stalk protein-3, MPIF-1, cysteine ​​protease protein S, ADA, IL-2 Rb, GFR α-1, Smad4, ICAM-1, MEF2C, TREM-1, L-selectin, transmembrane serine protease, CD42b, MCSF, RANK, CHST4, CA8, FCRL3, ASAH2, CF XIV, PYY, HGF, I-TAC, brain signaling protein 4C, SorCS3, Tie-1, IL-31 RA, Arginase 1, POGLUT1, IL-1ra, Flatfoot protein, TIM-3, CREG, CD300f, uPA, EphA2, LLRTM4, LIMPII, Tenosynovin R, CPE, PECAM-1, DNAM-1, DKK-1, OPG, CPB1, TSH, MMP-2, Salivary lectin-9, ICAM-3, Cysteine ​​protease inhibitor SA, Galactohemagglutinin-4, Pepsinogen II, Desmosome core protein-3, Stalk protein-4, SCF, Serine protease inhibitor A5, PTH, FGF-19, MSP, IL-28A, FGF-12, METAP2, ASAHL, EDIL3, NTAL, EGF R, TAFAS, Galactohemagglutinin-9, vWF-A2, TACE, Activator protein RIM, Cathepsin S, LDL RBMPR-IA, OX40, IL-13 R2, B7-H4, MMP-13, ANGPTL7, TRAIL R4, IGSF4B, Sirtuin 5, PEAR1, SH2D1A, Cerberus 1, GDF-11, Nrf2, TROP-2, NUDTS, ROR2, EphB4, phosphatidylinositol proteoglycan 1, LAP (TGFb1), Gash, contactin-1, IL-27, UNC5H4, ICAM-2, MBL, HS3ST3B1, RCOR1, IL-10 Rb, XEDAR, IL-22, PILR-α, NRG1-131, FABP4, RGM-A, RELT, TrkC, CSa, SREC-I, neural epithelial stem cell protein, TPO, ErbB3, Kirrel3, FLRT1, galactoglobulin-3, CXCL16, JAM-B, DR6, Nogo receptor, TLR4, VEGF R2, Tie-2, IL-15 R, Caspr2, LTbR, LAMP, ALCAM, GLP-1, NG2, IL-22 Rα 1, AMIGO2, HCC-1, TFPI-2, ULBP-2, desmosome core protein 2, agglutinin, synaptic fusion protein 4, VAMP-1, stalkin-2, FGF-21, Flt-3, GFAP, TIM-1, inhibin A, cadherin-4, PIGF-2, neurogranulin, HE4, IL-23 R, galactoglobulin-7, GALNT3, GITR L, CD14, R-vertebral protein 2, CK19, cardiotrophin-1, TREML1, HAPLN1, CD27, ANG-4, salivary immunoglobulin-7, CD155, VEGF-C, TNF RII, PGRP-S, SDF-1a, PDGF-AB, GPVI, CD40, SCF R, platelet-reactive protein-5, IL-1 RII, neurofeedin-2, cadherin-13, E-selectin, GITR, WISP-1, renin, AgRP, MDL-1, ROBO3, RANTES, endothelial cell-specific molecules, granzyme, hCGb, mesothelin, TLR1, TRAIL, MOG, DDR1, NGF R, TRAIL R3, trypsin 3, ARSB, LIF Rα, BAFFR, CD157, granzyme A, 2B4, ESAM, IL-1 R4, CXCL14, IL-31, SIRP α, urinary modulatory proteins, CTRC, CEACAM-1, TARC, MIP-3a, SDF-1b, NKp46, MCP-3, IL-32 α, TGFb3, FOLR2, CD58, IL-23, CD36, TNFb, Shh-N, fibrinogen-1, Reg4ILT2, Mer, TREM-2, Flt-3L, CDS, IL-6, CD229, Insulin, Synaptic Fusion Protein 6, GRO, Bcl-w, Lipocrine-2, PDGF-AA, IL-2 Ra, Angiopoietin, LYVE-1, CD4, RAGE, CDNF, Short Proteoglycan, NAP-2, PU.1, EDAR, ADAMTS13, Kynureninase, PTH1R, IFN-γ R1, CrkL, B7-1, PARC, Draxin, VE-cadherin, Procalcitonin, SOX15, Kallikrein 11, BCMA, Dendritic Cell-Associated C-Lectin-2, EpCAM, HCC-4, TGFa, IP-10, BLAME, CILP-1, PIGF, LOX-1, MCP-2, Resistin, HVEM, ENPP-7, Cohesin-Glycan-4, IL-2 Rg, MICA, dopa decarboxylase, NPDC-1, MCP-4, EG-VEGF, glycoprotein V, brain signaling protein 4G, IL-12p40, total PSA, IL-15, MAP1D, C1q, TNF4, Dtk, endothelial glycoprotein, ENA-78, Reg3A, MIP-1b, FGF-17, IL-6R, IL-8, galactolectin-8, CA4, cysteine ​​protease protein EM, FUT8, B7-H 3. GCP-2, CD40L, MDC, 4-1BB, HO-1, SOST, S100A13, kallikrein 7 or IL-13, or a combination of two or more thereof; (ii) hsa-let-7a-5p, hsa-let-7b-5p, hsa-let-7c-5p, hsa-let-7d-3p, hsa-let-7e-5p, hsa-let-7g-5p, hsa-let-7i, hs a-let-7i-5p, hsa-miR-100-5p, hsa-miR-103a-3p, hsa-miR-106a-5p, hsa-miR-106b-5p, hsa-mir- 10b, hsa-miR-10b-5p, hsa-mir-1246, hsa-miR-1246, hsa-miR-125a-5p, hsa-miR-125b-5p, hsa-mi R-130a-3p, hsa-mir-130b, hsa-miR-130b-3p, hsa-miR-132-3p, hsa-miR-136-5p, hsa-miR-138-5p , hsa-miR-139-5p, hsa-mir-140, hsa-miR-140-3p, hsa-miR-145-5p, hsa-mir-146a, hsa-miR-146a- 5p, hsa-miR-148a-3p,hsa-miR-152-3p, hsa-miR-15a-5p, hsa-miR-15b-5p, hsa-mir-16-1, hsa-mir-16-2, hsa-miR-16-5p, hsa-miR-1'7-5p, hsa-miR-181a-5p, hsa-miR-191-5p, hsa-miR-193a-5p, hsa-miR-193b-3p, hsa-miR-19'7-3p, hsa-miR-199a-3p, hsa-miR-199a-5p, hsa-miR-199b-5p, hsa-miR-19a-3p, hsa-mi R-19b-3p, hsa-miR-20a-5p, hsa-mir-203a, hsa-miR-203a-3p, hsa-miR-214-3p, hsa-mir-21, hsa-miR-21-3p, hsa-miR-21-5p, hsa-mir-221, hsa-miR-221-3p, hsa-mir-222, hsa-miR-222-3p, hsa-miR-22-3p, hsa-miR-23a-3p, hsa-miR-23b-3p, hsa-mir-24-1, hsa-mir-24-2, hsa-miR-24-3p, hsa- mir-25, hsa-miR-25-3p, hsa-miR-26a-5p, hsa-miR-27a-3p, hsa-mir-27b, hsa-miR-27b-3p, hsa-miR-29a-3p, hsa-miR-29c-3p, hsa-miR-30a-5p, hsa-miR-30a-5p, hsa-miR-30b-5p, hsa-miR-30c-5p, hsa-mir-30d, hsa-miR-30d-5p, hsa-mir-30e, hsa-miR-30e-5p, hsa-miR-31-3p, hsa-miR-31-5p hsa-miR-320a hsa-miR-342-3p hsa-miR-345-5p hsa-miR-34a-5p hsa-miR-361-5p hsa-miR-376a-3p hsa-miR-376c-3p hsa-miR-423-3p hsa -miR-423-5p, hsa-miR-424-5p, hsa-miR-484, hsa-mir-486-1, hsa-mir-486-2, hsa-miR-486-5p, hsa-miR-570-3p, hsa-miR-574-3p, hsa-miR-663ahsa-miR-874-3p, hsa-mir-92a-1, hsa-mir-92a-2, hsa-miR-92a-3p, hsa-miR-92b-3p, hsa-mir-93, hsa-miR-93-5p, hsa-miR-940, hsa-miR-99a-5p or hsa-miR-99b-5p, or a combination of two or more thereof; or both (iii), (i), and (ii).

[0144] 52. Use of a composition comprising a therapeutic mesenchymal stem cell (MSC) secretory composition containing extracellular vesicles (EVs) in the treatment of lumbar facet joint syndrome, wherein the composition comprises 0.5 mL of the therapeutic MSC secretory composition.

[0145] 53. The use as described in embodiment 52, wherein the therapeutic MSC secretory group composition is injected into the facet joint space.

[0146] definition As used in this specification and the appended claims, unless otherwise expressly stated, the singular forms of “a,” “an,” and “the” include plural references. It should also be noted that, unless otherwise expressly stated, the term “or” is generally used in its meaning including “and / or.” The terms “and / or” and “any combination thereof” and their grammatical equivalents, as used herein, may be used interchangeably.

[0147] The term "about" or "approximately" can refer to an acceptable range of error for a particular value, which can depend in part on how the value was measured or determined, such as limitations of the measurement system. For example, "about" can refer to a standard deviation of less than or greater than 1. Alternatively, "about" can refer to a range of up to 20%, up to 10%, up to 5%, or up to 1% of a given value. Alternatively, particularly with respect to biological systems or methods, the term can refer to within orders of magnitude, within 5 times, or within 2 times the value. When a particular value is described in the application and claims, unless otherwise stated, the term "about" should be presumed to refer to an acceptable range of error for the particular value.

[0148] As used in this specification and claims, the terms “comprising” (and any form of “comprising”, such as “comprise”, “comprises”), “having” (and any form of “having”, such as “having”, “suffering”), “including” (and any form of “including”, such as “includes”, “include”), or “containing” (and any form of “containing”, such as “contains”, “contain”) are inclusive or open-ended and do not exclude additional, unlisted elements or method steps.

[0149] The terms “individual,” “patient,” or “object” are used interchangeably. None of these terms require or are limited to situations characterized by supervision (e.g., continuous or intermittent) by a healthcare worker (e.g., physician, registered nurse, nurse practitioner, physician assistant, caregiver, or hospice worker).

[0150] Example The following embodiments are provided to further illustrate some implementations of this disclosure, but are not intended to limit the scope of this disclosure; it should be understood that, given their exemplary nature, other procedures, methods or techniques known to those skilled in the art may also be used alternatively.

[0151] Example 1: Production of the therapeutic composition The MSC secretome therapeutic composition was prepared by the following method: Human bone marrow-derived MSCs were cultured in culture dishes with growth medium to expand the MSC population. The growth medium was then removed, and the cells were washed with PBS. The MSCs were then cultured under hypoxic conditions in a glucose-reduced medium with a pH less than 7.0. The conditioned medium was then collected and percolated, followed by sterilization. The production method of the therapeutic product was performed under current Good Manufacturing Practice and Current Good Tissue Practice.

[0152] The tetraspan membrane protein profile of extracellular vesicles present in the therapeutic composition was determined, and it was found that more than 95% of the extracellular vesicles present in the therapeutic composition were CD63. + CD9 - CD81 - .

[0153] The protein contents of the therapeutic product were identified, and the following proteins were found: ferritin, NUP85, LAMP2, GPR115, serine protease inhibitor F1, OPN, PAI-1, DAPP1, cathepsin B, brain signaling protein 6C, PDGF Rα, sorting protein, serine protease inhibitor B6, Dkk-3, coagulation regulatory protein, PF4, MIF, periosteal protein, furin, TIMP-1, tectonic proteoglycan, PCK1, CD99, CD63, CD9, CD81, transferrin, DcR3, photoglucan, TIMP-2, SLITRK5, FAP, leptospirin, DPPII, cIAP-1, pentameric protein 3, lactone, enkephalin, albumin, galactolectin-1, UNC5H3, IL-20 Rβ, SREC-II, JAM-C, and TNF. RI, htPAPP-A, eNOS, MSP R, TPP1, LAMP1, B2M, NCAM-1, HIF-1 α, ST6GAL1, CD99-L2, convolutional protein A4, EMMPRIN, p53, brain signaling protein 7A, NKp80, cysteine ​​protease protein B, osteoadhesion, mid-term factor, calreticulin, osteoactivin, asparagine endopeptidase, TAZ, cathepsin L, RBP4, serine protease inhibitor A4, JAM-A, MCSF, LIMPII, OPG, IL-22, galactolectin-3, MOG, trypsin 3, SIRP α, cohesin-4, IGFBP-4, IL-1, R6 GSTM1, NUP85, LAMP2, transmembrane peptidase A, IL-1 F10, bIG-H3, GPR115, TGFb1, liver glycoside A4, CD109, serine protease inhibitor F1, IGFBP-6, HS3ST4, aminopeptidase LRAP, OPN, PAI-1, DAPP1, GDF-9, cathepsin B, IGFBP-2, brain signaling protein 6C, IGF-2, PDGF Rα, sorting protein, serine protease inhibitor B6, Dkk-3, CNTF, TSP-1, GM-CSF Ra, coagulation regulatory protein, endosaccharides, IGFBP-3, RGM-C, PF4, MIF, TGM4, periosteal protein, furin, TIMP-1, PAPP-A, dermal proteoglycan, PCK1, arylsulfatase A, CD99, CA2, PRDX4, transferrin, DCR3, GP73, LAIR2, ULBP-4, optical proteoglycan, TIMP-2, TFPI, SOX2, SLITRK5, FAP, spinal cord protein, ENPP-2, CD97, CTACK, integrin α1, EXTL3, IL-18, BPa, PD-L2, PSMA, IL-20Ra, Glyoxalase II, Trypsin I, IGF-2R, ADAMTS L1-1, Erythropoietin, Convolutional D1, DNMT3A, BCL-2, CL-P1, Hepatocyte-B3, FABP6, CHI3L1, FCRLS, TFF3, Nephlebotomycin, DPPII, cIAP-1, PDGF Rb, Pentanoic Acid 3, Angiotensinogen, Follicle-Stapressin, CF VII, Persephin, TRAIL R1, THAP11, CD200, CLEC-2, AMIGO, IGFBP-5, PON1, SOX7, GALNT10, Lactone, Granulosin Progenitor, PCSK2, GKN1, IL-18, Enkephalin, Stabilin-2, IL-17 RD, albumin, follicle-stimulating protein 1, MMP-10, FKBP51, LRRC4, Pref-1, galactoglobin-1, troponin C, UNC5H3, FLRT2, CD314, brain signaling protein 6B, cytokinin-4, CD27 ligand, IL-20 Rβ, brain signaling protein 6A, TSK, cytokeratin-8, CHST3, Mcl-1, DPPIV, SREC-II, norin, JAM-C, Bcl-10, Wnt-4, LSECtin, Kell, TNF RI, PTP1B, htPAPP-A, IDO, PDGF-CC, Glycopropyl peptide, Activator Protein A, TLR2, SCCA2, FABP1, eNOS, SHP-1, ICOS, C1qTNF9, MMP-1, TC-PTP, IL-24, gp130, C-myc, LILRB4, BMP-2, MIA, CD34, CD63, CD9, CD81, IFNab R2, Phosphatidylinositol Proteoglycan 2, MSP R, DSCAM, Membrane-type Serine Protease, KIR2DL3, CD30, Salivary Agglutinin-10, CLEC-1, TPP1, Ubiquitin+1, ANGPTL4, TWEAK R, Nestin-1, CD2, Kallikrein 1, TSLP R, LAMP1, TROY, VCAM-1, salivary agglutinin-11, S100A1, PAR1, thyroid peroxidase, aminopeptidase P2, IL-1 RI, ADAMS, OSM R β, platelet-reactive protein-2, SMPD1, B2M, MFRP, LRP-6, ST3GAL1, NCAM-1 (CD56), granzyme B, lipoconazole, IL-22BP, TPST2, PD-ECGF, LH, LEDGF, Cyr61, ULBP-3, IFNb, THSD1, FGF-23, LAMA4, lipoprotein, AIF, SorCS2, SULT2A1, CD39L2, insulin R, HIF-1α, OX40 ligand, Pax3, UCH-L3, cMASP3, Langerin, desmin, SOX9, ST6GAL1, MEP1B, CD99-L2, conglomerate A4, brain signaling protein 4D, ROBO2, PDX-1, APRIL, neuronal rank protein, transmembrane protein-2 with ring structure, EMMPRIN, activating protein RIB, neuroligand 2, epithelial regulatory protein, CASA, MMP-12, GALNT2, CEACAM-5, VEGF R1, DSPG3, SorCS1, extracellular matrix protein-2, sFRP-3, p53, EphB3, NCK1, brain signaling protein 7A, NKp80, prolactin, cysteine ​​agonist protein B, Sirtuin 1, FGF-16, FGF R5, NQO-1, Brain signaling protein 6D, FGF-3, GATA-4, VAP-A, CHST2, Pregnancy-associated plasma protein-2, Cohesin-3, Serpentin-1, AKR1C4, Oligosin-2, Osteoadhesin, NKp44, Thyroglobulin, IL-21R, Chemokines, EphA1, CD48, MICB, FGF-5, TRANCE, CES2, ULBP-1, Integrin α 5. VAMP-2, FLRG, Ret metaphase factor, CD73, TRAP, proGRP, granzyme H, PRX2, p2'7, salivary lectin-6, dendritic cell-associated C-type lectin-1, CD51, Notch-1, calreticulin, DR3, DCTN1, CDC25B, bone activator, ACE, CA125, HAO-1, ​​PSMA1, FCRLB, BMP-9, CRIM1, LIF, SPINK1, EphB6, RGM-B, HS3ST1, ROR1, CMG-2, 4-1BB ligand, L1CAM-2, p63, cathepsin V, testosterone-2, phosphatidylinositol proteoglycan 5, CD6, salivary lectin-2, asparagine endopeptidase, PRELP, CES1, TAZ, NSE, TECK, HTRA2, HIF-1 β, TAFA1, podocyte protein, RalA, CRELD2, GRAP2, SP-D, BID, GFRα-2, Notch-3, VEGF R3, DLL4, TGFb2, LIGHT, XIAP, ST8SIA1, cathepsin L, 6-Ckine, MIS RII, kallikrein 5, TGM3, FCAR, contactin-2, CD83, IL-1 R3, SALM4, GBA3, ROBO4, OSCAR, VEGF, IGSF3, disaccharide proteoglycan, neurodevelopmental factor, ILT4, uPAR, Axl, WIF-1, IL-7 Rα, GPR56, CEACAM-3, MCEMP1, FABP2, plexin B3, MEPE, activator RIIA, ANG-2, Cochlin, presenilin 1, NPTXR, SLAM, COMT, SPHK1, RBP4, stalkin-1, GUSB, nestin-2, IL-17F, SR-AI, TAFA2, N-cadherin, IL-17B, IL-17RC, MIP-3b, cysteine ​​protease C, cysteine ​​protease D, AMSH, FcERI, CLEC10A, HGF R, ANG-1, prolactin R, FGF-20, CD28, Nogo-A, HSD17B1, IL-19, intestinal peptidase, cathepsin E, TSLP, TCN2, GDF-15, epidermal morphogenetics, GRKS, PD-1, serine protease inhibitor A4, ADAM23, NOV, galactoglobulin-2, neuronal surface protein 3β, TLR3, Sirtuin 2, Numb, IL-28 Rα, IL-33, Lin28, FCRL1, KLF4, NKp30, lymphocyte chemokine, cysteine ​​protease protein SN, JAM-A, calreticulin-2, ErbB4, BMP-8, IL-27 Ra, Fas, IL-4 Ra, kallikrein 14, extracellular matrix protein-3, Oligo2, kallikrein 12, CA13, IL-9, stalk protein-3, MPIF-1, cysteine ​​protease protein S, ADA, IL-2 Rb, GFR α-1, Smad4, ICAM-1, MEF2C, TREM-1, L-selectin, transmembrane serine protease, CD42b, MCSF, RANK, CHST4, CA8, FCRL3, ASAH2, CF XIV, PYY, HGF, I-TAC, brain signaling protein 4C, SorCS3, Tie-1, IL-31 RA, Arginase 1, POGLUT1, IL-1ra, Flatfoot protein, TIM-3, CREG, CD300f, uPA, EphA2, LLRTM4, LIMPII, Tenosynovin R, CPE, PECAM-1, DNAM-1, DKK-1, OPG, CPB1, TSH, MMP-2, Salivary lectin-9, ICAM-3, Cysteine ​​protease inhibitor SA, Galactohemagglutinin-4, Pepsinogen II, Desmosome core protein-3, Stalk protein-4, SCF, Serine protease inhibitor A5, PTH, FGF-19, MSP, IL-28A, FGF-12, METAP2, ASAHL, EDIL3, NTAL, EGF R, TAFAS, Galactohemagglutinin-9, vWF-A2, TACE, Activator protein RIM, Cathepsin S, LDLR, BMPR-IA, OX40, IL-13 R2, B7-H4, MMP-13, ANGPTL7, TRAIL R4, IGSF4B, Sirtuin 5, PEAR1, SH2D1A, Cerberus1, GDF-11, Nrf2, TROP-2, NUDTS, ROR2, EphB4, phosphatidylinositol proteoglycan 1, LAP (TGFb1), Gash, contactin-1, IL-27, UNC5H4, ICAM-2, MBL, HS3ST3B1, RCOR1, IL-10 Rb, XEDAR, IL-22, PILR-α, NRG1-131, FABP4, RGM-A, RELT, TrkC, CSa, SREC-I, neural epithelial stem cell protein, TPO, ErbB3, Kirrel3, FLRT1, galactoglobulin-3, CXCL16, JAM-B, DR6, Nogo receptor, TLR4, VEGF R2, Tie-2, IL-15 R, Caspr2, LTbR, LAMP, ALCAM, GLP-1, NG2, IL-22 Rα1, AMIGO2, HCC-1, TFPI-2, ULBP-2, desmosome core protein 2, agglutinin, synaptic fusion protein 4, VAMP-1, stalkin-2, FGF-21, Flt-3, GFAP, TIM-1, inhibin A, cadherin-4, PIGF-2, neurogranulin, HE4, IL-23 R, galactoglobulin-7, GALNT3, GITR L, CD14, R-vertebral protein 2, CK19, cardiotrophin-1, TREML1, HAPLN1, CD27, ANG-4, salivary immunoglobulin-7, CD155, VEGF-C, TNF RII, PGRP-S, SDF-1a, PDGF-AB, GPVI, CD40, SCF R, platelet-reactive protein-5, IL-1 RII, neurofeedin-2, cadherin-13, E-selectin, GITR, WISP-1, renin, AgRP, MDL-1, ROBO3, RANTES, endothelial cell-specific molecules, particulate lysin, hCGb, mesothelin, TLR1, TRAIL, MOG, DDR1, NGF R, TRAIL R3, trypsin 3, ARSB, LIF Rα, BAFF R, CD157, Granulase A, 2B4, ESAM, IL-1R4, CXCL14, IL-31, SIRP α, Urinary Modulatory Protein, CTRC, CEACAM-1, TARC, MIP-3a, SDF-1b, NKp46, MCP-3, IL-32 α, TGFb3FOLR2, CD58, IL-23, CD36, TNFb, Shh-N, fibrinogen-1, Reg4, ILT2, Mer, TREM-2, Flt-3L, CDS, IL-6, CD229, Insulin, Synaptic Fusion Protein 6, GRO, Bcl-w, Lipocrine-2, PDGF-AA, IL-2 Ra, Angiopoietin, LYVE-1, CD4, RAGE, CDNF, Short Proteoglycan, NAP-2, PU.1, EDAR, ADAMTS13, Kynurenase, PTH1R, IFN-γ R1, CrkL, B7-1, PARC, Draxin, VE-cadherin, procalcitonin, SOX15, kallikrein 11, BCMA, dendritic cell-associated C-lectin-2, EpCAM, HCC-4, TGFa, IP-10, BLAME, CILP-1, PIGF, LOX-1, MCP-2, resistin, HVEM, ENPP-7, cohesin-4, IL-2 Rg, MICA, dopa decarboxylase, NPDC-1, MCP-4, EG-VEGF, glycoprotein V, brain signaling protein 4G, IL-12p40, total PSA, IL-15, MAP1D, C1q, TNF4, Dtk, endothelial glycoprotein, ENA-78, Reg3A, MIP-1b, FGF-17, IL-6R, IL-8, galactolectin-8, CA4, cysteine ​​protease protein EM, FUT8, B7-H3, GCP-2, CD40L, MDC, 4-1BB, HO-1, SOST, S100A13, kallikrein 7, and IL-13.

[0154] The nucleic acid content of the therapeutic product was determined, and the following nucleic acids were found: hsa-let-7a-5p, hsa-let-7b-5p, hsa-let-7c-5p, hsa-let-7d-3p, hsa-let-7e-5p, hsa-let-7g-5p, hsa-let-7i, hsa-let-7i-5p, hsa-miR-100-5p, hsa-miR-103a-3p, hsa-miR-106a-5p, hsa-miR-106b-5p, hsa-mir-10b, hsa-miR-10b-5p, hsa-mir-1246, hsa-miR-1246, hsa-miR-125a-5p, hsa-miR-125b-5p, hsa-miR-130a-3p, hsa-mir-130b, hsa-miR-130b-3p, hsa-miR-132-3p, hsa-miR-136-5p, hsa-miR-138-5p, hsa-miR-139-5p, hsa-mir-140, hsa-miR-140-3p, hsa-miR-145-5p, hsa-mir-146a, hsa-miR-146a- 5p, hsa-miR-148a-3p, hsa-miR-152-3p, hsa-miR-15a-5p, hsa-miR-15b-5p, hsa-mir-16-1, hsa-mir-16-2, hsa-miR-16-5p, hsa-miR-1’7-5p, hsa-miR-181a-5p, hsa-miR-191-5p, hsa-miR-193a-5p, hsa-miR-193b-3p, hsa-miR-19’7-3p, hsa-miR-199a-3p, hsa-miR-199a-5p, hsa-miR-199b-5p, hsa-miR-19a-3p, hsa-miR-19b-3p, hsa-miR-20a-5p, hsa-mir-203a, hsa-miR-203a-3p, hsa-miR-214-3p, hsa-mir-21, hsa-miR-21-3p, hsa-miR-21-5p, hsa-mir-221, hsa-miR-221-3p, hsa-mir-222, hsa-miR-222-3p, hsa-miR-22-3p, hsa-miR-23a-3p, hsa-miR-23b-3p, hsa-mir-24-1, hsa-mir-24-2, hsa-miR-24-3p, hsa-mir-25, hsa-miR-25-3p,hsa-miR-26a-5p, hsa-miR-27a-3p, hsa-mir-27b, hsa-miR-27b-3p, hsa-miR-29a-3p, hsa-m iR-29c-3p, hsa-miR-30a-5p, hsa-miR-30a-5p, hsa-miR-30b-5p, hsa-miR-30c-5p, hsa-mir -30d, hsa-miR-30d-5p, hsa-mir-30e, hsa-miR-30e-5p, hsa-miR-31-3p, hsa-miR-31-5p, hs a-miR-320a, hsa-miR-342-3p, hsa-miR-345-5p, hsa-miR-34a-5p, hsa-miR-361-5p, hsa-mi R-376a-3p, hsa-miR-376c-3p, hsa-miR-423-3p, hsa-miR-423-5p, hsa-miR-424-5p, hsa-mi R-484, hsa-mir-486-1, hsa-mir-486-2, hsa-miR-486-5p, hsa-miR-570-3p, hsa-miR-574-3 p, hsa-miR-663a, hsa-miR-874-3p, hsa-mir-92a-1, hsa-mir-92a-2, hsa-miR-92a-3p, hsa- miR-92b-3p, hsa-mir-93, hsa-miR-93-5p, hsa-miR-940, hsa-miR-99a-5p and hsa-miR-99b-5p. ,

[0155] Example 2: Production of the therapeutic composition The MSC secretome therapeutic composition was prepared by the following method: Human bone marrow-derived MSCs were cultured in culture dishes with growth medium to expand the MSC population. The growth medium was then removed, and the cells were washed with PBS. The MSCs were then cultured under hypoxic conditions in a glucose-reduced medium with a pH less than 7.0. The conditioned medium was then collected and percolated, followed by sterilization. The production of the therapeutic product was carried out in accordance with current good manufacturing practices and current good tissue practices.

[0156] The tetraspan membrane protein profile of extracellular vesicles present in the therapeutic composition was determined, and it was found that more than 95% of the extracellular vesicles present in the therapeutic composition were CD63. + CD9 - CD81 - .

[0157] The protein contents of the therapeutic product were identified, and the following proteins were found: ferritin, IGFBP-4 (insulin-like growth factor binding protein-4), IL-1 R6 (interleukin-1 receptor 6), LAMP2 (lysosome-associated membrane glycoprotein 2), bIG-H3 (transforming growth factor-β-inducible protein ig-h3), GPR115 (adhesion G protein-coupled receptor F4), CD63 antigen, CD109 antigen, serine protease inhibitor F1 (pigment epithelium-derived factor), IGFBP-6 (insulin-like growth factor binding protein-6), HS3ST4 (heparanol sulfate glucosamine 3-O-sulfotransferase 4), OPN (osteopontin), and PAI-1 (plasminogen activator inhibitor-1 or sERPINE). 1) Cathepsin B, IGFBP-2 (insulin-like growth factor binding protein-2), brain signaling protein 6C, IGF-2 (insulin-like growth factor-2), sorting protein, serine protease inhibitor B6, Dkk-3 (Dickkopf-related protein 3), CNTF (ciliary neurotrophic factor), TSP-1 (thromboretin-1), GM-CSF Ra (granulocyte-macrophage colony-stimulating factor receptor subunit α), coagulation regulatory protein, endoglucan, (podocyte protein-like protein 2) IGFBP-3 (insulin-like binding protein-3), RGM-C (hepcidin regulatory protein), PF4 (platelet factor 4), MIF (macrophage migration inhibitory factor), TGM4 (protein glutamine-γ-glutamyl transferase 4), periosteal protein, furin protease, TIMP-1 (MMP tissue inhibitor 1), gypsum glycan, PCK1 (cytosol-type phosphoenolpyruvate carboxykinase), CD9 antigen, CD99 antigen, CA2 (carbonic anhydrase 2), PRDX4 (peroxide reductase-4), transferrin, DcR3 (tumor necrosis factor receptor superfamily member 6B), GP73 (Golgi membrane protein 1), CD81 antigen, phytoglucan, and TIMP-2 (MMP tissue inhibitor 2).

[0158] The nucleic acid inclusions of the therapeutic product were identified, and the following nucleic acids were found to be present: hsa-miR-125b-5p, hsa-miR-145-5p, hsa-miR-191-5p, hsa-miR-199a-3p, hsa-miR-21-5p, hsa-miR-221-3p, hsa-miR-222-3p, hsa-miR-22-3p, and hsa-miR-23a-3p. , hsa-miR-23b-3p, hsa-miR-27a-3p, hsa-miR-27b-3p, hsa-miR-29a-3p, hsa-miR-29c-3p, hsa- miR-31-5p, hsa-miR-320a, hsa-miR-34a-5p, hsa-miR-423-3p, hsa-miR-424-5p and hsa-miR-940.

[0159] Example 3: Clinical study of bmMSC EV administration Research Design This article discloses a prospective, open-label, non-randomized safety study of a single therapeutic product injection for the treatment of lumbar facet joint pain. This study was approved by the Institute of Regenerative and Cellular Medicine (Protocol No. JW-FJE-001, Approval No. IRCM-2021-282). The study was conducted in accordance with the principles of the Declaration of Helsinki.

[0160] Twenty (20) healthy adult participants with lumbar facet joint syndrome were enrolled in the study, which was conducted at a single center (Interventional Pain Specialists, Naperville, IL). All participants had a history of chronic low back pain causing functional deficits. Imaging was performed to confirm lumbar facet joint degeneration. Participants also underwent a single diagnostic nerve block with local anesthetic at the L4-5 or L5-S1 segment to confirm facet joint syndrome. Baseline measurements were obtained on the day of treatment using three outcome assessments: Severity Index, Interference Index, and Oswestry Disability Index (ODI). These assessments were also obtained at 24 hours, 3 days, 1 week, 2 weeks, 1 month, 2 months, and 3 months post-injection. Communication was also conducted at follow-up sites throughout the study to discuss any potential adverse events. Informed consent was obtained from each participant prior to the start of the study.

[0161] Patient demographic characteristics All enrolled participants met the inclusion criteria (see below). The group consisted of 11 men and 9 women, with a mean age of 57.38 years (Table 2). All female participants underwent pregnancy screening prior to treatment. Participants with severe stenosis, cauda equina symptoms, or lumbar facet joint syndrome diagnosed by multiple factors were excluded.

[0162] Inclusion criteria All candidates in this study were eligible for inclusion if they met all of the following inclusion criteria: Voluntarily sign the approved informed consent form The target must be over 18 years old.

[0163] Diagnosis of degenerative facet joint pain (DFLBP) based on inclusion criteria for at least 6 months.

[0164] DFLBP can originate from any cause.

[0165] The patient must currently receive standard treatment and / or medication for his DFLBP diagnosis.

[0166] MRI evidence of degeneration in one or up to three facet joints.

[0167] The primary symptom complaint is low back pain due to degenerative facet joint disease. This will be established by MRI imaging of facet joint degeneration and image-guided diagnostic injection of a facet joint anesthetic that provides at least a 70% reduction in LBP over a period of time appropriate for the anesthetic used.

[0168] Exclusion criteria Candidates who meet any of the following exclusion criteria during the research process are ineligible for inclusion in the study: The subjects were unable to comply with the research protocol's follow-up procedures and visits.

[0169] Subjects with major risk factors, such as a history of narcotic drug abuse, lack of family support, unemployment, a history of physical or psychological abuse, or serious medical comorbidities.

[0170] Patients with any autoimmune disease.

[0171] Any patient whom the principal investigator deems not a suitable study patient.

[0172] Imaging evidence of isthmic spondylolysis or spondylolisthesis.

[0173] Symptomatic stenosis or herniated discs that cause leg pain to be greater than back pain.

[0174] Symptomatic discogenic pain.

[0175] Patients with blood cachexia, platelet dysfunction, sepsis / fever, malignancy, skin infection in the area to be treated, or severe mental disorder or unrealistic expectations.

[0176] Treatment Description The therapeutic product contains 60-80 billion extracellular vesicles / mL, which contain secreted proteins, mRNA, miRNA, growth factors, and signaling lipids. Primary EVs are derived from bone marrow mesenchymal stem cells from a single young, healthy donor. Donor bone marrow screening is performed by a Clinical Laboratory Improvement Amendment (CLIA) accredited laboratory that also tests for any viruses or infectious agents. According to USP... <71> The therapeutic product was subjected to a sterility test. It was stored frozen at -60°C to -80°C to maintain its biological activity. The product was thawed to room temperature before use. As an example, the product of Example 2 was used.

[0177] Injection technology Under fluoroscopic guidance, all lumbar facet joints were injected aseptically by the principal investigator. The patient was placed in a prone position with the abdominal area cushioned by a pillow. Strict aseptic technique was employed. The skin was prepared with chlorhexidine solution. The target facet joint was identified under multiplanar fluoroscopy. The target area was anesthetized with 1% lidocaine (PF). A 22-gauge needle was inserted into the facet joint space under fluoroscopy. Contrast agents were omitted to avoid diluting the extracellular vesicles during injection. After successful intra-articular puncture, 0.5 mL of the treatment product was injected into the confirmed joint space. All needles were removed intact, and a dressing was applied to the insertion site.

[0178] result Following successful lumbar facet joint injection, all twenty (20) participants were followed up for 3 months. No participants were lost to follow-up (100% follow-up). Each participant was followed up at 24 hours, 3 days, 1 week, 2 weeks, 1 month, and 3 months post-injection to assess any potential adverse events resulting from the use of the treatment product. No participants reported any adverse events or were identified as clinically deteriorating after treatment.

[0179] During follow-up, participants were provided with outcome assessments based on the Severity Index, Interference Index, and Oswestry Disability Index (ODI) to monitor their functional levels. Outcomes showed that, on average, participants experienced significant improvement in their assessments compared to baseline after receiving the injected therapeutic product. Figure 1Table 3 details the mean percentage of clinical improvement in each pain and functional outcome assessment compared to baseline for each time interval, and Table 4 lists the mean raw scores. By the 3-month follow-up endpoint, participants' mean severity index and interference index scores improved by 65.04% and 72.09%, respectively. At 90 days, participants' ODI scores also showed a statistical improvement of 58.43% (Table 4).

[0180] This preliminary IRB safety study on the treatment of lumbar facet joint syndrome demonstrates that the EV product (therapeutic product) derived from bmMSCs can be safely administered into the lumbar facet joint spaces. No complications or reported adverse events, whether minor or serious, occurred in any enrolled participant. No participant experienced a worsening of their condition due to the therapeutic injection. The safety profile of the injectable therapeutic product described in this study is consistent with another recent clinical study using the therapeutic product for the treatment of cervical and lumbar radiculopathy.

[0181] The results indicate that injecting bmMSC EV into the lumbar facet joints is a safe procedure and may be a universally effective treatment for lumbar facet joint syndrome.

[0182] Table 2. Description of Patient Demographic Characteristics Table 3. Average percentage improvement from baseline to each follow-up period. Table 4. Mean assessment values ​​for each time point. Paired t-tests yielded p-values ​​< 0.001 for each test compared to baseline. Example 4: Safety of extracellular vesicle injection of bone marrow-derived mesenchymal stem cells for lumbar facet joint pain This article discloses a preliminary 3-month study as described in Example 2 to evaluate the safety of injecting bone marrow-derived mesenchymal stem cell extracellular vesicle advanced research product (IP) into the lumbar facet joint space as a treatment for chronic low back pain. As an example, the IP of Example 2 is described.

[0183] Methods: Twenty healthy adults received IP injection (0.5 ml / joint) and underwent three functional assessments at 1, 3, 7, 14, 30, 60 and 90 days later.

[0184] Results: No adverse effects or complications occurred during the 3-month follow-up period. No pain worsening was reported. After 3 months, the mean scores of the groups showed significant improvement in the severity index (65.04%), interference index (72.09%), and Oswestry Disability Index (58.43%) (p<0.0001).

[0185] Conclusion: IP injection is safe and associated with significant functional improvements.

[0186] Study Design: This was a prospective, open-label, non-randomized safety study of a single-dose intraperitoneal (IP) injection for lumbar facet joint pain. The study was approved by the Institute for Regenerative and Cellular Medicine (Protocol No. JW-FJE-001, Approval No. IRCM-2021-282). The study was conducted in accordance with the principles of the Declaration of Helsinki. Twenty healthy adult participants with lumbar facet joint pain were enrolled in the study, which was conducted at a single center (Interventional Pain Specialists, IL, USA). All participants had a history of chronic low back pain (LBP) leading to reduced activities of daily living (ADL). MRI imaging confirmed lumbar facet joint degeneration. Participants received a single diagnostic medial branch block at the segment indicated by physical examination and MRI results. For suspected L4-5 facet joint pain, the diagnostic procedure was performed at L4; for suspected L5-S1 facet joint pain, the diagnostic procedure was performed at L5. The diagnostic medial branch injection was performed under aseptic conditions by the principal investigator under fluoroscopic guidance. Subjects were placed in a prone position with the abdominal area cushioned with a pillow. Strict aseptic technique was employed. The skin was prepared with chlorhexidine solution. The target medial branch of the nerve (L4 or L5) was identified under multiplanar fluoroscopy. The skin and subcutaneous tissue along the path leading to the target nerve were then anesthetized with 1% lidocaine (PF). Under real-time fluoroscopy, a 22-gauge needle was advanced to contact the pedicle of the vertebra to intersect the path of the medial branch of the nerve leading to the suspected facet joint. Next, 0.5 mL of 1% lidocaine (PF) was injected. All needles were removed intact. A sterile dressing was applied to the insertion site. Patients were monitored for the next 90 minutes. A 70% reduction in pain reported using the Visual Analog Scale within 0 to 90 minutes (the expected duration of the local anesthetic) was considered to confirm facet joint pain at the segment adjacent to the nerve. Only patients whose pain originated from the L4-L5 or L5-S1 spinal segment were included in this study after reviewing medical history, physical examination, and MRI imaging. Patients with MRI imaging showing involvement of additional cephalic or proximal arthritis segments were excluded. Baseline measurements of three pain or dysfunction indices were obtained on the day of treatment: the BPI-SI (Bareness Intensity Index-Severity Index), the BPI-II (Bareness Intensity Index-Disruption Index-II) (obtained from the Brief Pain Scale (BPI), and the Oswestry Disability Index (ODI). These assessments were also performed at 24 hours, 3 days, 1 week, 2 weeks, 1 month, 2 months, and 3 months post-injection. Communication was also conducted at follow-up points throughout the study to discuss any potential adverse events. Informed consent was obtained from each participant prior to the start of the study.

[0187] All candidates in this study were eligible for inclusion if they met all of the following inclusion criteria: Voluntarily sign the approved informed consent form The target must be over 18 years old Diagnosis of lumbar facet joint pain for at least 6 months based on inclusion criteria Lumbar facet joint pain can be caused by any etiology. The patient must currently receive standard treatment and / or medication for their diagnosis of lumbar facet joint pain. MRI evidence of degeneration in one or up to three facet joints The primary symptom of low back pain due to degenerative facet joint disease (LBP) is defined as follows: physical examination, MRI imaging of the L4-L5 or L5-51 lumbar spine to show facet joint degeneration, and a reported reduction of at least 70% in low back pain within 0 to 90 minutes following a diagnostic, fluoroscopically guided medial branch nerve block using 0.5 mL of 1% lidocaine (PF).

[0188] Candidates who meet any of the following exclusion criteria during the research process are ineligible for inclusion in the study: Subjects were unable to comply with the research protocol's follow-up procedures and visits. Subjects with key risk factors, such as a history of narcotic drug abuse, lack of family support, a history of physical or psychological abuse, or serious medical comorbidities. Individuals suffering from any autoimmune disease Any object that the principal investigator deems unsuitable as a research subject Radiographic evidence of pars interarticularis or spondylolisthesis Symptomatic stenosis or herniated disc causing leg pain to be greater than back pain Symptomatic discogenic pain Subjects with blood cachexia, platelet dysfunction, sepsis / fever, malignancy, skin infection in the area to be treated, or severe mental disorder or unrealistic expectations. No response to diagnostic medial branch nerve block Demographic characteristics of the participants: All enrolled participants met the inclusion criteria. The group consisted of 11 men and 9 women, with a mean age of 57.38 years. All female participants underwent pregnancy screening prior to treatment. Patients with severe stenosis, cauda equina symptoms, or a history of lumbar spine surgery were excluded.

[0189] Results: Following successful lumbar facet joint injection, all 20 participants were followed up for 3 months. No participants were lost to follow-up (100% follow-up). Each participant was followed up at 24 hours, 3 days, 1 week, 2 weeks, 1 month, and 3 months post-injection to assess any potential adverse events resulting from IP use. No participants reported any adverse events or were identified as clinically deteriorating after treatment. Analgesic use remained unchanged (or decreased) in all subjects during follow-up. No requests for additional medication were made during the study. All participants were provided with outcome assessments for BPI-SI and BPI-II, as well as ODI, to monitor functional levels. Outcomes showed that, at 3 months post-IP injection, participants experienced significant (p < 0.0001) improvement in all three assessments compared to baseline. Figure 2-4 BPI-SI and BPI-II scores showed significant improvement (p < 0.05) within 1 day. Figure 2-3 The average ODI reached significant within 3 days. Figure 4 By the 3-month follow-up endpoint, participants' average BPI-SI and BPI-II scores had improved by 65.04% and 72.09%, respectively. At 90 days, participants' ODI scores also showed an improvement of 58.43%.

[0190] Discussion: This preliminary IRB safety study on the treatment of lumbar facet joint pain demonstrates that the advanced BM-MSC EV IP can be safely administered to the lumbar facet joint space. No complications or reported adverse events, whether minor or serious, occurred in any enrolled participant. No participant experienced a worsening of their condition due to the therapeutic injection.

[0191] Example 5: One-month safety study of injecting a therapeutic product into the epidural space to treat lumbar or cervical radiculopathy. This article discloses a safety study to investigate the use of the disclosed therapeutic product in the treatment of cervical and lumbar radiculopathy. Ten healthy adults received treatment with the therapeutic product (n = 5 for each indication). Follow-up was conducted at 24 hours, 3 days, 1 week, 3 weeks, and 1 month post-injection.

[0192] Study Design: This study was a prospective, open-label, non-randomized IRB-approved safety study of a single therapeutic product injection for the treatment of cervical radiculopathy (n=5) and lumbar radiculopathy (n=5) caused by disc herniation. Participants were not responsible for any costs incurred for the study products and services provided. There is no reimbursement for participation in this study. The study protocol was approved by the Institute for Regenerative and Cellular Medicine IRB, Protocol No.: HM-EF-001, IRB Approval No.: IRCM-2020-274. All participants were consulted and provided with informed consent documents as required by the IRB. Ten (10) healthy adults were enrolled in the study, which was conducted at a single center (Hudson Medical). All participants had experienced radicular pain symptoms for many years and MRI showed mild to moderate disc herniation with foraminal compression. Medical history and physical examination were also performed. Baseline measurements were obtained 24 hours prior to injection using the Brief Pain Inventory (BPI), the Upper Extremity Functional Scale (UEFS), the QuickDash (QD), the Lower Extremity Functional Scale (LEFS), and the Oswestry Disability Index (ODI). These same outcome measures were obtained using the Qualtrics system at 24 hours, 3 days, 1 week, 3 weeks, and 1 month post-injection. Follow-up at these locations was conducted by telephone and email to discuss any potential adverse events and / or symptom improvement.

[0193] Injection Technique: All injections were performed by the principal investigator under standard aseptic conditions. Under fluoroscopic guidance, a 22-gauge 3.5-inch epidural Tuohy needle was advanced into the epidural space using the resistance disappearance technique. Then, 2–3 mL of Omnipaque 180 contrast agent was injected under real-time fluoroscopic imaging to confirm placement in the epidural space. A / P and lateral fluoroscopic images were saved. After repeated aspiration to remove blood or cerebrospinal fluid, a 3 mL solution of 2 mL of the treatment product and 1 mL of normal saline was injected. For patients with cervical radiculopathy, an interlaminar epidural injection was administered via a C5-6 or C6-7 segment approach. For patients with lumbar radiculopathy, an interlaminar epidural injection was administered via an L4-5 or L5-S1 segment approach. Figure 5 The placement of the injections is shown in the neck (top image) and waist (bottom image).

[0194] Results: Each participant was followed up at 24 hours, 3 days, 1 week, 3 weeks, and 1 month post-injection for outcome indicators and to review any potential adverse events associated with the use of the therapeutic product. One (1) participant withdrew from the study due to insufficient follow-up after the 5-day contact point. Another subject was enrolled to replace them, in accordance with the guidelines of the Institute for Regenerative and Cellular Medicine (IRB). Two patients experienced mildly worsened pain 24 hours post-injection, and four patients noted pain and soreness at the injection site. These adverse events subsided by the 3-day follow-up point. One subject experienced two headaches, one at the 3-day follow-up point and the other at 5 days post-injection. The second headache subsided on the day of onset, and the patient did not experience any further headaches for the remainder of the study period. No other adverse side effects were reported by participants post-injection, including fever, chills, headache, dizziness, nausea, and vomiting. By the 1-month follow-up point, no patient exhibited any worsening of cervical or lumbar radiculopathy as a result of the therapeutic product injection. At the 1-month follow-up point, patients showed an average improvement of 55% in BPI, 55.2% in QD, 25.4% in UEFS, 19.75% in ODI, and 26% in LEFS.

[0195] While preferred embodiments of this disclosure have been shown and described herein, it will be apparent to those skilled in the art that these embodiments are provided by way of example only. Many variations, alterations, and substitutions will now occur to those skilled in the art without departing from this disclosure. It should be understood that various alternatives to the embodiments of this disclosure may be employed in the practice of this disclosure. The scope of this disclosure is intended to be defined by the following claims, and thereby to cover the methods and structures within the scope of these claims and their equivalents.

Claims

1. A method for treating lumbar facet joint syndrome in a subject in need, the method comprising administering to the subject a composition comprising one or more extracellular vesicles (EVs); wherein the one or more EVs comprise hsa-miR-125b-5p, hsa-miR-145-5p, hsa-miR-191-5p, hsa-miR-199a-3p, hsa-miR-21-5p, hsa-miR-221-3p, hsa-miR-222-3p, hsa-miR-22 -3p, hsa-miR-23a-3p, hsa-miR-23b-3p, hsa-miR-27a-3p, hsa-miR-27b-3p, hsa-miR-29a-3p, hsa-miR-29c-3p, hsa-miR-31-5p, hsa-miR-320a, hsa-miR-34a-5p, hsa-miR-423-3p, hsa-miR-424-5p or hsa-miR-940, or a combination of two or more thereof.

2. A method for treating lumbar facet joint syndrome in a subject in need, the method comprising administering to the subject a composition comprising one or more extracellular vesicles (EVs); wherein at least 80% of the EVs are CD63+, CD9-, or CD81-.

3. A method for treating lumbar facet joint syndrome in a subject in need, the method comprising administering to the subject a composition comprising ferritin, IGFBP-4 (insulin-like growth factor binding protein-4), IL-1 R6 (interleukin-1 receptor 6), LAMP2 (lysosome-associated membrane glycoprotein 2), bIG-H3 (transforming growth factor-β-inducible protein ig-h3), GPR115 (adhesion G protein-coupled receptor F4), CD63 antigen, CD109 antigen, serine protease inhibitor F1 (pigment epithelial-derived factor), IGFBP-6 (insulin-like growth factor binding protein-6), HS3ST4 (heparanol sulfate glucosamine 3-O-sulfotransferase 4), OPN (osteopontin), and PAI-1 (plasminogen activator inhibitor-1 or sERPINE). 1) Cathepsin B, IGFBP-2 (insulin-like growth factor binding protein-2), brain signaling protein 6C, IGF-2 (insulin-like growth factor-2), sorting protein, serine protease inhibitor B6, Dkk-3 (Dickkopf-related protein 3), CNTF (ciliary neurotrophic factor), TSP-1 (thromboretin-1), GM-CSF Ra (granulocyte-macrophage colony-stimulating factor receptor subunit α), coagulation regulatory protein, endosaccharide, (podocyte protein-like protein 2) IGFBP-3 (insulin-like binding protein-3), RGM-C (hepcidin regulatory protein), PF4 (platelet factor 4), MIF (macrophage migration inhibitory factor), TGM4 (protein glutamine gamma-glutamyl transferase 4), periosteal protein, furin protease, TIMP-1 (MMP tissue inhibitor 1), gypsum proteoglycan, PCK1 (cytosol-type phosphoenolpyruvate carboxykinase), CD9 antigen, CD99 antigen, CA2 (carbonic anhydrase 2), PRDX4 (peroxide reductase-4), transferrin, DcR3 (tumor necrosis factor receptor superfamily member 6B), GP73 (Golgi membrane protein 1), CD81 antigen, luminescent proteoglycan, or TIMP-2 (MMP tissue inhibitor 2), or a combination of two or more thereof.

4. The method of claim 2, wherein the one or more EVs comprise hsa-miR-125b-5p, hsa-miR-145-5p, hsa-miR-191-5p, hsa-miR-199a-3p, hsa-miR-21-5p, hsa-miR-221-3p, hsa-miR-222-3p, hsa-miR-22-3p, hsa-miR-23a-3p, hsa- miR-23b-3p, hsa-miR-27a-3p, hsa-miR-27b-3p, hsa-miR-29a-3p, hsa-miR-29c-3p, hsa-miR-31-5p, hsa-miR-320a, hsa-miR-34a-5p, hsa-miR-423-3p, hsa-miR-424-5p, or hsa-miR-940, or a combination of two or more thereof.

5. The method of claim 1 or 2, wherein the composition comprises ferritin, IGFBP-4 (insulin-like growth factor binding protein-4), IL-1 R6 (interleukin-1 receptor 6), LAMP2 (lysosome-associated membrane glycoprotein 2), bIG-H3 (transforming growth factor-β inducible protein ig-h3), GPR115 (adhesion G protein-coupled receptor F4), CD63 antigen, CD109 antigen, serine protease inhibitor F1 (pigment epithelial-derived factor), IGFBP-6 (insulin-like growth factor binding protein-6), HS3ST4 (heparanol sulfate glucosamine 3-O-sulfotransferase 4), OPN (osteopontin), PAI-1 (plasminogen activator inhibitor-1 or sERPINE). 1) Cathepsin B, IGFBP-2 (insulin-like growth factor binding protein-2), brain signaling protein 6C, IGF-2 (insulin-like growth factor-2), sorting protein, serine protease inhibitor B6, Dkk-3 (Dickkopf-related protein 3), CNTF (ciliary neurotrophic factor), TSP-1 (thromboretin-1), GM-CSF Ra (granulocyte-macrophage colony-stimulating factor receptor subunit α), coagulation regulatory protein, endosaccharide, (podocyte protein-like protein 2) IGFBP-3 (insulin-like binding protein-3), RGM-C (hepcidin regulatory protein), PF4 (platelet factor 4), MIF (macrophage migration inhibitory factor), TGM4 (protein glutamine gamma-glutamyl transferase 4), periosteal protein, furin protease, TIMP-1 (MMP tissue inhibitor 1), gypsum proteoglycan, PCK1 (cytosol-type phosphoenolpyruvate carboxykinase), CD9 antigen, CD99 antigen, CA2 (carbonic anhydrase 2), PRDX4 (peroxide reductase-4), transferrin, DcR3 (tumor necrosis factor receptor superfamily member 6B), GP73 (Golgi membrane protein 1), CD81 antigen, luminescent proteoglycan, or TIMP-2 (MMP tissue inhibitor 2), or a combination of two or more thereof.

6. The method of any one of claims 1-5, wherein the subject suffers from chronic pain.

7. The method of any one of claims 1-6, wherein the subject suffers from back pain.

8. The method of any one of claims 1-7, wherein the subject suffers from chronic low back pain.

9. The method of claim 8, wherein the chronic low back pain causes functional impairment.

10. The method of claim 9, wherein the subject suffers from lumbar facet joint degeneration.

11. The method of any one of claims 1-10, wherein the subject has undergone imaging examinations and / or diagnostic nerve blocks to confirm lumbar facet joint syndrome.

12. The method of any one of claims 1-11, wherein the subject experiences improvement in one or more of the following symptoms after treatment: pain, stiffness, range of motion, posture, general health, mood, social interaction, sleep and / or walking ability, and combinations thereof.

13. The method of any one of claims 1-12, wherein administration includes intravenous administration.

14. The method of any one of claims 1-13, wherein the composition is prepared by a method comprising the steps of: (a) culturing bone marrow mesenchymal stem cells (BM-MSCs) under the following conditions to produce MSC conditioned medium: (i) oxygen partial pressure below 5%; and (ii) a medium with pH below 7; (b) harvesting the MSC conditioned medium; and (c) formulating the MSC conditioned medium to produce the composition.

15. The method of any one of claims 1-14, the method comprising preparing the composition prior to the administration, wherein the preparation of the composition is carried out by a method comprising the steps of: (a) culturing bone marrow mesenchymal stem cells (BM-MSCs) under the following conditions to produce MSC conditioned medium: (i) oxygen partial pressure below 5%; and (ii) a medium with pH below 7; (b) harvesting the MSC conditioned medium; and (c) preparing the MSC conditioned medium to produce the composition.

16. The method of claim 14 or 15, wherein the culture medium is serum-free.

17. The method of any one of claims 14-16, wherein the culture medium has a glucose concentration of less than 4.5 g / L.

18. The method of any one of claims 14-17, wherein preparing the MSC conditioned medium comprises replacing the conditioned medium with a pharmaceutically acceptable formulation.

19. The method of claim 18, wherein the pharmaceutically acceptable formulation comprises saline solution.

20. The method of any one of claims 1, 2, or 4, wherein the composition comprises at least 6 x 10 10 to 8 x 10 10 cells extracellular vesicles per ml and is administered in a dose of 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 mL.

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