Stem cell composition and method for repairing tissue

Abstract

Disclosed is a composition for use in promoting or enhancing repair or regeneration of damaged tissue or enhancing recovery from viral, bacterial, or fungal infection. The composition comprises small mobile stem (SMS) cells. Also disclosed are methods for preparing the composition, as well as methods for using the composition to treat or alleviate inflammatory diseases (such as fibrosis and COPD) and / or viral, bacterial, or fungal infections, or damage caused by such pathogens.

Description

Technical Field

[0001] Cross-reference to related applications This application claims the benefit of priority of U.S. Provisional Application No. 62 / 987,270, filed Mar. 9, 2020, which is hereby incorporated by reference in its entirety.

[0002] Aspects of the present disclosure relate to compositions and methods for promoting repair or regeneration of damaged tissue or organs and reducing substantial damage. In some aspects, the compositions of the invention comprise isolated small mobile stem cells, and the compositions and methods of the invention are used to treat or alleviate viral, bacterial, or fungal infections, or to treat or alleviate damage caused by these infections by repairing tissue damaged by viral, bacterial, or fungal infections, or to treat or alleviate adverse effects caused by inflammatory diseases such as fibrosis and COPD and / or inflammatory diseases associated with viral, bacterial, or fungal infections.

Background Art

[0003] The inflammatory process is important for the elimination of pathogens and is associated with various clinical disorders. The inflammatory response observed in patients can be more harmful than the original stimulus and can form pro-inflammatory fibrous scar tissue, threatening the function of normal organs. In addition, the occurrence of abnormal autoinflammation and chronic inflammation often results in incurable disorders and conditions accompanied by tissue degeneration.

[0004] Viral infectious diseases are major global health problems due to annual epidemics. Despite the implementation of a rational vaccination protocol using inactivated viruses, the situation often becomes complex due to high morbidity and mortality rates. Vaccines have several drawbacks, such as the need for re-administration due to the short-lived protective effect induced by the vaccine; the ability to induce only strain-specific antibody production responses; and the inability to repair or recover tissues or organs damaged by viral infectious diseases. Additionally, the high infectivity of viral strains and their constant changes due to antigenic discontinuous mutations caused by the exchange of RNA segments between viral strains or antigenic continuous mutations caused by point mutations also highlight the drawbacks of vaccines.

[0005] The coronavirus is an enveloped RNA virus family with a positive-sense single-stranded genome and infects specific hosts. The newly isolated coronavirus in Wuhan City, China, is more infectious than the past severe acute respiratory syndrome (SARS) that spread in 2002 and 2003, leading to the occurrence of coronavirus disease 2019 (COVID-19). The most severe form of COVID-19 infection is severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes acute respiratory failure after developing acute respiratory distress, and even with intensive supportive therapy, it can develop irreversible lung tissue damage and fibrotic scarring, resulting in relatively high morbidity and mortality. The pathophysiology of severe respiratory syndrome is multifactorial, with an excessive immune response occurring, accompanied by an inflammatory cytokine storm (and other terminal organ damage associated with it), and lysis of alveolar epithelial cells and bronchial epithelial cells, often leading to the development of secondary opportunistic pneumonia. Specific antiviral treatments and vaccines for the treatment and prevention of SARS-CoV-2 have just started to be developed and approved. Furthermore, there are concerns because SARS-CoV-2 variants that may have strong toxicity can be difficult to treat with current therapies. Therefore, critical care remains important and includes mechanical ventilation by endotracheal intubation, extracorporeal membrane oxygenation (ECMO), vasopressors for treating shock, and treatment of symptoms using antibiotics for treating possible opportunistic pneumonia. Also, patients with comorbidities such as diabetes and heart disease, as well as elderly patients, have a high risk of poor outcomes when infected with SARS-CoV-2, and it has become clear that they may experience long-term debilitation, permanent lung dysfunction, or even death even if they recover. The mortality rate in such groups is estimated to be about 10%. Therefore, the development of a safe and effective treatment approach for patients with severe coronavirus disease is needed.

Summary of the Invention

Means for Solving the Problems

[0006] The present disclosure generally relates to compositions for promoting or enhancing the repair or regeneration of damaged tissue or for enhancing recovery from viral, fungal, or bacterial infections or sequelae thereof, and methods of making and using such compositions. The compositions include small mobile stem (SMS) cells, which may be cells of the same species as the subject to whom the composition is administered, autologous cells obtained from the subject to whom the composition is administered, or cells obtained from peripheral blood. The viral, fungal, or bacterial infection may include a SARS-CoV-2 infection.

[0007] Accordingly, some of the embodiments provided herein are methods for promoting or enhancing the repair or regeneration of damaged tissue or for enhancing recovery from viral, fungal, or bacterial infections or sequelae thereof, comprising: selecting a subject afflicted with a viral, fungal, or bacterial infection or sequelae thereof; and administering to the subject a composition comprising a therapeutically effective amount of small mobile stem (SMS) cells and related to methods. In some embodiments, a subject who has not suffered from any of viral infections, fungal infections, bacterial infections, or sequelae thereof is selected, and the compositions provided herein are administered to prevent tissue damage in case of onset of viral infections, fungal infections, or bacterial infections. In some embodiments, the SMS cells are cells obtained from peripheral blood. In some embodiments, the SMS cells are cells of the same species as the subject. In some embodiments, the SMS cells are autologous cells obtained from the subject. In some embodiments, the damaged tissue is lung tissue. In some embodiments, by administering the composition, a decrease or suppression of alveolar cell damage, a decrease or suppression of respiratory endothelial cell damage, an increase or improvement in the repair of damaged lung tissue, an increase or enhancement in the regeneration of damaged lung tissue, or a decrease or suppression in the onset of pulmonary fibrosis is achieved. In some embodiments, the damaged tissue is tissue damaged by the viral infection, fungal infection, or bacterial infection or sequelae thereof. In some embodiments, the viral infection is caused by a single-stranded RNA virus, double-stranded RNA virus, plus-sense single-stranded RNA virus, minus-sense single-stranded RNA virus, double-stranded DNA virus, or single-stranded DNA virus.In some embodiments, the viral infection, fungal infection or bacterial infection or sequelae thereof are caused by coronavirus, poxvirus, variola virus, Marburg virus, flavivirus, influenza virus, parainfluenza virus, RSV, rubella virus, human immunodeficiency virus, human papillomavirus, varicella-zoster virus, herpes simplex virus, cytomegalovirus, Epstein-Barr virus, JC virus, rabies virus, rotavirus, rhinovirus, adenovirus, papillomavirus, parvovirus, picornavirus, poliovirus, hantavirus, filovirus, coxsackievirus, equine encephalitis virus, Rift Valley fever virus, alphavirus, hepatitis A virus, hepatitis B virus, hepatitis C virus, hepatitis D virus, hepatitis E virus, pneumonia, Streptococcus pneumoniae, Staphylococcus aureus, Haemophilus influenzae, Moraxella catarrhalis, anaerobic bacteria, Gram-negative bacteria, Mycoplasma pneumoniae, Chlamydia pneumoniae, group A streptococcus, Klebsiella pneumoniae, Legionella pneumophila, Streptococcus pyogenes, Streptococcus agalactiae, Peptostreptococcus spp., Corynebacterium diphtheriae, Bordetella pertussis, Mycobacterium tuberculosis, Pseudomonas aeruginosa, Escherichia coli, Curvularia spp., Pneumocystis spp., Cryptococcus spp., Histoplasma capsulatum, Aspergillus spp., Mucorales, Fusarium spp., Scedosporium spp., Penicillium spp., or any combination thereof. In some embodiments, the coronavirus is MERS-CoV, SARS-CoV or SARS-CoV-2. In some embodiments, the coronavirus is SARS-CoV-2. In some embodiments, the composition comprises aerosolized SMS cells, and the aerosolized SMS cells may be administered by inhalation, for example, via the nasal cavity or oral cavity. In some embodiments, the composition is administered intravenously. In some embodiments, the SMS cells are administered in combination with an antibiotic such as azithromycin, an antifungal agent such as voriconazole, amphotericin B, itraconazole, a vaccine, or an antiviral agent such as remdesivir.In some embodiments, the vaccine is a vaccine against one or more of coronavirus, cholera, dengue fever, diphtheria, Haemophilus influenzae type b infection, hepatitis A, hepatitis B, influenza, Japanese encephalitis, meningococcal meningitis, pertussis, polio, rabies, tetanus, tuberculosis, typhoid fever, and yellow fever. In some embodiments, the vaccine is a coronavirus COVID-19 vaccine.

[0008] Some of the embodiments described herein relate to a method of treating or suppressing an inflammatory disease. In some embodiments, the method includes the steps of selecting a subject having an inflammatory disease and administering to the selected subject a composition comprising a therapeutically effective amount of small mobile stem (SMS) cells. In some embodiments, the inflammatory disease is an inflammatory disease of the lung. In some embodiments, the inflammatory disease includes fibrosis. In some embodiments, the fibrosis is pulmonary fibrosis, hepatic fibrosis, renal fibrosis, or cardiac fibrosis. In some embodiments, the inflammatory disease includes chronic obstructive pulmonary disease (COPD). In some embodiments, the inflammatory disease includes acute respiratory distress syndrome (ARDS). In some embodiments, the inflammatory disease is associated with or caused by a viral infection, a fungal infection, and / or a bacterial infection. In some embodiments, the viral infection is caused by a single-stranded RNA virus, a double-stranded RNA virus, a plus-sense single-stranded RNA virus, a minus-sense single-stranded RNA virus, a double-stranded DNA virus, or a single-stranded DNA virus.In some embodiments, the viral infection, fungal infection or bacterial infection is caused by coronavirus, poxvirus, variola virus, Marburg virus, flavivirus, influenza virus, parainfluenza virus, RSV, rubella virus, human immunodeficiency virus, human papillomavirus, varicella-zoster virus, herpes simplex virus, cytomegalovirus, Epstein-Barr virus, JC virus, rabies virus, rotavirus, rhinovirus, adenovirus, papillomavirus, parvovirus, picornavirus, poliovirus, hantavirus, filovirus, coxsackievirus, equine encephalitis virus, Rift Valley fever virus, alphavirus, hepatitis A virus, hepatitis B virus, hepatitis C virus, hepatitis D virus, hepatitis E virus, pneumonia, Streptococcus pneumoniae, Staphylococcus aureus, Haemophilus influenzae, Moraxella catarrhalis, anaerobic bacteria, Gram-negative bacteria, Mycoplasma pneumoniae, Chlamydia pneumoniae, group A streptococcus, Klebsiella pneumoniae, Legionella pneumophila, Streptococcus pyogenes, Streptococcus agalactiae, Peptostreptococcus spp., Corynebacterium diphtheriae, Bordetella pertussis, Mycobacterium tuberculosis, Pseudomonas aeruginosa, Escherichia coli, Curvularia spp., Pneumocystis spp., Cryptococcus spp., Histoplasma capsulatum, Aspergillus spp., Mucorales, Fusarium spp., Scedosporium spp., Penicillium spp., or any combination thereof. In some embodiments, the viral infection is a coronavirus infection. In some embodiments, the viral infection is a SARS-CoV infection, a MERS-CoV infection or a SARS-CoV-2 infection. In some embodiments, the SMS cells are cells obtained from peripheral blood. In some embodiments, the SMS cells are cells of the same species as the subject or autologous cells obtained from the subject.In some embodiments, administration of the composition results in a decrease or reduction of alveolar cell injury, a decrease or reduction of respiratory endothelial cell injury, an increase or improvement in the repair of damaged lung tissue, an increase or enhancement in the regeneration of damaged lung tissue, or a decrease or suppression in the onset of pulmonary fibrosis, or any combination thereof. In some embodiments, the composition is formulated for administration by inhalation. In some embodiments, the composition is formulated for intravenous administration. In some embodiments, the composition is administered in combination with the standard treatment for the inflammatory disease. In some embodiments, the inflammatory disease is associated with a viral infection, a fungal infection or a bacterial infection, and the standard treatment is an antibiotic such as azithromycin; an antifungal agent such as voriconazole, amphotericin B, itraconazole; a vaccine; an antiviral agent such as dexamethasone, convalescent serum, tocilizumab, sarilumab, ribavirin, favipiravir, darunavir, galidesivir, interferon α, interferon β, lopinavir, ritonavir, remdesivir, triazavirin, umifenovir; or any combination thereof. In some embodiments, the vaccine is a vaccine against one or more of coronavirus, cholera, dengue fever, diphtheria, Haemophilus influenzae type b infection, hepatitis A, hepatitis B, influenza, Japanese encephalitis, meningococcal meningitis, pertussis, polio, rabies, tetanus, tuberculosis, typhoid fever and yellow fever. In some embodiments, the vaccine is a coronavirus COVID-19 vaccine.

[0009] Some of the embodiments provided herein relate to a composition comprising a therapeutically effective amount of small mobile stem (SMS) cells. In some embodiments, the composition is formulated for use in the repair or regeneration of damaged tissue or the improvement of recovery from viral, fungal, or bacterial infections (or sequelae thereof), wherein the viral, fungal, or bacterial infections are, for example, coronavirus, poxvirus, variola virus, Marburg virus, flavivirus, influenza virus, parainfluenza virus, RSV, rubella virus, human immunodeficiency virus, human papillomavirus, varicella-zoster virus, herpes simplex virus, cytomegalovirus, Epstein-Barr virus, JC virus, rabies virus, rotavirus, rhinovirus, adenovirus, papillomavirus, parvovirus, picornavirus, poliovirus, hantavirus, filovirus, coxsackievirus, equine encephalitis virus, Rift Valley fever virus, alphavirus, hepatitis A virus, hepatitis B virus, hepatitis C virus, hepatitis D virus, hepatitis E virus, pneumonia, Streptococcus pneumoniae, Staphylococcus aureus, Haemophilus influenzae, Moraxella catarrhalis, anaerobic bacteria, gram-negative bacteria, Mycoplasma pneumoniae, Chlamydia pneumoniae, group A streptococcus, Klebsiella pneumoniae, Legionella pneumophila, Streptococcus pyogenes, Streptococcus agalactiae, Peptostreptococcus spp., Corynebacterium diphtheriae, Bordetella pertussis, Mycobacterium tuberculosis, Pseudomonas aeruginosa, Escherichia coli, Curvularia spp., Pneumocystis spp., Cryptococcus spp., Histoplasma capsulatum, Aspergillus spp., Mucorales, Fusarium spp., Scedosporium spp., Penicillium spp., or any combination thereof, preferably MERS-CoV, SARS-CoV, or SARS-CoV-2. In some embodiments, the SMS cells are cells obtained from peripheral blood. In some embodiments, the composition comprises aerosolized SMS cells, and the aerosolized SMS cells may be formulated for inhalation administration.In some embodiments, the composition is formulated for intravenous administration. In some embodiments, the damaged tissue is tissue damaged by a viral infection. In some embodiments, the viral infection is caused by coronavirus, poxvirus, variola virus, Marburg virus, flavivirus, influenza virus, parainfluenza virus, RSV, rubella virus, human immunodeficiency virus, human papillomavirus, varicella-zoster virus, herpes simplex virus, cytomegalovirus, Epstein-Barr virus, JC virus, rabies virus, rotavirus, rhinovirus, adenovirus, papillomavirus, parvovirus, picornavirus, poliovirus, hantavirus, filovirus, coxsackievirus, equine encephalitis virus, Rift Valley fever virus, alphavirus, hepatitis A virus, hepatitis B virus, hepatitis C virus, hepatitis D virus, hepatitis E virus, or a combination thereof. In some embodiments, the coronavirus is SARS-CoV-2. In some embodiments, the therapeutically effective amount is an amount sufficient to induce a decrease or suppression of alveolar cell injury, a decrease or suppression of respiratory endothelial cell injury, a decrease or suppression of the development of pulmonary fibrosis, an increase or improvement in the repair of damaged lung tissue, or an increase or enhancement in the regeneration of damaged lung tissue. In some embodiments, the composition further comprises a therapeutically effective amount of an antibiotic, an antifungal agent, a vaccine or an antiviral agent (such as remdesivir). In some embodiments, the vaccine is a coronavirus vaccine. In some embodiments, the composition further comprises a pharmaceutically acceptable carrier, preservative, antioxidant, diluent or additive, or any combination thereof.

[0010] Some of the embodiments provided herein relate to the use of any of the compositions described herein for the treatment or suppression of viral infections, fungal infections or bacterial infections (or sequelae thereof), said viral infections, fungal infections or bacterial infections being, for example, coronavirus, poxvirus, variola virus, Marburg virus, flavivirus, influenza virus, parainfluenza virus, RSV, rubella virus, human immunodeficiency virus, human papillomavirus, varicella-zoster virus, herpes simplex virus, cytomegalovirus, Epstein-Barr virus, JC virus, rabies virus, rotavirus, rhinovirus, adenovirus, papillomavirus, parvovirus, picornavirus, poliovirus, hantavirus, filovirus, coxsackievirus, equine encephalitis virus, Rift Valley fever virus, alphavirus, hepatitis A virus, hepatitis B virus, hepatitis C virus, hepatitis D virus, hepatitis E virus, pneumonia, Streptococcus pneumoniae, Staphylococcus aureus, Haemophilus influenzae, Moraxella catarrhalis, anaerobic bacteria, gram-negative bacteria, Mycoplasma pneumoniae, Chlamydia pneumoniae, group A streptococcus, Klebsiella pneumoniae, Legionella pneumophila, Streptococcus pyogenes, Streptococcus agalactiae, Peptostreptococcus spp., Corynebacterium diphtheriae, Bordetella pertussis, Mycobacterium tuberculosis, Pseudomonas aeruginosa, Escherichia coli, Curvularia spp., Pneumocystis spp., Cryptococcus spp., Histoplasma capsulatum, Aspergillus spp., Mucorales, Fusarium spp., Scedosporium spp., Penicillium spp., or any combination thereof, preferably MERS-CoV, SARS-CoV or SARS-CoV-2. Some of the embodiments provided herein relate to any of the compositions described herein for use in a pharmaceutical.

[0011] Some of the embodiments provided herein relate to the use of any of the compositions disclosed herein for the treatment, suppression, alleviation, or reduction of inflammatory diseases. In some embodiments, the inflammatory disease is an inflammatory disease of the lung. In some embodiments, the inflammatory disease includes fibrosis. In some embodiments, the fibrosis is pulmonary fibrosis, hepatic fibrosis, renal fibrosis, or cardiac fibrosis. In some embodiments, the inflammatory disease includes chronic obstructive pulmonary disease (COPD). In some embodiments, the inflammatory disease includes acute respiratory distress syndrome (ARDS). In some embodiments, the inflammatory disease is associated with a viral infection, a fungal infection, or a bacterial infection. In some embodiments, the viral infection is a coronavirus infection. In some embodiments, the viral infection is a SARS-CoV infection, a MERS-CoV infection, or a SARS-CoV-2 infection.

[0012] Accordingly, some aspects of the embodiments described herein relate to the following numbered embodiments.

[0013] 1. A method of promoting or enhancing the repair or regeneration of damaged tissue or improving recovery from a viral infection, a fungal infection, a bacterial infection, or sequelae thereof, comprising: selecting a subject suffering from a viral infection, a fungal infection, a bacterial infection, or sequelae thereof, or a subject having a history of suffering from a viral infection, a fungal infection, a bacterial infection, or sequelae thereof; and administering to the selected subject a composition comprising a therapeutically effective amount of small mobile stem (SMS) cells. A method comprising the above.

[0014] 2. The method according to embodiment 1, wherein the SMS cells are cells obtained from peripheral blood.

[0015] 3. The method according to embodiment 1 or 2, wherein the SMS cells are cells of the same species as the subject.

[0016] 4. The method according to embodiment 1 or 2, wherein the SMS cells are autologous cells obtained from the subject.

[0017] 5. The method according to any one of embodiments 1 to 4, wherein the damaged tissue is lung tissue.

[0018] 6. By administering the composition, a decrease or suppression of alveolar cell damage, a decrease or suppression of respiratory endothelial cell damage, an increase or improvement in the repair of damaged lung tissue, an increase or enhancement in the regeneration of damaged lung tissue, or a decrease or suppression in the onset of pulmonary fibrosis is achieved. The method according to embodiment 5.

[0019] 7. The method according to any one of embodiments 1 to 6, wherein the damaged tissue is a tissue damaged by a viral infection, a bacterial infection, or a fungal infection.

[0020] 8. The method according to any one of embodiments 1 to 7, wherein the viral infection is caused by a single-stranded RNA virus, a double-stranded RNA virus, a plus-sense single-stranded RNA virus, a minus-sense single-stranded RNA virus, a double-stranded DNA virus, or a single-stranded DNA virus.

[0021] 9. The method according to any one of Embodiments 1 to 7, wherein the viral infection, fungal infection, or bacterial infection or sequelae thereof is caused by coronavirus, poxvirus, variola virus, Marburg virus, flavivirus, influenza virus, parainfluenza virus, RSV, rubella virus, human immunodeficiency virus, human papillomavirus, varicella-zoster virus, herpes simplex virus, cytomegalovirus, Epstein-Barr virus, JC virus, rabies virus, rotavirus, rhinovirus, adenovirus, papillomavirus, parvovirus, picornavirus, poliovirus, hantavirus, filovirus, coxsackievirus, equine encephalitis virus, Rift Valley fever virus, alphavirus, hepatitis A virus, hepatitis B virus, hepatitis C virus, hepatitis D virus, hepatitis E virus, pneumonia, Streptococcus pneumoniae, Staphylococcus aureus, Haemophilus influenzae, Moraxella catarrhalis, anaerobic bacteria, gram-negative bacteria, Mycoplasma pneumoniae, Chlamydia pneumoniae, group A streptococcus, Klebsiella pneumoniae, Legionella pneumophila, Streptococcus pyogenes, Streptococcus agalactiae, Peptostreptococcus spp., Corynebacterium diphtheriae, Bordetella pertussis, Mycobacterium tuberculosis, Pseudomonas aeruginosa, Escherichia coli, Curvularia spp., Pneumocystis spp., Cryptococcus spp., Histoplasma capsulatum, Aspergillus spp., Mucorales, Fusarium spp., Scedosporium spp., Penicillium spp., or any combination thereof.

[0022] 10. The method according to Embodiment 9, wherein the coronavirus is MERS-CoV, SARS-CoV or SARS-CoV-2.

[0023] 11. The method according to Embodiment 9, wherein the coronavirus is SARS-CoV-2.

[0024] 12. The method according to any one of Embodiments 1 to 11, characterized in that the composition contains aerosolized SMS cells, and the aerosolized SMS cells may be administered by inhalation.

[0025] 13. The method according to any one of Embodiments 1 to 11, wherein the composition is administered intravenously.

[0026] 14. The method according to any one of Embodiments 1 to 13, wherein the SMS cells are administered in combination with an antibiotic such as azithromycin, an antifungal agent such as voriconazole, amphotericin B, itraconazole, a vaccine, or an antiviral agent such as remdesivir.

[0027] 15. The method according to Embodiment 14, wherein the vaccine is a vaccine against one or more of coronavirus, cholera, dengue fever, diphtheria, Haemophilus influenzae type b infection, hepatitis A, hepatitis B, influenza, Japanese encephalitis, meningococcal meningitis, pertussis, polio, rabies, tetanus, tuberculosis, typhoid fever, and yellow fever.

[0028] 16. The method according to Embodiment 14 or 15, wherein the vaccine is a coronavirus COVID-19 vaccine.

[0029] 17. By administering the composition to the selected subject, Dickkopf-related protein 1 (DKK1), N-acetylglucosamine 2-epimerase (RENBP), growth / differentiation factor 15 (GDF15), dermokine (DMKN), ferritin light chain (FTL), tryptophan 2,3-dioxygenase (TDO2), apolipoprotein E (APOE), chitinase 3-like protein 1 (CHI3L1), or nuclear receptor subfamily 4 group A member 2 (NR4A2), or any combination thereof is upregulated in the subject. The method according to any one of Embodiments 1 to 16.

[0030] 18. By administering the composition to the selected subject, interleukin 11 (IL-11), SPRY domain-containing SOCS box protein 1 (SPSB1), cytochrome P450 26B1 (CYP26B1), or frizzled-8 (FZD8), or any combination thereof is downregulated in the subject, the method according to any one of embodiments 1 to 17.

[0031] 19. A composition for use in improving the repair or regeneration of damaged tissue (such as lung tissue) or the recovery from viral, fungal or bacterial infections or their sequelae in a subject in need thereof, the composition comprising a therapeutically effective amount of small mobile stem (SMS) cells, wherein the viral, fungal or bacterial infection or their sequelae is, for example, coronavirus, poxvirus, variola virus, Marburg virus, flavivirus, influenza virus, parainfluenza virus, RSV, rubella virus, human immunodeficiency virus, human papillomavirus, varicella-zoster virus, herpes simplex virus, cytomegalovirus, Epstein-Barr virus, JC virus, rabies virus, rotavirus, rhinovirus, adenovirus, papillomavirus, parvovirus, picornavirus, poliovirus, hantavirus, filovirus, coxsackievirus, equine encephalitis virus, Rift Valley fever virus, alphavirus, hepatitis A virus, hepatitis B virus, hepatitis C virus, hepatitis D virus, hepatitis E virus, pneumonia, Streptococcus pneumoniae, Staphylococcus aureus, Haemophilus influenzae, Moraxella catarrhalis, anaerobic bacteria, gram-negative bacteria, Mycoplasma pneumoniae, Chlamydia pneumoniae, group A streptococcus, Klebsiella pneumoniae, Legionella pneumophila, Streptococcus pyogenes, Streptococcus agalactiae, Peptostreptococcus spp., Corynebacterium diphtheriae, Bordetella pertussis, Mycobacterium tuberculosis, Pseudomonas aeruginosa, Escherichia coli, Curvularia spp., Pneumocystis spp., Cryptococcus spp., Histoplasma capsulatum, Aspergillus spp., Mucorales, Fusarium spp., Scedosporium spp., Penicillium spp., or any combination thereof, preferably MERS-CoV, SARS-CoV or SARS-CoV-2.

[0032] 20. The composition according to embodiment 19, wherein the SMS cells are cells obtained from peripheral blood.

[0033] 21. The composition according to embodiment 19 or 20, characterized in that the composition contains aerosolized SMS cells, and the aerosolized SMS cells may be formulated for inhalation administration.

[0034] 22. The composition according to any one of embodiments 19 to 21, which is formulated for intravenous administration.

[0035] 23. The composition according to any one of embodiments 19 to 22, wherein the damaged tissue is a tissue damaged by a viral infection.

[0036] 24. The composition according to embodiment 23, wherein the viral infection is caused by coronavirus, poxvirus, variola virus, Marburg virus, flavivirus, influenza virus, parainfluenza virus, RSV, rubella virus, human immunodeficiency virus, human papillomavirus, varicella-zoster virus, herpes simplex virus, cytomegalovirus, Epstein-Barr virus, JC virus, rabies virus, rotavirus, rhinovirus, adenovirus, papillomavirus, parvovirus, picornavirus, poliovirus, hantavirus, filovirus, coxsackievirus, equine encephalitis virus, Rift Valley fever virus, alphavirus, hepatitis A virus, hepatitis B virus, hepatitis C virus, hepatitis D virus, hepatitis E virus, or a combination thereof.

[0037] 25. The composition according to embodiment 24, wherein the coronavirus is SARS-CoV-2.

[0038] 26. The composition according to any one of embodiments 19 to 25, wherein the therapeutically effective amount is an amount sufficient to induce a decrease in alveolar cell damage, a decrease in respiratory endothelial cell damage, a decrease in the onset of pulmonary fibrosis, an increase in the repair of damaged lung tissue, or an increase in the regeneration of damaged lung tissue.

[0039] 27. The composition according to any one of Embodiments 19 to 26, further comprising a therapeutically effective amount of an antibiotic such as azithromycin, an antifungal agent such as voriconazole, amphotericin B, itraconazole, a vaccine, or an antiviral agent such as remdesivir.

[0040] 28. The composition according to Embodiment 27, wherein the vaccine is a coronavirus vaccine.

[0041] 29. The composition according to any one of Embodiments 19 to 28, further comprising a pharmaceutically acceptable carrier, preservative, antioxidant, diluent or additive, or any combination thereof.

[0042] 30. By the composition, Dickkopf-related protein 1 (DKK1), N-acetylglucosamine 2-epimerase (RENBP), growth / differentiation factor 15 (GDF15), dermokine (DMKN), ferritin light chain (FTL), tryptophan 2,3-dioxygenase (TDO2), apolipoprotein E (APOE), chitinase 3-like protein 1 (CHI3L1), or nuclear receptor subfamily 4 group A member 2 (NR4A2), or any combination thereof is upregulated in the subject. The composition according to any one of Embodiments 19 to 30.

[0043] 31. By the composition, interleukin 11 (IL-11), SPRY domain-containing SOCS box protein 1 (SPSB1), cytochrome P450 26B1 (CYP26B1), or frizzled-8 (FZD8), or any combination thereof is downregulated in the subject. The composition according to any one of Embodiments 19 to 30.

[0044] 32. Use of the composition according to any one of Embodiments 19 to 31 for the treatment or suppression of a viral infection, a fungal infection or a bacterial infection, or tissue damage caused by said infection, wherein the viral infection, fungal infection or bacterial infection is, for example, coronavirus, poxvirus, variola virus, Marburg virus, flavivirus, influenza virus, parainfluenza virus, RSV, rubella virus, human immunodeficiency virus, human papillomavirus, varicella-zoster virus, herpes simplex virus, cytomegalovirus, Epstein-Barr virus, JC virus, rabdovirus, rotavirus, rhinovirus, adenovirus, papillomavirus, parvovirus, picornavirus, poliovirus, hantavirus, filovirus, coxsackievirus, equine encephalitis virus, Rift Valley fever virus, alphavirus, hepatitis A virus, hepatitis B virus, hepatitis C virus, hepatitis D virus, hepatitis E virus, pneumonia, Streptococcus pneumoniae, Staphylococcus aureus, Haemophilus influenzae, Moraxella catarrhalis, anaerobic bacteria, Gram-negative bacteria, Mycoplasma pneumoniae, Chlamydia pneumoniae, group A streptococcus, Klebsiella pneumoniae, Legionella pneumophila, Streptococcus pyogenes, Streptococcus agalactiae, Peptostreptococcus spp., Corynebacterium diphtheriae, Bordetella pertussis, Mycobacterium tuberculosis, Pseudomonas aeruginosa, Escherichia coli, Curvularia spp., Pneumocystis spp., Cryptococcus spp., Histoplasma capsulatum, Aspergillus spp., Mucorales, Fusarium spp., Scedosporium spp., Penicillium spp., or any combination thereof, preferably MERS-CoV, SARS-CoV or SARS-CoV-2.

[0045] 33. The composition according to any one of Embodiments 19 to 31 for use in a medicament.

[0046] 34. The composition according to any one of Embodiments 19 to 31 for use in the treatment or suppression of an inflammatory disease.

[0047] 35. The composition according to embodiment 34, wherein the inflammatory disease is an inflammatory disease of the lung.

[0048] 36. The composition according to embodiment 34 or 35, wherein the inflammatory disease includes fibrosis such as pulmonary fibrosis, hepatic fibrosis, renal fibrosis, and cardiac fibrosis.

[0049] 37. The composition according to any one of embodiments 34 to 36, wherein the inflammatory disease includes chronic obstructive pulmonary disease (COPD).

[0050] 38. The composition according to any one of embodiments 34 to 37, wherein the inflammatory disease includes acute respiratory distress syndrome (ARDS).

[0051] 39. The composition according to any one of embodiments 34 to 38, wherein the inflammatory disease is related to or caused by a viral infection, a fungal infection, or a bacterial infection.

[0052] 40. The composition according to embodiment 39, wherein the viral infection is a coronavirus infection.

[0053] 41. The composition according to embodiment 39 or 40, wherein the viral infection is a SARS-CoV infection, a MERS-CoV infection, or a SARS-CoV-2 infection.

[0054] 42. A method for treating or suppressing an inflammatory disease, comprising:

[0055] selecting a subject suffering from an inflammatory disease; and

[0056] administering to the selected subject a composition comprising a therapeutically effective amount of small mobile stem (SMS) cells. A method comprising the above steps.

[0057] 43. The method according to embodiment 42, wherein the inflammatory disease is an inflammatory disease of the lung.

[0058] 44. The method according to embodiment 42 or 43, wherein the inflammatory disease includes fibrosis such as pulmonary fibrosis, liver fibrosis, renal fibrosis, and cardiac fibrosis.

[0059] 45. The method according to any one of embodiments 42 to 44, wherein the inflammatory disease includes chronic obstructive pulmonary disease (COPD).

[0060] 46. The method according to any one of embodiments 42 to 45, wherein the inflammatory disease includes acute respiratory distress syndrome (ARDS).

[0061] 47. The method according to any one of embodiments 42 to 46, wherein the inflammatory disease is associated with a viral infection, a fungal infection, or a bacterial infection.

[0062] 48. The method according to embodiment 47, wherein the viral infection is caused by a single-stranded RNA virus, a double-stranded RNA virus, a plus-sense single-stranded RNA virus, a minus-sense single-stranded RNA virus, a double-stranded DNA virus, or a single-stranded DNA virus.

[0063] 49. The method according to embodiment 47 or 48, wherein the viral infection, fungal infection or bacterial infection is caused by coronavirus, poxvirus, variola virus, Marburg virus, flavivirus, influenza virus, parainfluenza virus, RSV, rubella virus, human immunodeficiency virus, human papillomavirus, varicella-zoster virus, herpes simplex virus, cytomegalovirus, Epstein-Barr virus, JC virus, rabies virus, rotavirus, rhinovirus, adenovirus, papillomavirus, parvovirus, picornavirus, poliovirus, hantavirus, filovirus, coxsackievirus, equine encephalitis virus, Rift Valley fever virus, alphavirus, hepatitis A virus, hepatitis B virus, hepatitis C virus, hepatitis D virus, hepatitis E virus, pneumonia, Streptococcus pneumoniae, Staphylococcus aureus, Haemophilus influenzae, Moraxella catarrhalis, anaerobic bacteria, Gram-negative bacteria, Mycoplasma pneumoniae, Chlamydia pneumoniae, group A streptococcus, Klebsiella pneumoniae, Legionella pneumophila, Streptococcus pyogenes, Streptococcus agalactiae, Peptostreptococcus, Corynebacterium diphtheriae, Bordetella pertussis, Mycobacterium tuberculosis, Pseudomonas aeruginosa, Escherichia coli, Curvularia, Pneumocystis, Cryptococcus, Histoplasma capsulatum, Aspergillus, Mucorales, Fusarium, Scedosporium, Penicillium, or any combination thereof.

[0064] 50. The method according to any one of embodiments 47 to 49, wherein the viral infection is a coronavirus infection.

[0065] 51. The method according to any one of embodiments 47 to 50, wherein the viral infection is an SARS-CoV infection, an MERS-CoV infection or an SARS-CoV-2 infection.

[0066] 52. The method according to any one of embodiments 42 to 51, wherein the SMS cells are cells obtained from peripheral blood.

[0067] 53. The method according to any one of embodiments 42 to 52, wherein the SMS cells are cells of the same species as the subject or autologous cells obtained from the subject.

[0068] 54. By administering the composition, a decrease or suppression of alveolar cell damage, a decrease or suppression of respiratory endothelial cell damage, an increase or improvement in the repair of damaged lung tissue, an increase or enhancement in the regeneration of damaged lung tissue, or a decrease or suppression in the onset of pulmonary fibrosis, or any combination thereof is achieved. The method according to any one of embodiments 42 to 53.

[0069] 55. The method according to any one of embodiments 42 to 54, characterized in that the composition contains aerosolized SMS cells, and the aerosolized SMS cells may be administered by inhalation.

[0070] 56. The method according to any one of embodiments 42 to 55, wherein the composition is formulated for inhalation administration via, for example, the nasal cavity or oral cavity.

[0071] 57. The method according to any one of embodiments 42 to 56, wherein the composition is formulated for intravenous administration.

[0072] 58. The method according to any one of embodiments 42 to 57, wherein the composition is administered in combination with the standard treatment for the inflammatory disease.

[0073] 59. The inflammatory disease is associated with or caused by a viral infection, and the standard treatment is an antibiotic such as azithromycin, an antifungal agent such as voriconazole, amphotericin B, itraconazole, a vaccine, or an antiviral agent such as remdesivir. The method according to embodiment 58.

[0074] 60. The method according to embodiment 59, wherein the vaccine is a vaccine against one or more of coronavirus, cholera, dengue fever, diphtheria, Haemophilus influenzae type b infection, hepatitis A, hepatitis B, influenza, Japanese encephalitis, meningococcal meningitis, whooping cough, polio, rabies, tetanus, tuberculosis, typhoid fever, and yellow fever.

[0075] 61. The method according to embodiment 59 or 60, wherein the vaccine is a coronavirus COVID-19 vaccine.

[0076] 62. The method according to any one of embodiments 42 to 61, wherein administration of the composition upregulates Dickkopf-related protein 1 (DKK1), N-acetylglucosamine 2-epimerase (RENBP), growth / differentiation factor 15 (GDF15), dermokine (DMKN), ferritin light chain (FTL), tryptophan 2,3-dioxygenase (TDO2), apolipoprotein E (APOE), chitinase 3-like protein 1 (CHI3L1), or nuclear receptor subfamily 4 group A member 2 (NR4A2), or any combination thereof, in the subject.

[0077] 63. The method according to any one of embodiments 42 to 62, wherein administration of the composition downregulates interleukin 11 (IL-11), SPRY domain-containing SOCS box protein 1 (SPSB1), cytochrome P450 26B1 (CYP26B1), or frizzled-8 (FZD8), or any combination thereof, in the subject.

Brief Description of the Drawings

[0078] Additional features and modifications other than those described above will be readily understood from the following description of the drawings and representative embodiments. The following drawings illustrate representative embodiments and do not limit the scope of the present invention.

[0079]

FIG. 1A-C

[0080]

FIG. 2A-C

[0081]

FIG. 3A-C

Mode for Carrying Out the Invention

[0082] The embodiments provided herein relate to methods and compositions for treating, alleviating, suppressing or preventing, or delaying viral infections, fungal infections or bacterial infections or damage caused by these infections (e.g., coronavirus infection, pneumonia infection, etc.), or inflammatory diseases (e.g., but not limited to, inflammatory diseases caused by viral infections, fungal infections or bacterial infections). Such methods and compositions can repair or regenerate tissues or organs damaged by, for example, viral infections, fungal infections or bacterial infections or their sequelae, or inflammatory diseases, thereby providing an improved treatment or therapy for viral infections, fungal infections or bacterial infections or their sequelae or inflammatory diseases.

[0083] In some embodiments, the method comprises administering, to a subject or patient having a viral, fungal, or bacterial infection (e.g., coronavirus infection) or sequelae thereof, a therapeutically effective amount of a composition comprising small mobile stem (SMS) cells, either alone or in combination with a therapeutically effective amount of a suitable antibiotic, antifungal, or antiviral agent (e.g., azithromycin, vaccine, or remdesivir or any combination thereof). The subject can be selected or identified for stem cell therapy, and such selection or identification can be performed by diagnostic and / or clinical evaluations to confirm the presence or absence of a viral infection (e.g., MERS-CoV, SARS-CoV, or SARS-CoV-2).

[0084] Further, in some embodiments, a method of treating or suppressing an inflammatory disease, the method comprising: selecting a subject having an inflammatory disease; and administering to the subject, either alone or in combination with a therapeutically effective amount of a suitable standard treatment, a composition comprising a therapeutically effective amount of small mobile stem (SMS) cells is disclosed.

[0085] Further provided is a composition comprising a therapeutically effective amount of SMS cells alone, or a composition comprising a therapeutically effective amount of SMS cells and a therapeutically effective amount of a standard treatment, such as a suitable antibiotic, antifungal, antiviral agent (e.g., azithromycin, or vaccine, or remdesivir or both).

[0086] I. Definition of terms All patents, applications, published applications, and other publications cited herein are hereby expressly incorporated by reference in their entirety to the extent not otherwise indicated. In the event that there are multiple definitions for terms described herein, the definitions set forth in this section shall control, unless otherwise indicated.

[0087] Unless otherwise indicated, the technical and scientific terms used in this specification shall have the meanings commonly understood by those skilled in the art to which the present invention pertains. See, for example, Singleton et al., Dictionary of Microbiology and Molecular Biology 2nd ed., J. Wiley & Sons (New York, NY 1994); Sambrook et al., Molecular Cloning, A Laboratory Manual, Cold Springs Harbor Press (Cold Springs Harbor, NY 1989). For the purposes of the disclosure of the present invention, the following terms are defined as follows.

[0088] As used herein, the articles "a" and "an" are used to refer to one or more (e.g., at least one) of the grammatical objects of these articles. For example, "an element" means one component or a plurality of components.

[0089] "About" means that a particular quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length varies by 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2% or 1% compared to the reference quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length.

[0090] Throughout this specification, unless otherwise indicated, the terms "comprising" and "comprises" mean including the steps or elements or groups of steps or elements described herein, but not excluding other steps or elements or groups of steps or elements.

[0091] "consisting of" means containing only those recited before this term. Thus, the term "consisting of" indicates that the components recited before this term are necessary or essential, and means that other components may not be included. "Consisting essentially of" means containing the components recited before this term, and also means containing other components that do not interfere with or contribute to the activities or functions described in relation to the disclosure of these components. Thus, the term "consisting essentially of" indicates that the components recited before this term are necessary or essential, but other components are optional and may or may not be included depending on whether they substantially affect the activities or functions of the components recited before this term.

[0092] In some embodiments, the "purity" of a given agent (e.g., an antibody or a polypeptide-binding agent, etc.) in a composition may be specifically defined. For example, a particular composition may contain a drug with a purity of at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% (including decimal values between each number) when measured by, for example, high performance liquid chromatography (HPLC) (a kind of known column chromatography frequently used in the fields of biochemistry and analytical chemistry to separate, identify and quantify compounds, but not limited thereto).

[0093] As used herein, terms such as "function" and "functional" refer to biological functions, enzymatic functions or therapeutic functions.

[0094] "Isolated" means a material from which the components normally associated in its natural state have been substantially or essentially removed. For example, the "isolated cells" described herein include cells purified from their surrounding environment or organism in their natural state, cells recovered from a subject or culture, e.g., cells that are not significantly associated with in vivo or in vitro substances.

[0095] In the practice of the present disclosure, unless otherwise specified, molecular biological methods and recombinant DNA techniques conventionally known in the art are used, and most of these methods are described hereinafter for illustrative purposes. Such techniques are detailed in the literature. For example, Sambrook, et al., Molecular Cloning: A Laboratory Manual (3 rd Edition, 2000); DNA Cloning: A Practical Approach, vol. 1 & II (D. Glover, ed.); Oligonucleotide Synthesis (N. Gait, ed., 1984); Oligonucleotide Synthesis: Methods and Applications (P. Herdewijn, ed., 2004); Nucleic Acid Hybridization (B. Hames & S. Higgins, eds., 1985); Nucleic Acid Hybridization: Modern Applications (Buzdin and Lukyanov, eds., 2009); Transcription and Translation (B. Hames & S. Higgins, eds., 1984); Animal Cell Culture (R. Freshney, ed., 1986); Freshney, R.I. (2005) Culture of Animal Cells, a Manual of Basic Technique, 5 th Ed. Hoboken NJ, John Wiley & Sons; B. Perbal, A Practical Guide to Molecular Cloning (3rd Edition 2010); Farrell, R., RNA Methodologies: A Laboratory Guide for Isolation and Characterization (3 rd Edition 2005). See also.

[0096] As used herein, "subject", "individual" or "patient" refers to an animal that is the subject of treatment, therapy, observation or experiment. "Animal" includes cold-blooded vertebrates, warm-blooded vertebrates and invertebrates such as fish, crustaceans, reptiles, etc., and particularly includes mammals. "Mammal" includes, but is not limited to, mice, rats, rabbits, guinea pigs, dogs, cats, sheep, goats, cows, horses, primates (such as monkeys, chimpanzees, apes, etc.), and particularly humans.

[0097] As used herein, "treatment", "improvement", "promotion" or "therapy" does not necessarily mean complete cure or elimination of a damaged tissue or a viral infection. Anything that reduces the undesirable signs or symptoms of a viral infection, fungal infection or bacterial infection, or that improves the repair, growth or regeneration of a damaged tissue can be considered a treatment and / or therapy to any extent. Treatment may include enhancement, improvement, acceleration, promotion or alleviation of the healing or regeneration of tissue damage.

[0098] As used herein, "suppression" refers to a decrease or prevention of a viral infection (such as SARS-CoV-2), fungal infection or bacterial infection, or damage caused by such an infection. This decrease may be a decrease of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100%, or a decrease in a percentage within a range bounded by any two of these values. As used herein, "delay" has its ordinary meaning as understood in light of this specification, and refers to an event such as a viral infection being slowed, postponed or retarded to a time later than expected. This delay may be a delay of 0%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100%, or a delay in a percentage within a range bounded by any two of these values. "Suppression" or "delay" does not necessarily indicate 100% suppression or delay. Partial suppression or delay may be achieved.

[0099] As used herein, the term "viral infectious disease" has its ordinary meaning as understood in light of this specification and refers to an infectious disease caused by a virus in a subject. As used herein, the term "virus" has its ordinary meaning as understood in light of this specification and refers to an obligate intracellular parasite that can only replicate inside the cells of other organisms, and is composed of DNA or RNA and coat proteins, but does not have the characteristics of cells. The diameter of a virus is about 20 to about 300 nm. Group I viruses (Baltimore classification) have double-stranded DNA as their genome (such as adenoviruses, herpesviruses, poxviruses, etc.). Group II viruses have single-stranded DNA as their genome (such as parvoviruses, etc.). Group III viruses have double-stranded RNA as their genome (such as reoviruses, etc.). Group IV viruses have plus single-stranded RNA as their genome, and the genome itself functions as mRNA (such as picornaviruses and togaviruses, etc.). Group V viruses have minus single-stranded RNA, and the genome is used as a template for mRNA synthesis (such as orthomyxoviruses and rhabdoviruses, etc.). Group VI viruses have a plus single-stranded RNA genome, and DNA intermediates are utilized not only for replication but also for mRNA synthesis (such as retroviruses, etc.). Group VII viruses have a double-stranded DNA genome, but RNA intermediates are used in the life cycle (such as hepadnaviruses, etc.). Most viruses are recognized by the diseases they cause in plants, animals, and prokaryotes. Viruses of prokaryotes are known as bacteriophages.

[0100] In some embodiments, the virus is a DNA virus. Examples of DNA viruses include, but are not limited to, viruses belonging to the families Adenoviridae, Astroviridae, Hepadnaviridae, Herpesviridae, Papovaviridae, or Poxviridae. In another embodiment, the virus is an RNA virus. Examples of RNA viruses include, but are not limited to, viruses belonging to the families Arenaviridae, Bunyaviridae, Caliciviridae, Coronaviridae, Filoviridae, Flaviviridae, Orthomyxoviridae, Paramyxoviridae, Picornaviridae, Reoviridae, Retroviridae, Rhabdoviridae, or Togaviridae.

[0101] In some embodiments, the methods and compositions described herein are used in non-human animals. In some embodiments, the non-human animal virus is selected from bovine enterovirus, porcine enterovirus B, foot-and-mouth disease virus, equine rhinitis A virus, bovine rhinitis B virus, Yunnan virus, equine rhinitis B virus, echovirus, bovine kobuvirus, porcine teschen virus, porcine sapelovirus, simian sapelovirus, avian sapelovirus, avian encephalomyelitis virus, duck hepatitis A virus, simian enterovirus A, and other picornaviruses; border disease virus, bovine viral diarrhea virus, porcine cholera virus, and other pestiviruses; equine arteritis virus, porcine reproductive and respiratory syndrome virus, lactate dehydrogenase-elevating virus, simian hemorrhagic fever virus, and other arteriviruses; bovine coronavirus, porcine coronavirus, feline coronavirus, canine coronavirus, and other coronaviruses; Hendra virus, Nipah virus, canine distemper virus, rinderpest virus, Newcastle disease virus, bovine respiratory syncytial virus, and other paramyxoviruses; influenza A virus, influenza B virus, influenza C virus, and other orthomyxoviruses; bluetongue virus and other reoviruses; porcine circovirus; herpesviruses such as pseudorabies virus and bovine herpesvirus 1; African swine fever virus and other asfarviruses; simian immunodeficiency virus, feline immunodeficiency virus, bovine immunodeficiency virus, bovine leukemia virus, feline leukemia virus, Jaagsiekte sheep retrovirus, caprine arthritis-encephalitis virus, and other retroviruses; yellow fever virus, West Nile virus, dengue virus, tick-borne encephalitis virus, bovine viral diarrhea virus, and other flaviviruses; or rabies virus and other rhabdoviruses.

[0102] In some embodiments, the methods and compositions described herein are used in a human subject. In some embodiments, the virus infecting the human subject may be selected from coronavirus, adenovirus, astrovirus, hepadnavirus, herpesvirus, papovavirus, poxvirus, arenavirus, bunyavirus, calicivirus, filovirus, flavivirus, orthomyxovirus, paramyxovirus, picornavirus, reovirus, retrovirus, rhabdovirus or togavirus.

[0103] In some embodiments, examples of coronaviruses include, but are not limited to, human coronaviruses (the pathogen of severe acute respiratory syndrome (SARS)), such as SARS-CoV-2 (or 2019-NCOV). In some embodiments, examples of adenoviruses include, but are not limited to, human adenoviruses. In some embodiments, examples of astroviruses include, but are not limited to, mammalian astroviruses. In some embodiments, examples of hepadnaviruses include, but are not limited to, hepatitis B virus. In some embodiments, examples of herpesviruses include, but are not limited to, herpes simplex virus type 1, herpes simplex virus type 2, human cytomegalovirus, Epstein-Barr virus, varicella-zoster virus, roseolovirus, or Kaposi's sarcoma-associated herpesvirus. In some embodiments, examples of papovaviruses include, but are not limited to, human papillomavirus or human polyomavirus. In some embodiments, examples of poxviruses include, but are not limited to, variola virus, vaccinia virus, cowpox virus, monkeypox virus, molluscum contagiosum virus, parapoxvirus, orf virus, tanapox virus, yaba tumor virus, or infectious soft-tissue tumor virus. In some embodiments, examples of arenaviruses include, but are not limited to, lymphocytic choriomeningitis virus, Lassa virus, Machupo virus, or Junin virus. In some embodiments, examples of bunyaviruses include, but are not limited to, hantavirus, nairovirus, orthobunyavirus, or phlebovirus. In some embodiments, examples of caliciviruses include, but are not limited to, vesivirus, norovirus (such as Norwalk virus and sapovirus). In some embodiments, examples of filoviruses include, but are not limited to, Ebola virus or Marburg virus.In some embodiments, flaviviruses include, but are not limited to, yellow fever virus, West Nile virus, dengue virus, hepatitis C virus, tick-borne encephalitis virus, Japanese encephalitis virus, Murray Valley encephalitis virus, Saint Louis encephalitis virus, Russian spring-summer encephalitis virus, Omsk hemorrhagic fever virus, bovine viral diarrhea virus, Kyasanur Forest disease virus, or Powassan encephalitis virus. In some embodiments, orthomyxoviruses include, but are not limited to, influenza A virus, influenza B virus, or influenza C virus. In some embodiments, paramyxoviruses include, but are not limited to, parainfluenza virus, rubulavirus (mumps), morbillivirus (measles), pneumovirus (such as human respiratory syncytial virus), or subacute sclerosing panencephalitis virus. In some embodiments, picornaviruses include, but are not limited to, poliovirus, rhinovirus, coxsackievirus group A, coxsackievirus group B, hepatitis A virus, echovirus, or enterovirus. In some embodiments, reoviruses include, but are not limited to, Colorado tick fever virus or rotavirus. In some embodiments, retroviruses include, but are not limited to, lentivirus (such as human immunodeficiency virus) or human T-lymphotropic virus (HTLV). In some embodiments, rhabdoviruses include, but are not limited to, lyssavirus (such as rabies virus), vesicular stomatitis virus, or infectious hematopoietic necrosis virus. In some embodiments, togaviruses include, but are not limited to, alphavirus (such as Ross River virus, O'nyong'nyong virus, Sindbis virus, Venezuelan equine encephalitis virus, eastern equine encephalitis virus, western equine encephalitis virus, etc.) or rubella virus.

[0104] Coronaviruses are enveloped viruses with positive-strand RNA and belong to the Coronaviridae family of the order Nidovirales. Coronaviruses have RNA that is directly translated into one or more polyproteins, which are cleaved by viral proteases to generate mature viral proteins or viral protein intermediates. This viral protease is essential for viral replication. Coronaviruses typically cause respiratory and intestinal infections and are infectious to both animals and humans. The toxicity of coronaviruses to humans is considered relatively low. Four human coronaviruses (229E, NL63, OC43, and HKU1) are known as human coronaviruses that are frequently infected worldwide, and generally, upper respiratory tract infections showing cold symptoms occur. However, coronaviruses can evolve into strains that infect humans and cause fatal diseases. Examples of this include SARS-CoV and MERS-CoV, and more recently, SARS-CoV-2 (or 2019-nCoV) has been identified.

[0105] SARS-CoV-2 is highly infectious and has caused coronavirus disease 2019 (COVID-19) worldwide. COVID-19 is both an important public health issue and a potential bioterrorism threat. These problems are becoming even more serious because the number of specific anti-SARS-CoV-2 therapies and vaccines is limited. Therefore, there is an urgent need to develop antiviral therapies for the treatment and prevention of SARS-CoV-2 infections and for the alleviation of tissue damage caused by this virus.

[0106] Viral infections such as SARS-CoV-2 disrupt tissue homeostasis by altering cell functions and their structure. In response to tissue damage, organ systems initiate an inflammatory response, causing vascular changes and cellular reactions simultaneously to start the healing process. Viral infections induce acute and / or chronic inflammatory responses, leading to short-term and / or long-term tissue damage. For example, the pathophysiology of severe respiratory syndrome caused by SARS-CoV-2 is multifactorial, with an excessive immune response occurring, accompanied by an inflammatory cytokine storm (resulting in other end-organ damage), and lysis of alveolar epithelial cells and bronchial epithelial cells, often leading to secondary opportunistic pneumonia. In the absence of appropriate treatment, as in the case of COVID-19, tissue damage follows a chronic course. Thus, even after the underlying viral infection has resolved, the problem of tissue damage remains.

[0107] Stem cells are immature undifferentiated cells that can self-renew over a long period through cell division. Under specific conditions, stem cells can differentiate into mature functional cells. Stem cells play various roles in tissue repair and regeneration. The use of stem cells and the cells derived from them is currently attracting high interest in medical research, particularly with the expectation that they may provide therapeutic agents for treating tissues damaged by various causes such as genetic disorders, trauma, and diseases.

[0108] In recent years, small mobile stem (SMS) cells have been isolated and their characteristics evaluated, for example, in WO2014 / 200940 and WO2017 / 172638 (both of which are hereby expressly incorporated by reference in their entirety). SMS cells are adherent cells with a diameter of 4.5 - 5.5 μm and can be obtained from cell sources such as umbilical cord, peripheral blood, bone marrow, and solid tissues. In some embodiments, the use of SMS cells enables the repair or regeneration of tissue damage caused by viral infections.

[0109] SMS cells exhibit excellent characteristics useful for tissue repair and regeneration. SMS cells can be easily isolated from plasma, are very small, difficult to stain and observe under a microscope, and are distinguished from other types of stem cells such as mesenchymal stem cells (MSCs) in that they have no significant immunogenicity.

[0110] Human bone marrow-derived mesenchymal stem cells (MSCs) have been safely administered to patients with acute respiratory distress syndrome (ARDS) and septic shock (Phase I / II trials), but there are still major problems regarding the short-term and long-term safety of intravenous administration of MSCs. Since MSCs are relatively large cells, when MSCs are infused, aggregation (clumping) may occur in the damaged capillary bed, and parenchymal damage may occur due to ischemia and infarction in the local tissue. In addition, since MSCs are highly immunogenic, they may be targeted by the host immune system.

[0111] Such concerns can be minimized by providing a treatment method containing SMS cells to subjects suffering from infectious diseases. Since SMS cells have relatively few membrane proteins, (unlike MSCs) they have less tendency to adhere to each other and form clumps. Therefore, SMS cells can be used more safely as a therapeutic intravenous drip than MSCs. Furthermore, since SMS cells have few immunogenic membrane proteins and are cells found in the circulatory system, problems related to administration into the circulatory system and graft rejection are minimized.

[0112] Since SMS cells have shown a robust angiogenesis effect in vitro and in cell culture, they have a remarkable effect on tissue regeneration. Therefore, the embodiments provided herein relate to a composition comprising SMS cells and a method of using this composition. This method includes administering SMS cells to a subject having a viral infection, a fungal infection, or a bacterial infection to reduce substantial damage and / or repair lung damage caused by a pathogen such as SARS-CoV-2, and may include the step of selecting a subject (preferably a human) for whom treatment is to be performed to improve lung recovery after suffering from a viral infection, a fungal infection, or a bacterial infection. For example, the subject can be selected or identified by conventional diagnostic methods or clinical evaluations of symptoms associated with SARS-CoV-2 infection.

[0113] Studies using experimental animals have shown that wounds in damaged skin can be healed by SMS cells, and in particular, it has been recognized that angiogenesis and granulation formation have been promoted. Therefore, in this specification, by using SMS cells, the damage caused by the strong inflammatory state due to the cytokine storm associated with SARS-CoV-2 can be reduced or alleviated, alveolar endothelial cell damage and / or respiratory endothelial cell damage can be decreased or suppressed, and more rapid repair of damaged lung tissue can be promoted. SMS cells have been found to reduce the activity of fibroblasts, and administering them to a subject who requires a reduction in fibroblast activity can reduce the onset of pulmonary fibrosis that occurs after suffering from a viral infection, a fungal infection, or a bacterial infection. From the above, by using the SMS cells described in this specification, the severe pathological conditions caused by viral infections (such as COVID-19, especially SARS-CoV-2, etc.), fungal infections, or bacterial infections can be treated, reduced, alleviated, or suppressed, the course of such infections can be shortened, the overall mortality rate due to such infections can be reduced, and / or the post-infection debilitation of recovered patients can be suppressed.

[0114] As used herein, "mesenchymal stem cell (MSC)" refers to rare fibroblast-like cells that can differentiate into various types of cells such as osteocytes, chondrocytes, and adipocytes. For the identification of human MSCs, surface markers that are positive for CD73, CD90, and CD105 and negative for CD14, CD19, CD34, CD45, and HLA-DR have been conventionally used. Mesenchymal stem cells are known to be responsible for immunomodulation of various immune cells through factors such as prostaglandin E2, nitric oxide, indoleamine 2,3-dioxygenase, IL-6, FasL, PD-L1, and PD-L2. Mesenchymal stem cell populations can be isolated from cell sources such as adipose tissue, dental pulp, peripheral blood, or tissues derived from childbirth (e.g., amniotic fluid, umbilical cord, or placenta).

[0115] As used herein, "fibroblast" refers to common cells that constitute connective tissue. Fibroblasts can synthesize extracellular matrix and collagen in biological tissues, thereby forming the stroma. Furthermore, fibroblasts are also involved in inflammation and / or pathogen invasion in tissue damage through chemokine signaling. Fibrosis is a process consisting of tissue remodeling and the formation of scar tissue that replaces normal parenchymal tissue, and it occurs when stimulated fibroblasts produce new connective tissue. Fibrosis is a common sequela that interferes with the function of normal organs and is observed in both chronic and acute inflammation.

[0116] As used herein, "alveolar epithelial cell" refers to a cell population composed of type I alveolar epithelial cells and type II alveolar epithelial cells that cover most of the surface of the lung. Type I alveolar cells (more than 95% of the alveolar epithelial cell population) are large squamous epithelial cells and are involved in the gas exchange process between alveoli and blood. Type II alveolar cells (accounting for 2 - 5% of the alveolar epithelial cell population) produce pulmonary surfactant. Type I alveolar epithelial cells usually do not have self-renewal ability, but type II alveolar epithelial cells can proliferate and function as progenitor cells for other types of cells including type I alveolar epithelial cells.

[0117] In some embodiments, the compositions and methods provided herein may be used for the prevention or suppression of tissue damage. For example, a composition containing SMS cells may be used in a subject not suffering from any viral, fungal, or bacterial infection for the purpose of strengthening or enhancing undamaged tissue or cells. By such preventive means, when a viral, fungal, or bacterial infection occurs, tissue damage can be prevented, minimized, or rendered substantially non - existent.

[0118] Furthermore, provided herein are compositions and methods for promoting or enhancing the repair or regeneration of damaged tissue or for improving recovery from viral, fungal, or bacterial infections. The composition is provided to a subject in need of promoting or enhancing the repair or regeneration of damaged tissue or improving recovery from viral, fungal, or bacterial infections and comprises a therapeutically effective amount of SMS cells.

[0119] As disclosed herein, SMS cells have been found to be capable of regulating gene expression in human cells. In some embodiments, when a composition containing SMS cells or SMS cells are brought into contact with human cells, in these human cells, Dickkopf-related protein 1 (DKK1), N-acetylglucosamine 2-epimerase (RENBP), growth / differentiation factor 15 (GDF15), dermokine (DMKN), ferritin light chain (FTL), tryptophan 2,3-dioxygenase (TDO2), apolipoprotein E (APOE), chitinase 3-like protein 1 (CHI3L1), or nuclear receptor subfamily 4 group A member 2 (NR4A2), or any combination thereof is upregulated. In some embodiments, when a composition containing SMS cells or SMS cells are brought into contact with human cells, in these human cells, interleukin 11 (IL-11), SPRY domain-containing SOCS box protein 1 (SPSB1), cytochrome P450 26B1 (CYP26B1), or frizzled-8 (FZD8), or any combination thereof is downregulated. In some embodiments, the regulation of gene expression in cells exerts an effect on cell signaling, blood vessel diameter, cell differentiation, cell proliferation, or protection from pathogens, or any combination thereof. In some embodiments, the human cells brought into contact with SMS cells in these embodiments are type II alveolar cells.

[0120] As is known in the art, Dickkopf-related protein 1 (DKK1) is a major Wnt antagonist that contributes to the suppression of Wnt / β-catenin signaling in alveolar epithelial cells of acute pneumonia. Intratracheal administration of Wnt3a or anti-DKK1 antibody has been shown to suppress the influx of neutrophils into the alveolar lumen of damaged lungs. In some embodiments, contacting SMS cells can activate or increase the expression of DKK1 in cells such as type II alveolar cells. In some embodiments, contacting SMS cells can activate or increase the expression of DKK1 in cells such as type II alveolar cells by, for example, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 210%, 220%, 230%, 240% or 250%, or a percentage within a range bounded by any two of these percentages. In some embodiments, contacting SMS cells can activate or increase the expression of DKK1 in cells such as type II alveolar cells by 55%, about 55%, at least 55%, or at least about 55%. Accordingly, some embodiments relate to a method of increasing the expression of DKK1 in cells such as type II alveolar cells by contacting the cells with SMS cells, which method may include evaluating or measuring the expression level of DKK1 in cells such as type II alveolar cells after contacting with SMS cells, and / or selecting a subject to administer a pharmaceutical for increasing the expression level of DKK1 and administering SMS cells to the subject, which administration is preferably performed by contacting the cells of the subject, such as type II alveolar cells, with SMS cells.

[0121] As is known in the art, N - acylglucosamine 2 - epimerase (RENBP) inhibits renin, reduces blood pressure, and causes dilation of blood vessel diameter (vascular dilation). In some embodiments, contacting SMS cells can activate or increase the expression of RENBP in cells such as type II alveolar cells. In some embodiments, contacting SMS cells can activate or increase the expression of RENBP in cells such as type II alveolar cells by, for example, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 210%, 220%, 230%, 240% or 250%, or a percentage within a range with any two of these percentages as the upper and lower limits. In some embodiments, contacting SMS cells can activate or increase the expression of RENBP in cells such as type II alveolar cells by 60%, about 60%, at least 60%, or at least about 60%. Thus, some embodiments relate to a method of increasing the expression of RENBP in cells such as type II alveolar cells by contacting the cells with SMS cells, which method may include evaluating or measuring the expression level of RENBP in cells such as type II alveolar cells after contacting with SMS cells, and / or selecting a subject to which a pharmaceutical for increasing the expression level of RENBP is to be administered and administering SMS cells to the subject, which administration is preferably performed by contacting the cells of the subject, which are cells such as type II alveolar cells, with SMS cells.

[0122] As is known in the art, both growth / differentiation factor 15 (GDF15) and dermokine (DMKN) can induce epithelial-mesenchymal transition (EMT). In some embodiments, contacting SMS cells can activate or increase the expression of GDF15 and / or DMKN in cells such as type II alveolar cells. In some embodiments, contacting SMS cells can activate or increase the expression of GDF15 in cells such as type II alveolar cells by, for example, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 210%, 220%, 230%, 240% or 250%, or a percentage within a range bounded by any two of these percentages. In some embodiments, contacting SMS cells can activate or increase the expression of GDF15 in cells such as type II alveolar cells by 58%, about 58%, at least 58%, or at least about 58%. In some embodiments, contacting SMS cells can activate or increase the expression of DMKN in cells such as type II alveolar cells by, for example, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 210%, 220%, 230%, 240% or 250%, or a percentage within a range bounded by any two of these percentages. In some embodiments, contacting SMS cells can activate or increase the expression of DMKN in cells such as type II alveolar cells by 130%, about 130%, at least 130%, or at least about 130%.Accordingly, some embodiments relate to a method of increasing the expression of GDF15 and / or DMKN in cells such as type II alveolar cells by contacting the cells with SMS cells, the method may include evaluating or measuring the expression level of GDF15 and / or DMKN in cells such as type II alveolar cells after contacting with SMS cells, and / or selecting a subject to which a pharmaceutical for increasing the expression level of GDF15 and / or DMKN is administered, and administering SMS cells to the subject, and this administration is preferably performed by contacting the cells of the subject, which are such as type II alveolar cells, with SMS cells.

[0123] As is known in the art, ferritins such as ferritin light chain (FTL) and ferritin heavy chain (FTH) are associated with lung protection against pathogens and angiogenesis. In some embodiments, contacting SMS cells can activate or increase the expression of FTL and / or FTH in cells such as type II alveolar cells. In some embodiments, contacting SMS cells can activate or increase the expression of FTL and / or FTH in cells such as type II alveolar cells by, for example, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 210%, 220%, 230%, 240% or 250%, or a percentage within a range bounded by any two of these percentages. In some embodiments, contacting SMS cells can activate or increase the expression of FTL and / or FTH in cells such as type II alveolar cells by 70%, about 70%, at least 70%, or at least about 70%. Accordingly, some embodiments relate to a method of increasing the expression of FTL and / or FTH in cells such as type II alveolar cells by contacting the cells with SMS cells, the method may include evaluating or measuring the expression level of FTL and / or FTH in cells such as type II alveolar cells after contacting with SMS cells, and / or selecting a subject to administer a pharmaceutical for increasing the expression level of FTL and / or FTH, and administering SMS cells to the subject, which administration is preferably performed by contacting the cells of the subject, such as type II alveolar cells, with SMS cells.

[0124] As is conventionally known, tryptophan 2,3-dioxygenase (TDO2) is involved in the protection of the lungs against pathogens. The activity of TDO2 reduces the amount of tryptophan that pathogens require. Pathogens that are sensitive to tryptophan deficiency include viruses such as herpes simplex virus and measles virus, and streptococcus. In some embodiments, the expression of TDO2 in cells such as type II alveolar cells can be activated or increased by contacting them with SMS cells. In some embodiments, by contacting with SMS cells, the expression of TDO2 in cells such as type II alveolar cells can be activated or increased by, for example, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 210%, 220%, 230%, 240% or 250%, or a percentage within a range bounded by any two of these percentages. In some embodiments, by contacting with SMS cells, the expression of TDO2 in cells such as type II alveolar cells can be activated or increased by 85%, about 85%, at least 85%, or at least about 85%. Accordingly, some embodiments relate to a method of increasing the expression of TDO2 in cells such as type II alveolar cells by contacting the cells with SMS cells, which method may include evaluating or measuring the expression level of TDO2 in cells such as type II alveolar cells after contacting with SMS cells, and / or selecting a subject to which a pharmaceutical for increasing the expression level of TDO2 is to be administered and administering SMS cells to the subject, which administration is preferably carried out by contacting the cells of the subject, which are type II alveolar cells or the like, with SMS cells.

[0125] As is known in the art, apolipoprotein E (APOE) is involved in the protection of the lung against pathogens. APOE has been found to have anti-inflammatory and antioxidant effects that reduce the severity of lung diseases in mouse models. In some embodiments, contacting SMS cells can activate or increase the expression of APOE in cells such as type II alveolar cells. In some embodiments, contacting SMS cells can activate or increase the expression of APOE in cells such as type II alveolar cells by, for example, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 210%, 220%, 230%, 240% or 250%, or a percentage within a range bounded by any two of these percentages. In some embodiments, contacting SMS cells can activate or increase the expression of APOE in cells such as type II alveolar cells by 110%, about 110%, at least 110%, or at least about 110%. Accordingly, some embodiments relate to a method of increasing the expression of APOE in cells such as type II alveolar cells by contacting the cells with SMS cells, the method may include evaluating or measuring the expression level of APOE in cells such as type II alveolar cells after contacting with SMS cells, and / or selecting a subject to administer a pharmaceutical for increasing the expression level of APOE and administering SMS cells to the subject, which administration is preferably performed by contacting the cells of the subject, which are cells such as type II alveolar cells, with SMS cells.

[0126] As is known in the art, chitinase 3-like protein 1 (CHI3L1) is involved in the protection of the lung against pathogens. Although the role of CHI3L1 has not been fully elucidated, its association with cytotoxicity against pathogenic bacteria, regulation of cell death, inflammation, and cell remodeling has been pointed out. In some embodiments, contacting with SMS cells can activate or increase the expression of CHI3L1 in cells such as type II alveolar cells. In some embodiments, contacting with SMS cells can activate or increase the expression of CHI3L1 in cells such as type II alveolar cells by, for example, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 210%, 220%, 230%, 240% or 250%, or a percentage within a range bounded by any two of these percentages. In some embodiments, contacting with SMS cells can activate or increase the expression of CHI3L1 in cells such as type II alveolar cells by 150%, about 150%, at least 150%, or at least about 150%. Thus, some embodiments relate to a method of increasing the expression of CHI3L1 in cells such as type II alveolar cells by contacting the cells with SMS cells, which method may include evaluating or measuring the expression level of CHI3L1 in cells such as type II alveolar cells after contacting with SMS cells, and / or selecting a subject to which a pharmaceutical for increasing the expression level of CHI3L1 is to be administered, and administering SMS cells to the subject, which administration is preferably carried out by contacting the cells of the subject, which are cells such as type II alveolar cells, with SMS cells.

[0127] As is known in the art, nuclear receptor subfamily 4 group A member 2 (NR4A2) acts as an inhibitor of inflammation and improves DNA repair. In some embodiments, contacting with SMS cells can activate or increase the expression of NR4A2 in cells such as type II alveolar cells. In some embodiments, contacting with SMS cells can activate or increase the expression of NR4A2 in cells such as type II alveolar cells by, for example, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 210%, 220%, 230%, 240% or 250%, or a percentage within a range bounded by any two of these percentages. In some embodiments, contacting with SMS cells can activate or increase the expression of NR4A2 in cells such as type II alveolar cells by 55%, about 55%, at least 55%, or at least about 55%. Thus, some embodiments relate to a method of increasing the expression of NR4A2 in cells such as type II alveolar cells by contacting the cells with SMS cells, the method may include evaluating or measuring the expression level of NR4A2 in cells such as type II alveolar cells after contacting with SMS cells, and / or selecting a subject to administer a pharmaceutical for increasing the expression level of NR4A2 and administering SMS cells to the subject, and this administration is preferably performed by contacting the cells of the subject, which are type II alveolar cells or the like, with SMS cells.

[0128] As is conventionally known, interleukin 11 (IL-11) is a major cytokine associated with fibrosis, parenchymal tissue dysfunction, and chronic airway inflammation. In some embodiments, contacting SMS cells can suppress or reduce the expression of IL-11 in cells such as type II alveolar cells. In some embodiments, contacting SMS cells can suppress or reduce the expression of IL-11 in cells such as type II alveolar cells by, for example, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100%, or a percentage within a range bounded by any two of these percentages. In some embodiments, contacting SMS cells can suppress or reduce the expression of IL-11 in cells such as type II alveolar cells by 40%, about 40%, at least 40%, or at least about 40%. Accordingly, some embodiments relate to a method of suppressing or reducing the expression of IL-11 in cells such as type II alveolar cells by contacting the cells with SMS cells, which method may include evaluating or measuring the expression level of IL-11 in cells such as type II alveolar cells after contacting with SMS cells, and / or selecting a subject to whom a pharmaceutical for suppressing or reducing the expression level of IL-11 is to be administered, and administering SMS cells to the subject, which administration is preferably performed by contacting the cells of the subject, which are such as type II alveolar cells, with SMS cells.

[0129] As is known in the art, Sprouty domain-containing SOCS box protein 1 (SPSB1) is responsible for the negative regulation of nitric oxide (NO) and causes the narrowing of blood vessel diameter (vasoconstriction). In some embodiments, the expression of SPSB1 in cells such as type II alveolar cells can be suppressed or reduced by contacting them with SMS cells. In some embodiments, by contacting with SMS cells, the expression of SPSB1 in cells such as type II alveolar cells can be suppressed or reduced by, for example, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100%, or a percentage within a range bounded by any two of these percentages. In some embodiments, by contacting with SMS cells, the expression of SPSB1 in cells such as type II alveolar cells can be suppressed or reduced by 50%, about 50%, at least 50%, or at least about 50%. Accordingly, some embodiments relate to a method of suppressing or reducing the expression of SPSB1 in cells such as type II alveolar cells by contacting the cells with SMS cells, which method may include evaluating or measuring the expression level of SPSB1 in cells such as type II alveolar cells after contacting with SMS cells, and / or selecting a subject to which a pharmaceutical for suppressing or reducing the expression level of SPSB1 is administered and administering SMS cells to the subject, which administration is preferably carried out by contacting the cells of the subject, which are type II alveolar cells or the like, with SMS cells.

[0130] As is known in the art, cytochrome P450 26B1 (CYP26B1) is involved in the catabolism of retinoic acid, which is essential for the differentiation of lung cells. In some embodiments, the expression of CYP26B1 in cells such as type II alveolar cells can be suppressed or decreased by contacting the cells with SMS cells. In some embodiments, the expression of CYP26B1 in cells such as type II alveolar cells can be suppressed or decreased by contacting the cells with SMS cells by, for example, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100%, or a percentage within a range bounded by any two of these percentages. In some embodiments, the expression of CYP26B1 in cells such as type II alveolar cells can be suppressed or decreased by contacting the cells with SMS cells by 50%, about 50%, at least 50%, or at least about 50%. Accordingly, some embodiments relate to a method of suppressing or decreasing the expression of CYP26B1 in cells such as type II alveolar cells by contacting the cells with SMS cells, the method may include evaluating or measuring the expression level of CYP26B1 in cells such as type II alveolar cells after contacting the cells with SMS cells, and / or selecting a subject to which a pharmaceutical for suppressing or decreasing the expression level of CYP26B1 is to be administered, and administering SMS cells to the subject, and this administration is preferably performed by contacting the cells of the subject, which are cells such as type II alveolar cells, with SMS cells.

[0131] As is known in the art, frizzled-8 (FZD8) causes the differentiation and transformation of alveolar epithelial cells from type II alveolar epithelial cells to type I alveolar epithelial cells during the lung recovery process. In some embodiments, the expression of FZD8 in cells such as type II alveolar cells can be suppressed or reduced by contacting with SMS cells. In some embodiments, by contacting with SMS cells, the expression of FZD8 in cells such as type II alveolar cells can be suppressed or reduced by, for example, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100%, or a percentage within a range bounded by any two of these percentages. In some embodiments, by contacting with SMS cells, the expression of FZD8 in cells such as type II alveolar cells can be suppressed or reduced by 50%, about 50%, at least 50%, or at least about 50%. Accordingly, some embodiments relate to a method of suppressing or reducing the expression of FZD8 in cells such as type II alveolar cells by contacting the cells with SMS cells, which method may include evaluating or measuring the expression level of FZD8 in cells such as type II alveolar cells after contacting with SMS cells, and / or selecting a subject to which a pharmaceutical for suppressing or reducing the expression level of FZD8 is administered and administering SMS cells to the subject, and this administration is preferably carried out by contacting the cells of the subject, which are type II alveolar cells or the like, with SMS cells.

[0132] The term "therapeutically effective amount" is used to indicate the amount of an active compound or pharmaceutical that induces the biological or medical response described herein. For example, a therapeutically effective amount of a compound may be the amount necessary to prevent, reduce, or alleviate the symptoms of a disease, or the amount necessary to extend the survival rate of a subject being treated. Such responses may be observed in tissues, systems, animals, or humans, and include the alleviation of the signs or symptoms of a disease being treated. A therapeutically effective amount can be readily determined by one of ordinary skill in the art taking into account the disclosure herein. The therapeutically effective amount required for administration of the compounds disclosed herein will depend on the route of administration, the type of animal being treated (including humans), and the physical characteristics of the particular animal being treated. The dosage can be adjusted to obtain the desired effect, but is also subject to factors such as body weight, diet, concomitant medications, and other factors recognized by one of ordinary skill in the medical arts.

[0133] II. Method for isolating SMS cells Some of the embodiments provided herein relate to methods of isolating SMS cells and methods of manufacturing the compositions provided herein. Methods of isolating SMS cells have been reported in the past and are described, for example, in WO2014 / 200940 and WO2017 / 172638 (both of which are hereby incorporated by reference in their entirety).

[0134] In some embodiments, the method includes culturing a population of SMS cells for a time sufficient to obtain a therapeutically effective amount of SMS cells.

[0135] As used herein, "cell culture" or "cultured cells" refers to cells or tissues maintained, cultured, or propagated in an artificial in vitro environment. These terms include continuous cell lines (e.g., immortalized phenotype cell lines), primary cell cultures, finite lifespan cell lines (e.g., non-transformed cells), and other cell populations maintained in vitro. In this context, primary cells are cells obtained directly from tissues or organs of animals such as humans without undergoing culture. Primary cells can generally be passaged up to 10 passages in vitro until senescence or growth arrest, although there are exceptions.

[0136] "Maintain" means to sustain the survival of a cell or cell population, which may sometimes be accompanied by an increase in cell number. The terms "proliferate", "reproduce", "expand", and "grow" may be used interchangeably and refer to an increase in cell number. According to one embodiment, "proliferate" refers to the survival of cells being sustained over a period of at least 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 32 weeks, 48 weeks, 52 weeks, 104 weeks or more, or a period within a range bounded by any two of these periods. In another embodiment, the survival of cells is maintained over at least 25 passages, 26 passages, 27 passages, 28 passages, 29 passages, 30 passages or more, or a number of passages within a range bounded by any two of these numbers of passages.

[0137] As used herein, "cell suspension" refers to a cell culture in which most of the cells are freely suspended in a medium (usually a culture medium (culture system)), and these cells are suspended as single cells, cell aggregates, and / or cell clumps. In other words, these cells maintain their survival and proliferate in the medium without adhering to a solid substrate or a semi-solid substrate. Also, as used herein, "adherent cells" refers to cells or cell populations that are adhered to a substrate or surface.

[0138] As used herein, "culture system" refers to culture conditions that support the maintenance and growth of SMS cells or somatic cells derived therefrom, as well as selected conditions that support the induction of differentiation and growth of undifferentiated or differentiated SMS cells. Also, "culture system" refers to a combination of components that may include a basal medium (usually a cell culture medium containing a basal solution (including salts, sugars, and amino acids) composed of known components) and a serum replacement additive. The culture system may further include other components such as extracellular matrix (ECM) components, additional serum or serum substitutes, culture (nutrient) media, and other externally added factors, but is not limited to these components, and the cooperation of these components provides appropriate conditions for supporting the growth of SMS cells, the maintenance of cell culture, cell differentiation, or the expression of various molecules. In this regard, "culture system" includes cells cultured in the culture system.

[0139] SMS cells may be cultured in a T25 flask containing growth medium (e.g., in an incubator at 37 °C and 5% CO2). This SMS cell population may include a heterogeneous cell population consisting of undifferentiated SMS cells and differentiated cells derived from SMS cells. Undifferentiated SMS cells exist as a floating fraction and an adherent fraction, and most of the floating fraction is occupied by undifferentiated SMS cells (e.g., the proportion occupied by undifferentiated SMS cells is 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more, or an amount within a range with any two of these numerical values as the upper and lower limits). Therefore, some embodiments relate to a suspension of undifferentiated non-adherent SMS cells, and these undifferentiated non-adherent SMS cells are preferably cultured in a liquid medium in such a way that cell adhesion is inhibited (e.g., using a container or flask made of polypropylene). In some embodiments, in the undifferentiated floating SMS cell population, the proportion occupied by undifferentiated SMS cells is 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more, or an amount within a range with any two of these numerical values as the upper and lower limits.

[0140] Undifferentiated SMS cells can be isolated or purified by fractionation centrifugation. First, centrifuge at a low speed to remove cell clumps or differentiated cells, and then centrifuge at a high speed to recover undifferentiated SMS cells. As another method, undifferentiated SMS cells may be isolated by filtration, for example, by fractional filtration in which the pore size of the filter is gradually reduced to 3 - 5 μm. As another method, undifferentiated SMS cells may be isolated by immunobinding (for example, binding a binding partner (such as an antibody) specific to the stem cell receptor on SMS cells to beads (such as magnetic beads) or detecting by FACS cell sorting), or by fractional filtration in which the pore size of the filter is gradually reduced to 3 - 5 μm. After isolating undifferentiated SMS cells, confirm the uniformity under a microscope. Before performing one or more of these isolation protocols, by subculturing undifferentiated SMS cells to at least passage 25 (for example, passage 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39 or 40, or the passage number within the range with any two of these passage numbers as the upper and lower limits), a population of SMS cells with improved uniformity can be obtained.

[0141] SMS cells can be grown using various types of serum-containing or serum-free media, in the presence or absence of a differentiation-inducing compound (such as insulin). Once a week, centrifuge the SMS cells at 4200×g for 15 minutes to precipitate the SMS cells and replace the cell growth medium. The centrifugation speed may be 3000×g, 3500×g, 4000×g, 4100×g, 4200×g, 4300×g, 4500×g or 5000×g, or may be a speed within a range having any two of these speeds as the upper and lower limits, and the centrifugation time may be adjusted accordingly. Under such conditions, the growth of SMS cells is limited according to the amount of the medium (cell density). The uniformity of SMS cells is evaluated under a microscope, and the number of SMS cells is estimated by evaluating the turbidity of the cell suspension with a spectrophotometer and / or measuring the size of the pellet after high-speed centrifugation. When SMS cells are cultured in suspension, it becomes easy to aliquot and / or transfer the SMS cells into a new tube containing the growth medium, facilitating the transfer and cloning of SMS cells. This method of aliquoting and / or transferring cultured cells from an existing culture to a new culture is performed without using an enzyme (such as trypsin) for detaching cells from a culture dish or a basal cell layer. Most of the SMS cells grow as individual cells without forming cell aggregates, and the suspension of SMS cells can be maintained in an undifferentiated state despite the cell transfer operation being performed. Also, suspension culture can be scaled up, and the number of cells obtained by increasing the amount of the medium can be increased.

[0142] In some embodiments, a composition for administration to a subject is prepared using the cultured SMS cells. In some embodiments, the composition is formulated for administration by various routes such as, for example, topical administration, transrespiratory administration, local administration. In some embodiments, the methods of the present disclosure also contemplate systemic administration, enteral administration or parenteral administration, for example, transrespiratory administration (inhalation administration or intranasal administration), subcutaneous administration, intraperitoneal administration, intravenous administration, intramuscular administration, intraarterial administration, oral administration, enteral administration, subdermal administration, transdermal administration, sublingual administration, buccal administration, rectal administration or vaginal administration.

[0143] In some embodiments, the cultured SMS cells are formulated for co - administration with another treatment. In some embodiments, this other treatment may be a standard treatment, for example, a standard treatment for an inflammatory disease or a viral, fungal, or bacterial infection known in the art. For example, the SMS cells may be formulated for use in combination with an antibiotic treatment, an antifungal treatment, or an antiviral treatment (such as a vaccine or remdesivir).

[0144] As used herein, "antiviral" treatment includes any method and agent used to treat, suppress, manage, or alleviate a viral infection. Examples of antiviral treatments include, for example, vaccines or antiviral agents, such as dexamethasone, convalescent serum, tocilizumab, sarilumab, ribavirin, favipiravir, darunavir, galidesivir, interferon alpha, interferon beta, lopinavir, ritonavir, remdesivir, triazavirin, umifenovir, or other known agents or vaccines used for the treatment, suppression, or management of viral infections, or other agents or vaccines developed for the purpose of treating, suppressing, or managing viral infections.

[0145] III. Method of using the composition Some of the embodiments provided herein relate to methods of promoting or enhancing the repair or regeneration of damaged tissue or improving recovery from viral, fungal, or bacterial infections or sequelae thereof using the compositions described herein. In some embodiments, the method comprises selecting a subject suffering from a viral, fungal, or bacterial infection or sequelae thereof, and administering to the selected subject a composition comprising a therapeutically effective amount of small mobile stem (SMS) cells. In some embodiments, the SMS cells are cells obtained from peripheral blood. In some embodiments, the SMS cells are cells of the same species as the subject. In some embodiments, the SMS cells are autologous cells obtained from the subject. In some embodiments, the damaged tissue is lung tissue.

[0146] In some embodiments, by promoting or enhancing the repair or regeneration of damaged tissue or improving recovery from viral, fungal, or bacterial infections or sequelae thereof, a decrease in alveolar cell injury, a decrease in respiratory endothelial cell injury, an increase in repair of damaged lung tissue, an increase in regeneration of damaged lung tissue, or a decrease in the development of pulmonary fibrosis, or any combination thereof, is achieved.

[0147] In some embodiments, the damaged tissue is tissue damaged by the viral infection, fungal infection or bacterial infection or sequelae thereof. In some embodiments, the viral infection is caused by a single-stranded RNA virus, double-stranded RNA virus, plus-sense single-stranded RNA virus, minus-sense single-stranded RNA virus, double-stranded DNA virus or single-stranded DNA virus. In some embodiments, the viral infection, fungal infection or bacterial infection is caused by coronavirus, poxvirus, smallpox virus, Marburg virus, flavivirus, influenza virus, parainfluenza virus, RS virus, rubella virus, human immunodeficiency virus, human papillomavirus, varicella-zoster virus, herpes simplex virus, cytomegalovirus, Epstein-Barr virus, JC virus, rabies virus, rotavirus, rhinovirus, adenovirus, papillomavirus, parvovirus, picornavirus, poliovirus, hantavirus, filovirus, coxsackievirus, equine encephalitis virus, Rift Valley fever virus, alphavirus, hepatitis A virus, hepatitis B virus, hepatitis C virus, hepatitis D virus, hepatitis E virus, pneumonia, Streptococcus pneumoniae, Staphylococcus aureus, Haemophilus influenzae, Moraxella catarrhalis, anaerobic bacteria, Gram-negative bacteria, Mycoplasma pneumoniae, Chlamydia pneumoniae, group A streptococcus, Klebsiella pneumoniae, Legionella pneumophila, Streptococcus pyogenes, Streptococcus agalactiae, Peptostreptococcus genus, Corynebacterium diphtheriae, Bordetella pertussis, Mycobacterium tuberculosis, Pseudomonas aeruginosa, Escherichia coli, Curvularia genus, Pneumocystis genus, Cryptococcus genus, Histoplasma capsulatum, Aspergillus genus, Mucorales, Fusarium genus, Scedosporium genus, Penicillium genus, or any combination thereof. In some embodiments, the coronavirus is MERS-CoV, SARS-CoV or SARS-CoV-2. In some embodiments, the coronavirus is SARS-CoV-2. In some embodiments, the composition comprises aerosolized SMS cells.In some embodiments, the composition is administered by inhalation. In some embodiments, the composition is formulated for inhalation administration. In some embodiments, the composition is administered intravenously. In some embodiments, the composition is formulated for intravenous administration.

[0148] Examples of the subject include a subject suffering from a viral infection (e.g., SARS-CoV-2 infection), a fungal infection, or a bacterial infection, a subject suspected of suffering from a viral infection, a fungal infection, or a bacterial infection, or a subject who has recently recovered from a viral infection, a fungal infection, or a bacterial infection. The subject may be a subject having tissue damage such as damaged lung tissue, pulmonary fibrosis, or cytotoxicity, or a combination thereof. The presence or absence of a viral infection (e.g., SARS-CoV-2 infection), a fungal infection, or a bacterial infection in the subject may be examined, or a diagnosis of these infections may be made, for example, using real-time reverse transcription polymerase chain reaction (RT-PCR) or other tests used for infectious disease testing (e.g., antibody testing).

[0149] In some embodiments, SMS cells are administered in combination with an antibiotic, an antifungal agent, a vaccine, or an antiviral agent. In some embodiments, the antiviral agent is dexamethasone, convalescent serum, tocilizumab, sarilumab, ribavirin, favipiravir, darunavir, galidesivir, interferon α, interferon β, lopinavir, ritonavir, remdesivir, triazavirin, umifenovir, or any combination thereof. In some embodiments, the vaccine is a coronavirus vaccine.

[0150] In some embodiments, by administering any of the compositions disclosed herein to a subject, Dickkopf-related protein 1 (DKK1), N-acetylglucosamine 2-epimerase (RENBP), growth / differentiation factor 15 (GDF15), dermokine (DMKN), ferritin light chain (FTL), tryptophan 2,3-dioxygenase (TDO2), apolipoprotein E (APOE), chitinase 3-like protein 1 (CHI3L1), or nuclear receptor subfamily 4 group A member 2 (NR4A2), or any combination thereof is upregulated in the subject. In some embodiments, by administering any of the compositions disclosed herein to a subject, interleukin 11 (IL-11), SPRY domain-containing SOCS box protein 1 (SPSB1), cytochrome P450 26B1 (CYP26B1), or frizzled-8 (FZD8), or any combination thereof is downregulated in the subject.

[0151] In some embodiments, the compositions of the invention are administered to a subject in an amount and for a period sufficient to promote or enhance the repair or regeneration of damaged tissue, or to improve recovery from viral, fungal, or bacterial infections or sequelae thereof. Since viral, fungal, or bacterial infections can vary significantly in terms of severity, curability, or chronicity, it will be well understood that the amount or treatment period of the compositions of the invention will also vary. As an example, the compositions of the invention may be administered at a frequency of at least three times a day, once a day, once a week, once a month, or once a year, or within a range having any two of these numerical values as the upper and lower limits.

[0152] Furthermore, provided herein is a method for treating or suppressing an inflammatory disease. In some embodiments, the method includes selecting a subject having an inflammatory disease and administering to the subject a composition comprising a therapeutically effective amount of small mobile stem (SMS) cells. In some embodiments, the inflammatory disease is an inflammatory disease of the lung. In some embodiments, the inflammatory disease includes fibrosis. In some embodiments, the fibrosis is pulmonary fibrosis, hepatic fibrosis, renal fibrosis, or cardiac fibrosis. In some embodiments, the inflammatory disease includes chronic obstructive pulmonary disease (COPD). In some embodiments, the inflammatory disease includes acute respiratory distress syndrome (ARDS). In some embodiments, the inflammatory disease is associated with a viral infection, a fungal infection, or a bacterial infection. In some embodiments, the viral infection is caused by a single-stranded RNA virus, a double-stranded RNA virus, a plus-sense single-stranded RNA virus, a minus-sense single-stranded RNA virus, a double-stranded DNA virus, or a single-stranded DNA virus.In some embodiments, the viral infection, fungal infection or bacterial infection is caused by an infection by coronavirus, poxvirus, variola virus, Marburg virus, flavivirus, influenza virus, parainfluenza virus, RSV, rubella virus, human immunodeficiency virus, human papillomavirus, varicella-zoster virus, herpes simplex virus, cytomegalovirus, Epstein-Barr virus, JC virus, rabies virus, rotavirus, rhinovirus, adenovirus, papillomavirus, parvovirus, picornavirus, poliovirus, hantavirus, filovirus, coxsackievirus, equine encephalitis virus, Rift Valley fever virus, alphavirus, hepatitis A virus, hepatitis B virus, hepatitis C virus, hepatitis D virus, hepatitis E virus, pneumonia, Streptococcus pneumoniae, Staphylococcus aureus, Haemophilus influenzae, Moraxella catarrhalis, anaerobic bacteria, Gram-negative bacteria, Mycoplasma pneumoniae, Chlamydia pneumoniae, group A streptococcus, Klebsiella pneumoniae, Legionella pneumophila, Streptococcus pyogenes, Streptococcus agalactiae, Peptostreptococcus, Corynebacterium diphtheriae, Bordetella pertussis, Mycobacterium tuberculosis, Pseudomonas aeruginosa, Escherichia coli, Curvularia, Pneumocystis, Cryptococcus, Histoplasma capsulatum, Aspergillus, Mucorales, Fusarium, Scedosporium, Penicillium, or any combination thereof. In some embodiments, the viral infection is a coronavirus infection. In some embodiments, the viral infection is an SARS-CoV infection, an MERS-CoV infection or an SARS-CoV-2 infection. In some embodiments, the SMS cells are cells obtained from peripheral blood. In some embodiments, the SMS cells are cells of the same species as the subject or autologous cells obtained from the subject.In some embodiments, administration of the composition results in a decrease or suppression of alveolar cell damage, a decrease or suppression of respiratory endothelial cell damage, an increase or improvement in the repair of damaged lung tissue, an increase or enhancement in the regeneration of damaged lung tissue, or a decrease or suppression in the onset of pulmonary fibrosis, or any combination thereof. In some embodiments, the composition is formulated for administration by inhalation, for example, via the nasal cavity or oral cavity. In some embodiments, the composition is formulated for intravenous administration. In some embodiments, the composition is administered in combination with the standard treatment for the inflammatory disease. In some embodiments, the inflammatory disease is associated with a viral infection, a fungal infection, or a bacterial infection, and the standard treatment is an antibiotic, an antifungal agent, a vaccine, or an antiviral agent, such as dexamethasone, convalescent serum, tocilizumab, sarilumab, ribavirin, favipiravir, darunavir, galidesivir, interferon α, interferon β, lopinavir, ritonavir, remdesivir, triazavirin, umifenovir, or any combination thereof. In some embodiments, the vaccine is a vaccine against one or more of coronavirus, cholera, dengue fever, diphtheria, Haemophilus influenzae type b infection, hepatitis A, hepatitis B, influenza, Japanese encephalitis, meningococcal meningitis, pertussis, polio, rabies, tetanus, tuberculosis, typhoid fever, and yellow fever. In some embodiments, the vaccine is a coronavirus COVID-19 vaccine.

[0153] In some embodiments, administration of any of the compositions disclosed herein to the subject upregulates Dickkopf-related protein 1 (DKK1), N-acylglucosamine 2-epimerase (RENBP), growth / differentiation factor 15 (GDF15), dermokine (DMKN), ferritin light chain (FTL), tryptophan 2,3-dioxygenase (TDO2), apolipoprotein E (APOE), chitinase 3-like protein 1 (CHI3L1), or nuclear receptor subfamily 4 group A member 2 (NR4A2), or any combination thereof, in the subject. In some embodiments, administration of any of the compositions disclosed herein to the subject downregulates interleukin 11 (IL-11), SPRY domain-containing SOCS box protein 1 (SPSB1), cytochrome P450 26B1 (CYP26B1), or frizzled-8 (FZD8), or any combination thereof, in the subject.

[0154] IV. Composition Some of the embodiments disclosed herein relate to compositions comprising a therapeutically effective amount of SMS cells for promoting or enhancing the repair or regeneration of damaged tissue or improving recovery from viral infections.

[0155] As used herein, "small mobile stem (SMS) cells" refers to a cell or population of cells characterized as adherent cells with a diameter of about 5 μm. SMS cells are of uniform size, are completely radially symmetric, and when observed under an optical microscope, have a spherical nucleus and translucent cytoplasm containing spheroids with different contrasts centered around them. Further, SMS cells exhibit extremely high resistance to various non-physiological conditions such as low or high temperatures, freeze-thawing in standard growth media, dehydration, high pH values, and fluctuations in ionic strength. Additionally, SMS cells are characterized by a high motility of up to about 1.5 μm / second. In some embodiments, the SMS cells are cells obtained from peripheral blood.

[0156] "Therapeutically effective amount" or "effective dosage" is used to indicate the amount of an active compound or pharmaceutical agent that induces a biological or medical response described herein. For example, an effective amount of a compound may be the amount necessary to reduce or alleviate the symptoms of a disease, or the amount necessary to extend the survival rate of a subject undergoing treatment. Such responses may be observed in tissues, systems, animals or humans, and include the alleviation of signs or symptoms of a disease being treated. An effective amount can be readily determined by one of ordinary skill in the art in view of the disclosure herein. The effective amount required for administration of the compounds disclosed herein depends on the route of administration, the type of animal being treated (including humans), and the physical characteristics of the particular animal being treated. The dosage can be adjusted to obtain the desired effect, but is also influenced by factors such as body weight, diet, concomitant medications, and other factors recognized by one of ordinary skill in the medical arts.

[0157] "Pharmaceutically acceptable salts" include relatively non-toxic inorganic acid addition salts, organic acid addition salts or base addition salts of a composition (including, but not limited to, analgesics, therapeutic agents, and other components). Examples of pharmaceutically acceptable salts include salts of inorganic acids such as hydrochloric acid and sulfuric acid, and salts of organic acids such as ethanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid. Examples of inorganic bases suitable for salt formation include phosphates, hydroxides, carbonates, and bicarbonates of ammonia, sodium, lithium, potassium, calcium, magnesium, aluminum, zinc, etc. Salts may also be formed from suitable organic bases, examples of which include non-toxic organic bases strong enough to form such salts. For example, such types of organic bases include monoalkylamines, dialkylamines or trialkylamines such as methylamine, dimethylamine, and triethylamine; monohydroxyalkylamines, dihydroxyalkylamines or trihydroxyalkylamines such as monoethanolamine, diethanolamine, and triethanolamine; amino acids such as glycine, arginine, and lysine; guanidine; N-methylglucosamine; N-methylglucamine; L-glutamine; N-methylpiperazine; morpholine; ethylenediamine; N-benzylphenethylamine; and trihydroxymethylaminoethane, but are not limited thereto.

[0158] As used herein, the terms "formulation", "pharmaceutical composition", and "composition" are used in the same sense as the terms used to refer to the composition of the substance to be administered to a subject.

[0159] "Pharmaceutically acceptable" means compatible with the treatment of a subject, particularly a human.

[0160] "Agent" refers to an active agent that has biological activity and may be used for treatment. Also, the term "agent" is used in the same sense as "at least one agent", "compound" or "at least one compound", and may refer to any form of agent, for example, derivatives, analogs, salts or prodrugs of the agent. The agent may be in various forms, may be a component of a molecular complex, or may be a pharmaceutically acceptable salt (for example, hydrochloride, hydrobromide, sulfate, phosphate, nitrate, borate, acetate, maleate, tartrate and salicylate). Also, "agent" may refer to a pharmaceutical molecule or pharmaceutical compound, a therapeutic molecule or therapeutic compound, a matrix-forming molecule or matrix-forming compound, a polymer, a synthetic molecule or synthetic compound, a natural molecule or natural compound, or any combination thereof.

[0161] In some embodiments, the composition comprises a therapeutically effective amount of small motile stem cells (SMS cells) for use in the repair or regeneration of damaged tissue or the improvement of recovery from viral, fungal or bacterial infections or sequelae thereof in a subject in need thereof. In some embodiments, the viral, fungal or bacterial infection may be an infection by any bacterium, fungus or virus, or any combination of bacteria, fungi or viruses, and such bacteria, fungi or viruses include, for example, coronavirus, poxvirus, variola virus, Marburg virus, flavivirus, influenza virus, parainfluenza virus, RSV, rubella virus, human immunodeficiency virus, human papillomavirus, varicella-zoster virus, herpes simplex virus, cytomegalovirus, Epstein-Barr virus, JC virus, rabies virus, rotavirus, rhinovirus, adenovirus, papillomavirus, parvovirus, picornavirus, poliovirus, hantavirus, filovirus, coxsackievirus, equine encephalitis virus, Rift Valley fever virus, alphavirus, hepatitis A virus, hepatitis B virus, hepatitis C virus, hepatitis D virus, hepatitis E virus, pneumonia, Streptococcus pneumoniae, Staphylococcus aureus, Haemophilus influenzae, Moraxella catarrhalis, anaerobic bacteria, Gram-negative bacteria, Mycoplasma pneumoniae, Chlamydia pneumoniae, group A streptococcus, Klebsiella pneumoniae, Legionella pneumophila, Streptococcus pyogenes, Streptococcus agalactiae, Peptostreptococcus spp., Corynebacterium diphtheriae, Bordetella pertussis, Mycobacterium tuberculosis, Pseudomonas aeruginosa, Escherichia coli, Curvularia spp., Pneumocystis spp., Cryptococcus spp., Histoplasma capsulatum, Aspergillus spp., Mucorales, Fusarium spp., Scedosporium spp., Penicillium spp., or any combination thereof. In some embodiments, the viral infection is an infection with MERS-CoV, SARS-CoV or SARS-CoV-2.In some embodiments, the SMS cells are cells obtained from peripheral blood. In some embodiments, the SMS cells are obtained from a subject, and administration of the cells to the subject is autologous administration. In some embodiments, the SMS cells are obtained from an individual other than the subject, and administration of the cells to the subject is allogeneic administration. In some embodiments, Dickkopf-related protein 1 (DKK1), N-acetylglucosamine 2-epimerase (RENBP), growth / differentiation factor 15 (GDF15), dermokine (DMKN), ferritin light chain (FTL), tryptophan 2,3-dioxygenase (TDO2), apolipoprotein E (APOE), chitinase 3-like protein 1 (CHI3L1), or nuclear receptor subfamily 4 group A member 2 (NR4A2), or any combination thereof, is upregulated in the subject by the composition. In some embodiments, interleukin 11 (IL-11), SPRY domain-containing SOCS box protein 1 (SPSB1), cytochrome P450 26B1 (CYP26B1), or frizzled-8 (FZD8), or any combination thereof, is downregulated in the subject by the composition.

[0162] In some embodiments, the composition is formulated according to an administration method suitable for the subject, such as topical administration, transrespiratory administration, local administration, etc. In some embodiments, the methods of the present disclosure also contemplate systemic administration, enteral administration or parenteral administration, for example, inhalation administration, intranasal administration, subcutaneous administration, intraperitoneal administration, intravenous administration, intramuscular administration, intraarterial administration, oral administration, enteral administration, subdermal administration, transdermal administration, sublingual administration, buccal administration, rectal administration or vaginal administration, etc. are also contemplated. In some embodiments, the composition is formulated for administration using a nebulizer, and this formulation can be inhaled into the lungs or introduced into an inhaler, and this inhaler can be used to introduce the composition into the nasal cavity, paranasal sinuses or pharynx.

[0163] In some embodiments, the composition is formulated as an aerosol depending on the method of administration, for example, formulated into an inhalation formulation suitable for an inhaler or a nebulizer, or formulated into a nasal formulation. In some embodiments, such formulations are suitable for pressurized metered-dose inhalers (pMDIs), dry powder inhalers (DPIs) or soft mist inhalers (SMIs).

[0164] Furthermore, in some embodiments, the use of any of the compositions disclosed herein for the treatment or suppression of inflammatory diseases is disclosed. In some embodiments, the inflammatory disease is an inflammatory disease of the lung. In some embodiments, the inflammatory disease includes fibrosis. In some embodiments, the fibrosis is pulmonary fibrosis, hepatic fibrosis, renal fibrosis or cardiac fibrosis. In some embodiments, the inflammatory disease includes chronic obstructive pulmonary disease (COPD). In some embodiments, the inflammatory disease includes acute respiratory distress syndrome (ARDS). In some embodiments, the inflammatory disease is associated with a viral infection, a fungal infection or a bacterial infection. In some embodiments, the viral infection is a coronavirus infection. In some embodiments, the viral infection is a SARS-CoV infection, a MERS-CoV infection or a SARS-CoV-2 infection.

[0165] In some embodiments, the composition further comprises a therapeutically effective amount of at least one additional compound. In some embodiments, the at least one additional compound is an antibiotic such as azithromycin; an antifungal agent such as voriconazole, amphotericin B, itraconazole; or a vaccine or antiviral agent such as dexamethasone, convalescent serum, tocilizumab, sarilumab, ribavirin, favipiravir, darunavir, galidesivir, interferon α, interferon β, lopinavir, ritonavir, remdesivir, triazavirin, umifenovir, or other known drugs or vaccines used for the treatment, suppression or management of viral infections, or other drugs or vaccines developed for the purpose of treating, suppressing or managing viral infections.

[0166] In some embodiments, the at least one additional compound is a pharmaceutically acceptable carrier, preservative, antioxidant, diluent or additive, or any combination thereof. In some embodiments, the at least one additional compound is a carrier. As used herein, "carrier" refers to a compound that facilitates the uptake of a compound into cells or tissues. Representative carriers include, but are not limited to, water, saline, buffered saline, dextrose, glycerol, ethanol, a partial glyceride mixture of saturated or unsaturated plant fatty acids, wax, a polyethylene polyoxypropylene block polymer, starches such as corn starch and potato starch, and combinations thereof.

[0167] In some embodiments, the at least one additional compound is a diluent. As used herein, "diluent" refers to a component in a pharmaceutical composition that has no pharmacological activity but may be required or desired pharmaceutically. For example, a diluent may be used to increase the volume of a drug when the amount of the effective drug is too small to be manufactured and / or administered. Further, a diluent may be a liquid for dissolving a drug administered by injection, oral ingestion or inhalation. A common form of diluent in the art is a buffered aqueous solution, such as, but not limited to, phosphate buffered saline that mimics the composition of human blood.

[0168] In some embodiments, the at least one additional compound is an additive. As used herein, "additive" refers to an inert substance added to a pharmaceutical composition for the purpose of imparting to the pharmaceutical composition properties such as (but not limited to) volume, viscosity, stability, binding force, lubricity, disintegrating force, etc. "Diluent" is a type of additive. Additives having desired properties include preservatives, adjuvants, stabilizers, solvents, buffers, diluents, solubilizers, detergents, surfactants, chelating agents, antioxidants, alcohols, ketones, aldehydes, ethylenediaminetetraacetic acid (EDTA), citric acid, salts, sodium chloride, sodium bicarbonate, sodium phosphate, sodium borate, sodium citrate, potassium chloride, potassium phosphate, magnesium sulfate, saccharides, dextrose, dextran, fructose, mannose, lactose, galactose, sucrose, sorbitol, cellulose, methylcellulose, hydroxypropylmethylcellulose (hypromellose), glycerin, polyvinyl alcohol, povidone, propylene glycol, serum, amino acids, polyethylene glycol, polysorbate 20, polysorbate 80, sodium deoxycholate, sodium taurodeoxycholate, magnesium stearate, octylphenol ethoxylate, benzethonium chloride, thimerosal, gelatin, esters, ethers, 2-phenoxyethanol, urea or vitamins, or any combination thereof, but not limited thereto. The content of the additive in the pharmaceutical composition may be 0%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 100% (w / w), or a weight percentage within a range bounded by any two of these numerical values as the upper and lower limits.

[0169] In some embodiments, the at least one additional compound is an adjuvant therapy that may be used for the treatment or suppression of viral infections (e.g., SARS-CoV-2 infection), fungal infections, or bacterial infections or sequelae thereof. For example, this adjuvant therapy may be an anti-inflammatory compound, immunotherapy, analgesic, or other suitable therapy. As used herein, "anti-inflammatory compound" refers to a compound for the treatment of inflammation. Examples of anti-inflammatory compounds include, for example, non-steroidal anti-inflammatory drugs (NSAIDs; aspirin, ibuprofen, naproxen, methyl salicylate, diflunisal, indomethacin, sulindac, diclofenac, ketoprofen, ketorolac, carprofen, fenoprofen, mefenamic acid, piroxicam, meloxicam, methotrexate, celecoxib, valdecoxib, parecoxib, etoricoxib, nimesulide, etc.), corticosteroids (prednisone, betamethasone, budesonide, cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, triamcinolone, or fluticasone), rapamycin, compounds that increase high-density lipoprotein (HDL) or HDL cholesterol (rosiglitazone), Rho kinase inhibitors, antimalarial agents (hydroxychloroquine or chloroquine), acetaminophen, glucocorticoids, steroids, beta agonists, anticholinergics, methylxanthines, gold injections (sodium aurothiomalate), sulfasalazine, penicillamine, anti-angiogenic agents, dapsone, psoralen, antiviral agents, or statins.

[0170] The presence, amount, dosage, and ratio of the at least one additional compound may be determined according to the formulation of the composition of the present invention, whether the composition of the present invention is a formulation for external administration, a formulation for oral administration, a formulation for intravenous administration, or other types of formulations. Further, the presence, amount, dosage, and ratio of the at least one additional compound may be determined according to the type of wound, the severity of the wound, pain, the severity of an infectious disease or inflammation, or the intended treatment. Therefore, the amount of the at least one additional compound may be, for example, an amount in the range of 0.001% to 90%, for example, 0.001%, 0.005%, 0.01%, 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 60%, 70%, 80%, or 90%, or an amount within a range having any two of these numerical values as the upper and lower limits.

[0171] When a numerical range is indicated, the upper and lower limit values of the range, and the numerical values between the upper and lower limit values are also included in the above-described embodiment.

[0172] In this specification, “% w / w” or “% wt / wt” has the general meaning understood in light of this specification, and refers to 100 multiplied by the ratio of the weight of a component or drug to the total weight of the composition of the present invention. In this specification, “% v / v” or “% vol / vol” has the general meaning understood in light of this specification, and refers to 100 multiplied by the ratio of the liquid volume of a compound, substance, component, or drug to the total liquid volume of the composition of the present invention.

[0173] To describe various embodiments of the present invention, the present invention is generally disclosed in positive expressions in this specification. The present invention also includes embodiments in which all or part of the subject matter of the present invention, such as substances or materials, process steps and conditions of methods, protocols or procedures, is excluded.

Examples

[0174] In the following examples, some of the aspects of the foregoing embodiments will be disclosed in more detail. However, the following examples do not limit the scope of the present disclosure in any way. As will be understood by those skilled in the art, many other embodiments are also included within the scope of the present invention, as described in this specification and the claims.

[0175] Example 1 Isolation of SMS cells for the preparation of the composition The method for isolating SMS cells for use in the compositions provided herein is shown in the following examples.

[0176] Grow small mobile stem (SMS) cells in a T25 flask containing growth medium (37 °C, 5% CO2). This SMS cell population may contain a heterogeneous cell population consisting of undifferentiated SMS cells and differentiated cells derived from SMS cells.

[0177] Undifferentiated SMS cells are present in both the floating fraction and the adherent fraction. Most of the floating fraction is occupied by undifferentiated SMS cells.

[0178] As previously reported, floating undifferentiated SMS cells, which can be identified by their characteristic morphology, are obtained from the medium of SMS cells cultured in a T25 flask.

[0179] Undifferentiated SMS cells can be isolated by fractionation centrifugation. First, centrifuge at low speed to remove cell clumps or differentiated cells, and then centrifuge at high speed to recover undifferentiated SMS cells. Alternatively, undifferentiated cells may be isolated by filtration, for example, by fractional filtration in which the pore size of the filter is gradually reduced to 3 - 5 μm. The isolated undifferentiated SMS cells are confirmed for uniformity under a microscope.

[0180] Grow undifferentiated SMS cells in polypropylene tubes (e.g., 15 ml bioreactor tubes provided by Techno Plastic Products AG (TPP)).

[0181] As a growth medium, for example, to a basal medium with a high sugar concentration (Dulbecco's Modified Eagle Medium (DMEM), [+] 6 g / L D-glucose, [-] sodium pyruvate, [-] L-glutamine, [-] phenol red), 1% GlutaMAX TM -I (100×), 10% fetal bovine serum, and 5 μg / mL human insulin are added. Alternatively, a medium without fetal bovine serum can also be used. The cells are occasionally suspended by swirling.

[0182] Centrifuge the SMS cells at 4200×g for 15 minutes once a week to precipitate the SMS cells and replace the complete medium. The centrifugation speed may be 3000×g, 3500×g, 4000×g, 4100×g, 4200×g, 4300×g, 4500×g, or 5000×g, or it may be a speed within the range with any two of these speeds as the upper and lower limits, and the centrifugation time is adjusted accordingly.

[0183] Under such conditions, the growth of SMS cells is restricted according to the amount of the medium (cell density). The uniformity of SMS cells is evaluated under a microscope, and the number of SMS cells is estimated by evaluating the turbidity of the cell suspension using a spectrophotometer and / or measuring the size of the pellet after high-speed centrifugation.

[0184] The growth ability of SMS cells is evaluated by inoculating SMS cells into a new tube containing the growth medium. Most of the SMS cells grow as individual cells without forming cell aggregates, and most of them remain undifferentiated under this condition. Suspension culture can be scaled up, and the number of cells obtained can be increased by increasing the amount of the medium.

[0185] Example 2 Treatment of viral infectious diseases using the composition The use of the composition for treating coronavirus infectious disease provided in this specification is shown in the following examples.

[0186] The SMS cells isolated in Example 1 are aerosolized to prepare an aerosol composition, formulated as a nasal preparation for inhalation, or prepared as an intravenous administration preparation. Select severely ill SARS-CoV-2 patients who test positive for COVID-19 infection (confirmed by RT-PCR test or antibody test). Randomly divide the selected subjects into a control group, a test group, and a group treated with various concentrations of SMS.

[0187] The treatment period is at most one week, and the subjects are treated by administering aerosolized SMS cells or SMS cells for intravenous administration daily for 7 days. After the treatment is completed, regular evaluations are performed over a period of 60 days. Specifically, evaluations are performed daily from the 1st day to the 7th day after treatment; evaluations are performed twice a week from the 8th day to the 14th day after treatment, once a week from the 3rd week to the 4th week after treatment, and once every two weeks during the remaining evaluation period.

[0188] The subjects are evaluated based on several outcomes. Examples of the methods for evaluating the subjects include, for example, the time to weaning from mechanical ventilation, the time until the end of monitoring in the ICU, or the time to clinical improvement measured from the time until the end of administration of vasopressors; mortality; the frequency and characteristics of adverse events and serious adverse events; tolerance; pulmonary function tests; lymphocyte counts; complete blood counts; biochemical routine tests; and / or chest radiograph examinations.

[0189] The subjects treated with the composition described in this specification have an improved survival rate and improved symptoms related to viral infections.

[0190] Example 3 Animal safety test of SMS cell therapy The acute toxicity was evaluated when a preparation was prepared by suspending live SMS cells in a lactated Ringer's solution containing 5% rat serum and this suspension preparation was repeatedly administered by intravenous injection. This study was conducted in accordance with the following research protocol and appropriate standard operating procedure manuals.

[0191] Two (n = 2) male Sprague Dawley rats were used. They were randomly assigned one each to the test group and the control group. The test substance and the control substance were prepared and gradually administered intravenously from the tail vein at a rate of approximately 0.1 mL / second using a 25G needle. Test substance: Live SMS cells suspended in lactated Ringer's solution (B. Braun #L7500) containing 5% rat serum (Sigma #R9759). Control substance: Lactated Ringer's solution (B. Braun #L7500) containing 5% rat serum (Sigma #R9759). The test substance or the control substance was administered on days 1, 3, and 5. Each dosage was calculated based on the body weight at the start of the test.

[0192] On the day of administration, the rats were observed individually at least three times. After the last administration, the rats were observed at least once a day. The body weights of the rats were measured on the day of administration (day 1), day 8, and day 14, and the changes in body weight were observed. On the last day of the test (day 15), the rats were euthanized, their body weights were measured, and gross anatomy was performed. On the last day of the test (day 15), a blood sample (1 mL) was collected by cardiac puncture, and the obtained blood sample was processed to obtain plasma. The plasma was stored frozen until use.

[0193] Results: During the test, all the rats appeared healthy, and no significant biological abnormalities were observed. After administration, the body weights of both the test rats and the control rats decreased slightly, but an overall increase in body weight was observed on days 8 and 14. No abnormalities were found during gross anatomy.

[0194] Conclusion: Both the test substance and the control substance showed high tolerance when administered intravenously at a dosage of approximately 0.2 mL per rat on days 1, 3, and 5. No signs of toxicity were observed in any of the tested rats, and an increase in body weight was seen before sacrifice. During gross anatomy, all the major organs were normal. The summarized results are shown in Tables 1 - 3.

Table 1

Table 2

Table 3

[0195] Example 4 Interaction between SMS cells and mesenchymal stem cells Adhesion of SMS cells to human adipose-derived mesenchymal stem cells

[0196] Commercially available primary human adipose-derived mesenchymal stem cells (StemPro TM human adipose-derived stem cells, Gibco, #R7788115) were purchased from Thermo Fisher Scientific. Thawed human adipose-derived mesenchymal stem cells cryopreserved in liquid nitrogen were seeded at a density of 2100 cells / cm 2 in a 24-well culture plate containing DMEM medium supplemented with 10% human serum and 0.2% antibiotics (gentamicin / amphotericin) and cultured for 5 days. Fluorescently stained SMS cells were added to the adherent human adipose-derived mesenchymal stem cells. The co-culture was incubated overnight and each well was washed with growth medium. Images were taken using an inverted fluorescence microscope. From the fluorescence of the captured images, it was confirmed that SMS cells strongly adhered to human adipose-derived mesenchymal stem cells (Figure 1A).

[0197] The adherent human adipose-derived mesenchymal stem cells and the SMS cells adhered thereto were detached from the surface of the well by a standard trypsinization protocol and analyzed using a flow cytometer (CytoFLEX) to detect the fluorescence of FITC. Since the fluorescence was positive in human adipose-derived mesenchymal stem cells, it was shown that SMS cells strongly adhered to human adipose-derived mesenchymal stem cells and this adhesion was maintained (Figure 1B). The adhesion between these two types of cells was maintained even after detaching the human adipose-derived mesenchymal stem cells from the well by trypsin treatment.

[0198] Stimulation of human adipose-derived mesenchymal stem cells by SMS cells

[0199] Commercially available human adipose-derived primary mesenchymal stem cells (StemPro TM human adipose-derived stem cells, Gibco, #R7788115) were purchased from Thermo Fisher Scientific. Thawed human adipose-derived mesenchymal stem cells cryopreserved in liquid nitrogen were placed in a 24-well culture plate containing DMEM medium supplemented with 10% human serum and 0.2% antibiotics (gentamicin / amphotericin) and cultured at a density of 2100 cells / cm 2 for 5 days. After transferring human adipose-derived mesenchymal stem cells to a flask and culturing them for 2 days (54.5 hours), SMS cells were added to the flask labeled "treated with SMS". Five days later, before reaching confluence, human adipose-derived mesenchymal stem cells to which SMS cells were added (the "treated" cells) or human adipose-derived mesenchymal stem cells to which SMS cells were not added (control) were detached and collected simultaneously using a standard trypsinization protocol. The collected cells were counted using appropriate gate parameters (8 - 48 μm) on a Countess Automated Cell Counter (Invitrogen). From the results of cell counting, it was shown that adding SMS cells to human adipose-derived mesenchymal stem cells cultured under optimal in vitro conditions further stimulated the growth and proliferation of human adipose-derived mesenchymal stem cells (Figure 1C).

[0200] Example 5 Interaction between SMS cells and fibroblasts Adhesion of SMS cells to human fibroblasts

[0201] Commercially available human dermal fibroblasts were purchased from Lonza Scientific (CC-2511). Thawed human-derived fibroblasts cryopreserved in liquid nitrogen were placed in a 24-well culture plate containing DMEM medium supplemented with 10% human serum and 0.2% antibiotics (gentamicin / amphotericin) and cultured at a density of 2100 cells / cm 2They were cultured at a density of . Fluorescently stained SMS cells were added to the cultured fibroblasts. This co-culture was incubated overnight, and each well was washed with growth medium. Images were taken using an inverted fluorescence microscope. From the fluorescence of the captured images, it was confirmed that SMS cells strongly adhered to human skin fibroblasts (Figure 2A).

[0202] The adherent cultured human fibroblasts and the SMS cells adhered thereto were detached from the surface of the well by a standard trypsin treatment detachment protocol and analyzed using a flow cytometer (CytoFLEX) to detect the fluorescence of FITC. As a result of the analysis by flow cytometry, since the fluorescence was positive in human fibroblasts, it was shown that SMS cells strongly adhered to human fibroblasts and this adhesion was maintained (Figure 2B). The adhesion between these two types of cells was maintained even after detaching human fibroblasts from the well by trypsin treatment.

[0203] Inhibition of fibroblast proliferation by SMS cells

[0204] Fibroblasts (Fb) were seeded at a density of 1500 cells / cm 2 in a 48-well plate containing DMEM medium supplemented with 10% fetal bovine serum and incubated under standard culture conditions (37 °C, 10% CO2). The medium was changed after 24 hours. As shown in Table 4, SMS cells at various dilution ratios (1, 1 / 3, 1 / 9, 1 / 27, 1 / 81 or a control without adding SMS cells) were added to each well in triplicate. This co-culture was incubated under standard culture conditions (37 °C, 10% CO2) for 4 days in DMEM medium supplemented with 10% fetal bovine serum. After incubation, the cells were washed, detached by trypsin treatment, and counted using a Countess Automated Cell Counter (Invitrogen). From the results of counting the cells, it was shown that the growth of fibroblasts was significantly suppressed in proportion to the exposure amount to SMS cells (Figure 2C).

Table 4

[0205] Example 6 Interaction between SMS cells and alveolar epithelial cells Isolation and culture of primary type II alveolar epithelial cells

[0206] Commercially available human primary type I alveolar epithelial cells and human primary type II alveolar epithelial cells were purchased from ScienCell Research Laboratories (HPAEpiC, #3200). The human primary type I alveolar epithelial cells and human primary type II alveolar epithelial cells cryopreserved in liquid nitrogen were thawed. The content of the vial was transferred to a poly-L-lysine-coated T75 culture flask equilibrated with alveolar epithelial cell medium (ScienCell, AEpiCM, #3201) supplemented with 2% fetal bovine serum, 1% epithelial cell growth supplement (ScienCell, EpiCGS, #4152) and 1% penicillin / streptomycin, and cultured at 37 °C in a 5% CO2 incubator. The seeding density was 10,000 cells / cm 2 2. The medium was changed three times a week. Type II alveolar epithelial cells were grown by continuous culture for 2 weeks to eliminate non-proliferative type I alveolar epithelial cells. The human primary type II alveolar epithelial cells were detached from the culture vessel by trypsin treatment and frozen in cryopreservation medium.

[0207] Fluorescently stained SMS cells were added to the human primary type II alveolar epithelial cells adhered and cultured after isolation. This co-culture was incubated overnight and each well was washed with growth medium. Imaging was performed using an inverted fluorescence microscope. It was confirmed from the captured images that SMS cells adhered strongly to the human primary type II alveolar epithelial cells (Figure 3A).

[0208] Next, the cultured primary human type II alveolar epithelial cells and the SMS cells adhered to them were detached from the well surface by a standard trypsin treatment detachment protocol and analyzed using a flow cytometer (CytoFLEX) to detect the fluorescence of FITC. As a result of the analysis by flow cytometry, since the fluorescence was positive in the primary human type II alveolar epithelial cells, it was shown that the SMS cells strongly adhered to the primary human type II alveolar epithelial cells and this adhesion was maintained (Figure 3B). The adhesion between these two types of cells was maintained even after detaching the alveolar epithelial cells from the well by trypsin treatment.

[0209] Stimulation of human primary type II alveolar epithelial cells by SMS cells in the absence of fetal bovine serum

[0210] The primary human type II alveolar epithelial cells cryopreserved after isolation were thawed in an alveolar epithelial cell medium supplemented with 1% epithelial cell growth supplement in the absence of 2% fetal bovine serum.

[0211] After transferring the type II alveolar epithelial cells to a flask and culturing them for 3 days (74.5 hours), SMS cells were added to the flask of type II alveolar epithelial cells labeled "treated with SMS". Eight days later, before reaching confluence, the cells with SMS cells added ("treated") or the cells without SMS cells added (control) were simultaneously collected by detaching them according to a standard trypsin treatment protocol. The collected cells were counted using appropriate gate parameters (8 - 60 μm) in a Countess Automated Cell Counter (Invitrogen). From the result of counting the cells, it was shown that adding SMS cells to primary human type II alveolar epithelial cells cultured under in vitro conditions with serum removed stimulated the growth and proliferation of the primary human type II alveolar epithelial cells (Figure 3C).

[0212] Differential gene expression of human type II alveolar epithelial cells in the presence of stimulation by SMS cells and in the absence of fetal bovine serum

[0213] Differential gene expression was detected using human type II alveolar epithelial cells cultured with the addition of SMS cells and human type II alveolar epithelial cells cultured without the addition of SMS cells (the above reference). Each cell was centrifuged and resuspended in pre-cooled PBS to adjust the density of each cell to 300,000 or more per 100 μL. The supernatant was removed so that the pellet would not break, and it was placed in a -80 °C freezer for instant freezing. The pellet was packaged with dry ice and sent to Active Motif for mRNA analysis. Total RNA was isolated from the cells, sequenced to identify individual RNAs, and their relative amounts were evaluated. Using DESeq2 (available from bioconductor.org / packages / release / bioc / html / DESeq2.html on the World Wide Web), the fold change and the log2 fold change (logFC) determined by the shrunken centroid method were calculated. From the results of RNA analysis of human type II alveolar epithelial cells, it was shown that 764 genes were upregulated and 546 genes were downregulated by the interaction with SMS cells in vitro (Table 5). Among the top 40 genes with the largest changes between the group treated with SMS cells and the control group, 13 representative genes and their expression levels are shown in Table 6. When the ratio of the logFC of the untreated condition to the logFC of the treated condition determined by the shrunken centroid method is a negative value, it indicates that the gene expression level increased after treatment with SMS cells, and when the ratio of the logFC of the untreated condition to the logFC of the treated condition determined by the shrunken centroid method is a positive value, it indicates that the gene expression level decreased after treatment with SMS cells. For detailed information on DESeq2, see Love et al., “Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2” Genome Biology (2014) 15(12):550 (this reference is incorporated herein by reference in its entirety). The logFC determined by the shrunken centroid method is a more accurate estimated value of the log2 fold change considering cases with low count numbers or large variations, and it does not have a significant impact on the results of differential gene expression.

[0214] Examples of genes upregulated in type II alveolar epithelial cells treated with SMS cells include Dickkopf-related protein 1 (DKK1), N-acetylglucosamine 2-epimerase (RENBP), growth / differentiation factor 15 (GDF15), dermokine (DMKN), ferritin light chain (FTL), tryptophan 2,3-dioxygenase (TDO2), apolipoprotein E (APOE), chitinase 3-like protein 1 (CHI3L1), and nuclear receptor subfamily 4 group A member 2 (NR4A2).

[0215] Examples of genes downregulated in type II alveolar epithelial cells treated with SMS cells include interleukin 11 (IL-11), SPRY domain-containing SOCS box protein 1 (SPSB1), cytochrome P450 26B1 (CYP26B1), and frizzled-8 (FZD8).

[0216] From the identification results of the regulated genes, it was shown that treatment with SMS cells has an anti-inflammatory effect, a blood vessel diameter expansion effect, a cell differentiation inhibition effect, a cell proliferation enhancement effect, and a protective enhancement effect against pathogens. [Table 5] [Table 6]

[0217] Example 7 Treatment of inflammatory diseases by SMS cells The subject presents with an inflammatory disease. Examples of inflammatory diseases include fibrosis such as pulmonary fibrosis; chronic obstructive pulmonary disease (COPD); or inflammation due to infection with a pathogen such as a viral infection (e.g., SARS-CoV-2 infection), but are not limited thereto.

[0218] The pharmaceutical composition of SMS cells is administered to the subject by enteral administration, oral administration, intranasal administration, parenteral administration, subcutaneous administration, intramuscular administration, intradermal administration or intravenous administration. This pharmaceutical composition may contain 10 3 cells, 10 4 cells, 10 5 cells, 10 6 cells, 10 7 cells, 10 8 cells, 10 9 cells, 10 10 cells, or 10 11 cells of SMS cells, or may contain a number of SMS cells within a range having any two of these numerical values as the upper and lower limits. The number of administrations of the pharmaceutical composition may be 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 times, and may be at least 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 times. When multiple administrations are performed, the administration interval may be once a day, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once every 7 days, once every 8 days, once every 9 days, once every 10 days, once every 11 days, once every 12 days, once every 24 days, once every 36 days, or once every 48 days, and may be once a week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, once every 6 weeks, once every 7 weeks, once every 8 weeks, once every 9 weeks, once every 10 weeks, once every 11 weeks, once every 12 weeks, once every 24 weeks, once every 36 weeks, or once every 48 weeks, and may be a time within a range having any two of these times as the upper and lower limits.

[0219] After administering the pharmaceutical composition of SMS cells, improvement of an inflammatory disease or its symptoms is observed in the subject.

[0220] In some embodiments, the pharmaceutical composition of SMS cells may be administered in combination with another standard treatment. For example, when the inflammatory disease is related to a viral infection, antiviral treatment may be performed on the subject, and examples of this antiviral treatment include, for example, dexamethasone, convalescent serum, tocilizumab, sarilumab, ribavirin, favipiravir, darunavir, galidesivir, interferon α, interferon β, lopinavir, ritonavir, remdesivir, triazavirin, umifenovir, or other standard antiviral treatments.

[0221] In at least some of the foregoing embodiments, one or more of the components used in these embodiments can be used interchangeably with the components of another embodiment, unless technically impossible. It will be readily understood by those skilled in the art that various omissions, additions, and modifications other than those described above may be made to the above-described methods and structures without departing from the scope of the subject matter claimed. All such modifications and changes are considered to be within the scope of the subject matter of the present invention as defined by the appended claims.

[0222] As used herein, terms in substantially plural and / or singular forms can be interpreted by those skilled in the art as plural terms as singular terms and / or singular terms as plural terms, as appropriate for the description and / or use herein. For the sake of clarity of the present invention, various singular / plural terms are intentionally used distinctively.

[0223] One of ordinary skill in the art will understand that the terms described herein, particularly the terms described in the appended claims (e.g., the main body of the appended claims), are generally "open-ended" terms (e.g., the term "including" should be construed as "including, but not limited to", the term "having" should be construed as "having at least", and the term "include" should be construed as "including, but not limited to"). Further, one of ordinary skill in the art will understand that if a specific number is recited in a claim, the foregoing intent is also clearly recited in the claim, and if no specific number is recited, such intent does not exist. Specifically, for example, in the claims described hereinafter, there may be a preamble such as "at least one" or "one or more" for defining the claim. However, just because such a preamble is recited, a claim in which an element is recited using the indefinite article "a" or "an" should not be limited to an embodiment including only one element, and even if the same claim includes both a preamble such as "one or more" or "at least one" and an indefinite article such as "a" or "an", it should not be limited to an embodiment including only one element (e.g., "a" and / or "an" should be construed as meaning "at least one" or "one or more"). This is the same for claims recited using the definite article. Also, even if a specific number is clearly recited in a claim, one of ordinary skill in the art will understand that it is the number with the "at least" recited (e.g., the recitation of "two" without a modifier means "at least two" or "two or more").Furthermore, when frequently used phrases such as "at least one of A, B, and C" are used, usually, such phrases are described in the meaning that those skilled in the art would normally understand them (for example, "a system having at least one of A, B, and C" includes, but is not limited to, a system having only A, a system having only B, a system having only C, a system having A and B, a system having A and C, a system having B and C, and / or a system having A, B, and C, etc.). Also, when frequently used phrases such as "at least one of A, B, or C" are used, usually, such phrases are described in the meaning that those skilled in the art would normally understand them (for example, "a system having at least one of A, B, or C" includes, but is not limited to, a system having only A, a system having only B, a system having only C, a system having A and B, a system having A and C, a system having B and C, and / or a system having A, B, and C, etc.). Furthermore, those skilled in the art would understand that disjunctive terms and / or disjunctive phrases for representing two or more alternatives may include one of the recited terms, any of the recited terms, or both of the recited terms in any of the specification, claims, or drawings. For example, the expression "A or B" may include "only A" or "only B" or "A and B".

[0224] Furthermore, if the features or aspects of the present disclosure are described in Markush form, those skilled in the art would understand that each member described in Markush form or subgroups consisting of them are also described.

[0225] For any purpose such as providing a detailed description, those skilled in the art will understand that any range described in this specification includes all possible partial ranges and combinations thereof. Any of the above ranges are fully described as being divided at least into equal parts, thirds, fourths, fifths, tenths, etc. of the same range, and it will be easily understood that the present invention can be implemented within such divided ranges. For example, any range described in this specification can be easily divided into thirds such as low, medium, and high ranges, but is not limited thereto. Also, terms such as "below", "at least", "greater than", "less than" all include the recited numerical values and, as described above, also refer to ranges that can be divided into partial ranges, which those skilled in the art will understand. Furthermore, those skilled in the art will understand that the ranges described in this specification include each member. Thus, for example, a group having 1 to 3 members refers to a group having 1 member, a group having 2 members, or a group having 3 members. Similarly, a group having 1 to 5 members refers to a group having 1 member, a group having 2 members, a group having 3 members, a group having 4 members, or a group having 5 members, etc.

[0226] Although various aspects and embodiments have been described in this specification, those skilled in the art will easily understand other aspects and embodiments. The various aspects and embodiments disclosed in this specification are for the purpose of explaining the present invention and do not limit the present invention in any way. The scope and gist of the present invention are indicated by the following claims.

Claims

**Claim 1** A composition comprising a therapeutically effective amount of small mobile stem (SMS) cells for use in promoting or improving recovery from viral, bacterial or fungal infections or sequelae thereof in a subject. **Claim 2** The composition according to claim 1, wherein the viral infection is caused by a single-stranded RNA virus, double-stranded RNA virus, plus-sense single-stranded RNA virus, minus-sense single-stranded RNA virus, double-stranded DNA virus or single-stranded DNA virus. **Claim 3** The viral, bacterial or fungal infection or sequelae thereof is caused by infection with coronavirus, poxvirus, variola virus, Marburg virus, flavivirus, influenza virus, parainfluenza virus, RS virus, rubella virus, human immunodeficiency virus, human papillomavirus, varicella-zoster virus, herpes simplex virus, cytomegalovirus, Epstein-Barr virus, JC virus, rabies virus, rotavirus, rhinovirus, adenovirus, papillomavirus, parvovirus, picornavirus, poliovirus, hantavirus, filovirus, coxsackievirus, equine encephalitis virus, Rift Valley fever virus, alphavirus, hepatitis A virus, hepatitis B virus, hepatitis C virus, hepatitis D virus, hepatitis E virus, Streptococcus pneumoniae, Staphylococcus aureus, Haemophilus influenzae, Moraxella catarrhalis, anaerobic bacteria, Gram-negative bacteria, Mycoplasma pneumoniae, Chlamydia pneumoniae, group A streptococcus, Klebsiella pneumoniae, Legionella pneumophila, Streptococcus pyogenes, Streptococcus agalactiae, Peptostreptococcus spp., Corynebacterium diphtheriae, Bordetella pertussis, Mycobacterium tuberculosis, Pseudomonas aeruginosa, Escherichia coli, Curvularia spp., Pneumocystis spp., Cryptococcus spp., Histoplasma capsulatum, Aspergillus spp., Mucorales, Fusarium spp., Scedosporium spp., Penicillium spp., or any combination thereof, preferably caused by infection with MERS-CoV, SARS-CoV or SARS-CoV-2, the composition according to claim 1 or 2. **Claim 4** The composition according to any one of claims 1 to 3, wherein the SMS cells are cells obtained from peripheral blood.

5. The composition according to any one of claims 1 to 4, wherein the SMS cells are cells of the same species as the subject.

6. The composition according to any one of claims 1 to 4, wherein the SMS cells are autologous cells obtained from the subject.

7. The composition according to any one of claims 1 to 6, wherein the subject has damaged lung tissue.

8. The composition according to any one of claims 1 to 7, wherein the composition reduces or suppresses alveolar cell injury, reduces or suppresses respiratory endothelial cell injury, increases or improves the repair of damaged lung tissue, increases or enhances the regeneration of damaged lung tissue, or reduces the onset of pulmonary fibrosis, or achieves any combination thereof.

9. The composition according to any one of claims 1 to 8, comprising aerosolized SMS cells.

10. The composition according to any one of claims 1 to 9, formulated for intravenous administration.

11. The composition according to any one of claims 1 to 10, further comprising an antibiotic such as azithromycin, an antifungal agent such as voriconazole, amphotericin B, itraconazole, a vaccine, or an antiviral agent such as remdesivir.

12. The composition according to claim 11, wherein the vaccine is a vaccine against one or more of coronavirus, cholera, dengue fever, diphtheria, Haemophilus influenzae type b infection, hepatitis A, hepatitis B, influenza, Japanese encephalitis, meningococcal meningitis, whooping cough, polio, rabies, tetanus, tuberculosis, typhoid fever, and yellow fever.

13. The composition according to claim 12, wherein the vaccine is a coronavirus COVID-19 vaccine.

14. The composition according to any one of claims 1 to 13, further comprising a pharmaceutically acceptable carrier, preservative, antioxidant, diluent, or additive, or any combination thereof.

15. The composition according to any one of claims 1 to 14, wherein Dickkopf-related protein 1 (DKK1), N-acylglucosamine 2-epimerase (RENBP), growth / differentiation factor 15 (GDF15), dermokine (DMKN), ferritin light chain (FTL), tryptophan 2,3-dioxygenase (TDO2), apolipoprotein E (APOE), chitinase 3-like protein 1 (CHI3L1), or nuclear receptor subfamily 4 group A member 2 (NR4A2), or any combination thereof is upregulated in the subject.

16. The composition according to any one of claims 1 to 15, wherein interleukin 11 (IL-11), SPRY domain-containing SOCS box protein 1 (SPSB1), cytochrome P450 26B1 (CYP26B1), or frizzled-8 (FZD8), or any combination thereof is downregulated in the subject.

17. A composition comprising a therapeutically effective amount of small mobile stem (SMS) cells for use in the treatment or suppression of an inflammatory disease in a subject, wherein the inflammatory disease is chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS), or fibrosis such as pulmonary fibrosis, liver fibrosis, renal fibrosis, or cardiac fibrosis, or the inflammatory disease is associated with a viral infection, a bacterial infection, or a fungal infection.

18. The composition according to claim 17, wherein the viral infection is a coronavirus infection.

19. The composition according to claim 18, wherein the viral infection is a SARS-CoV infection, a MERS-CoV infection, or a SARS-CoV-2 infection.

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