The rising role of mesenchymal stem cells in the treatment of COVID-19 infections

Infectious diseases are a leading cause of death worldwide [1,2]. The Mid-20th century witnessed most of the antimicrobial discoveries but recently there is dramatic shortage of new classes of antimicrobial agents due to failure to build a sustainable antimicrobial discovery platform [1-4]. For example, antibiotics comprise ˂ 1.5% of the compounds under investigation at the major pharmaceutical and biotechnology companies [1,5]. Recently, the pipeline for new antimicrobials has become extremely dry as pharmaceutical companies largely withdrew in the late 1990s due to: antimicrobial therapy being less profitable than medications used to treat cancer and other chronic medical conditions; difficulty in discovering novel and efficient antimicrobials; complexity of conducting controlled clinical trials; and emergence of multidrug resistant organisms [1,6-13].

Dozens of viruses constantly infect human beings and represent sustained health and economic burden [14]. Between 1975 and 2015, > 50 new viruses that cause human disease have been described [15]. The emergence of high morbidity viruses such as: severe acute respiratory syndrome coronavirus (SARS-CoV) in 2004, the Middle East respiratory syndrome (MERS-CoV) in 2012, and human metapneumovirus in 2001 represent global threats and highlight the importance of international collaboration on respiratory virus research [14,16]. The development of antiviral drugs is slow, complicated and full of hurdles [15]. Between 1963 and 2016, approximately 90 antiviral drugs have been approved for the treatment of several viruses including herpersviruses, hepatitis B and C viruses, and human immunodeficiency virus [15,17]. Drug resistant viral mutants which are frequently encountered in RNA viruses represent a major problem in antiviral therapy [18]. There is urgent need to control viral infections that cause human diseases particularly those caused by drug-resistant viruses [14]. Broad-spectrum antiviral agents can cover multiple viruses and reduce the likelihood of developing drug resistance [14,19]. Unfortunately, no specific antiviral drugs or vaccines are available for Coronaviridae in general [17,19].

Coronavirus disease 2019 (COVID-19) pandemic has already caused massive life losses all over the globe and has practically disturbed almost every single aspect of life and its repercussions have adversely affected world economy [20-22]. Clinically, patients with COVID-19 present predominantly with fever and respiratory manifestations but the illness may be complicated by severe pneumonia, acute respiratory distress syndrome (ARDS), and respiratory failure that may be followed by multiorgan failure and death [20,21,23-26]. The pathogenesis of COVID-19 involves: immune-mediated mechanisms; direct cytotoxicity; antibody-dependent enhancement; viral sepsis; severe pneumonia, ARDS, respiratory failure followed by multiorgan failure; and cytokine storm with significant elevation of proinflammatory cytokines [27-30]. SARS-CoV-2 infects lung alveolar epithelial cells by receptor-mediated endocytosis in association with angiotensin converting enzyme 2 (ACE-2) [31,32]. Myocardial injury associated with COVID-19 can be explained by: direct infection through ACE-2, imbalance between myocardial oxygen supply and demand, and the presence of an abnormal immune response [31-33]. In patients with COVID-19, high levels of neutrophil extracellular traps (NETs) have been documented and the release of NETs (NETosis) may be responsible for many of the serious complications associated with COVID-19 including: ARDS, respiratory failure, cytokine storm, thromboembolic complications, and acute organ dysfunction that leads to multiorgan failure [34-37]. Leukemia inhibitory factor, which belongs to the interleukin-6 family of cytokines, could protect the lungs from further injury during pneumonia and may enhance endogenous cardiomyocyte regeneration following myocardial infarction and hence it may be useful in patients with COVID-19 pneumonia with cardiac decompensation [38,39]. In the absence of specific antiviral treatment and vaccines, the available therapeutic interventions are: symptomatic measures and supportive care including: oxygen administration, non-invasive ventilation, and mechanical ventilation; drug repurposing using mainly antiviral agents, anti-inflammatory drugs, and monoclonal antibodies; and other lines of treatment including use of convalescent plasma, removal of cytokines, Chinese traditional medicines, and mesenchymal stem cell (MSC) therapies [21,24,26,40,41].

MSCs have antimicrobial, anti-inflammatory and immunomodulatory properties and they have been used in the treatment of several infectious diseases and their complications such as ARDS both in animal models and in human clinical trials [42-49]. MSCs derived from umbilical cord blood (UCB) and adipose tissue are more advantageous than other sources of MSCs [50-55]. MSCs exhibit the following antimicrobial properties: detection and elimination of the invading pathogen by enhancing bacterial clearance; activation of the host immune response by induction of proinflammatory gradients or responses; and secretion of antimicrobial proteins [43,53,56]. MSCs have the following effects on the lungs: immunomodulatory effects; protection of alveolar epithelial cells; restoration of pulmonary microenvironment; prevention of pulmonary fibrosis; reversal of pulmonary dysfunction and control of COVID-19 pneumonia; prevention of cytokine release; and promotion of endogenous repair. Also, after intravenous (IV) administration, a significant proportion of MSCs accumulate in the lungs so a limitation can become an advantage in case of acute lung injury (ALI) or ARDS [54,57]. Additionally, MSCs have been found to modulate the functions of the following immune cells: T-cells, B-cells, natural killer cells (NKCs), dendritic cells (DCs), cytotoxic T-cells, macrophages, and neutrophils [58].

MSCs produce biologically active substances, secretomes, that are made of extracellular vesicles including exosomes, microvesicles and apoptotic bodies; soluble proteins such as cytokines, chemokines, and growth factors; lipids; nucleic acids; and conditioned media [59-64]. Advantages of secretomes include: ability to bypass the side effects of MSC-based therapy thus they are generally safer than MSCs; immediate availability for emergency use in the treatment of acute conditions; massive production from commercially available cell lines; the technical advantage of being manipulated and stored more easily than MSCs; and the lower costs compared to other therapeutic interventions such as ticilizumab [59-61]. Therapeutic effects of MSC-secretomes include: antimicrobial effects; suppression of cytokine production in ALI; enhancement of wound healing and tissue repair; anti-oxidant effects; immunomodulatory and immunosuppressive effects; regulation of angiogenesis and suppression of collagen deposition in lung tissues; as well as antitumor effects and neuroprotective effects [59-64]. After IV injection of MSC-secretome, the secretome remains highly stable in the peripheral circulation and it spreads into lung tissues to provide: immunomodulation, resolution of inflammation, restoration of capillary barrier function, and enhancement of bacterial clearance [59]. Recently it has been shown that MSCs and their secretomes have promising results in the treatment of sepsis, viral pneumonia, ALI, and ARDS thus making the secretory products of MSCs superior to pure cellular therapies [56,57,62]. MSC-secretome acts on several cytokines simultaneously and synergistically and if MSC-secretome can be formulated as a freeze-dried powder and administered as IV or by inhalation, it may represent a suitable approach for the treatment of COVID-19 pneumonia particularly in patients who are critically ill [59].

Since January 2020, several reports have been published on the success of MSC therapies in the treatment of COVID-19 complications in conjunction with other therapeutic modalities [65-68]. There are two published studies from China on the use of MSCs in the treatment of COVID-19: one included 7 patients and the second one was a single case report [65-67]. Recently, 2 commercial companies; Pluristem and Mesoblast; made press releases announcing their preliminary results on the use of MSCs in the treatment of patients having severe COVID-19 [54,69,70]. Countries such as China, the United States of America, Jordan, and Iran have begun using cellular therapies in clinical trials for the treatment of COVID-19 infections with approximately 70 registered trials, 20 of them in China. The vast majority of trials use MSCs derived from UCB and some trials are using: NKCs, embryonic stem cells, and products of MSCs such as exosomes and few of these trials use the combination of MSCs and NKCs or ruxolitinib [53,57,71]. In China, at least 4 clinical trials on the use of MSCs in the treatment of COVID-19 pneumonia, mainly using UCB-MSCs were registered in February and March 2020 [53]. Currently, MSCs are being tested in several clinical trials including: NCT04269525, NCT04288102, and NCT04252118 [57,67,71,72].

The following are required before adopting MSCs in the treatment of COVID-19 infections: updated minimal criteria for characterization of cellular therapies; updated guidelines on the use of cellular therapies in infectious diseases; updated cell therapy routines that reflect specific needs of patients requiring this form of treatment; and the use of ACE2 negative MSCs in the treatment of patients with COVID-19 having ALI and ARDS [73-75]. In the era of COVID-19 pandemic, several groups of scientists from all over the world have recommended the use of MSCs in the treatment of severe COVID-19 infections as MSCs and their secretomes have the following beneficial effects: suppression of viral replication; enhancement of the generation of regulatory T-cells that are suppressed by COVID-19; shifting the phenotype of antigen presenting cells including DCs, B-lymphocytes, and macrophages; modulation of the proliferation and activation of naïve and effector T-cells, NKCs, and mononuclear cells; prevention of the formation of NETs; inhibition of the cytokine storm induced by COVID-19; the antiviral, antibacterial, and analgesic effects of MSC-secretomes; reduction in pulmonary edema associated with ARDS in COVID-19; entrapment of IV infused MSCs in the lungs; enhancement of tissue regeneration and promotion of endogenous repair and healing in ALI; as well as safety and efficacy of MSCs and their products provided good manufacturing practice guidelines and quality control measures are taken into consideration [8,13,34,44,52,54,73,75-86].

So, the emergence of new viruses that cause serious human infections is faced with slow and complicated antiviral drug development. In the absence of specific and curative antiviral therapy for COVID-19, plenty of medications are being repurposed with variable efficacy. MSCs and their secretomes are recommended by several groups of scientists as they can potentially control several complications of COVID-19 infections such as pneumonia, ARDS, ALI, and the associated cytokine storm.

1. Spellberg B, Powers JH, Brass EP, Miller LG, Edwards JE Jr. Trends in antimicrobial drug development: implications for the future. Clin Infect Dis. 2004; 38: 1279‐1286. PubMed: https://pubmed.ncbi.nlm.nih.gov/15127341/
2. Hoffman PS. Antibacterial discovery: 21st century challenges. Antibiotics (Basel). 2020; 9: E213. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/32353943
3. Piddock L, Garneau-Tsodikova S, Garner C. Ask the experts: how to curb antibiotic resistance and plug the antibiotics gap? Future Med Chem. 2016; 8: 1027‐1032. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/27327784
4. Stehr M, Elamin AA, Singh M. Filling the pipeline - new drugs for an old disease. Curr Top Med Chem. 2014; 14: 110‐129. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/24236723
5. Gottfried J. History repeating? Avoiding the return to the pre-antibiotic age. Harvard University’s DASH Repository. 2005; 1-72. http://dash/harvard.edu/bitstream/handle/1/8889467/Gottfried05.pdf?sequence=1  
6. Jackson N, Czaplewski L, Piddock LJV. Discovery and development of new antibacterial drugs: learning from experience? J Antimicrob Chemother. 2018; 73: 1452‐1459. PubMed: https://pubmed.ncbi.nlm.nih.gov/29438542/
7. Luepke KH, Mohr JF 3rd. The antibiotic pipeline: reviving research and development and speeding drugs to market. Expert Rev Anti Infect Ther. 2017; 15: 425‐433. PubMed: https://pubmed.ncbi.nlm.nih.gov/28306360/
8. Metlay JP, Powers JH, Dudley MN, Christiansen K, Finch RG. Antimicrobial drug resistance, regulation, and research. Emerg Infect Dis. 2006; 12: 183‐190. PubMed: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3373116/
9. Singer AC, Kirchhelle C, Roberts AP. Reinventing the antimicrobial pipeline in response to the global crisis of antimicrobial-resistant infections. F1000 Res. 2019; 8: 238. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/30906539
10. Carlet J, Jarlier V, Harbarth S, Voss A, Goossens H, et al. Ready for a world without antibiotics? The Pensières Antibiotic Resistance Call to Action. Antimicrob Resist Infect Control. 2012; 1: 11. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/22958833
11. Gupta SK, Nayak RP. Dry antibiotic pipeline: Regulatory bottlenecks and regulatory reforms. J Pharmacol Pharmacother. 2014; 5: 4‐7. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/24554902
12. Powers JH. Antimicrobial drug development-the past, the present, and the future. Clin Microbiol Infect. 2004; 10 Suppl 4: 23‐31. PubMed: https://pubmed.ncbi.nlm.nih.gov/15522037/
13. Monnet DL. Antibiotic development and the changing role of the pharmaceutical industry. Int J Risk Safety Med. (IOS Press). 2005; 17: 133-145. PubMed: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5746591/
14. Ianevski A, Zusinaite E, Kuivanen S, Strand M , Lysvand H, et al. Novel activities of safe-in-human broad-spectrum antiviral agents. Antiviral Res. 2018; 154: 174‐182. PubMed: https://pubmed.ncbi.nlm.nih.gov/29698664/
15. Bryan-Marrugoa OL, Ramos-Jiménez J, Barrera-Saldañaa H, Rojas-Martíneza A, Vidaltamayo R, et al. History and progress of antiviral drugs: From acyclovir to direct-acting antiviral agents (DAAs) for Hepatitis C. Medicina Universitaria. 2015; 17: 165-174. PubMed:
16. Beigel JH, Nam HH, Adams PL, Krafft A, Ince WL, et al. Advances in respiratory virus therapeutics - A meeting report from the 6th isirv Antiviral Group conference. Antiviral Res. 2019; 167: 45‐67. PubMed: https://pubmed.ncbi.nlm.nih.gov/30974127/
17. De Clercq E, Li G. Approved antiviral drugs over the past 50 years. Clin Microbiol Rev. 2016; 29: 695‐747. PubMed: https://pubmed.ncbi.nlm.nih.gov/27281742/
18. Richman DD, Nathanson N. Antiviral therapy. In: Viral pathogenesis (third edition) from basics to systems biology. Academic Press. 2016; 271-287. PubMed: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7149377/
19. Totura AL, Bavari S. Broad-spectrum coronavirus antiviral drug discovery. Expert Opin Drug Discov. 2019; 14: 397‐412. PubMed: https://pubmed.ncbi.nlm.nih.gov/30849247/
20. Sohrabi C, Alsafi Z, O'Neill N, Khan M, Kerwan A, et al. World Health Organization declares global emergency: A review of the 2019 novel coronavirus (COVID-19). Int J Surg. 2020; 76: 71-76. PubMed: https://pubmed.ncbi.nlm.nih.gov/32112977/
21. Tu H, Tu S, Gao S, Shao A, Sheng J. The epidemiological and clinical features of COVID-19 and lessons from this global infectious public health event. J Infect. 2020. pii: S0163-4453(20)30222-X. PubMed: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7166041/
22. Acter T, Uddin N, Das J, Akhter A, Choudhury TR, et al. Evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as coronavirus disease 2019 (COVID-19) pandemic: A global health emergency. Sci Total Environ. 2020; 730: 138996. PubMed: https://pubmed.ncbi.nlm.nih.gov/32371230/
23. Park SE. Epidemiology, virology, and clinical features of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2; Coronavirus Disease-19). Clin Exp Pediatr. 2020; 63: 119-124. PubMed: https://pubmed.ncbi.nlm.nih.gov/32252141/
24. Wang L, Wang Y, Ye D, Liu Q. Review of the 2019 novel coronavirus (SARS-CoV-2) based on current evidence. Int J Antimicrob Agents. 2020: 105948. PubMed: https://pubmed.ncbi.nlm.nih.gov/32201353/
25. Singhal T. A review of coronavirus disease-2019 (COVID-19). Indian J Pediatr. 2020; 87: 281‐286. PubMed: https://pubmed.ncbi.nlm.nih.gov/32166607/
26. Al-Anazi KA, Al-Anazi WK, Al-Jasser AM. Neutrophils, NETs, NETosis and their paradoxical roles in COVID-19. J Stem Cell Ther Transplant. 2020; 4: 003-010. PubMed: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7184981/
27. Rothan HA, Byrareddy SN. The epidemiology and pathogenesis of coronavirus disease (COVID-19) outbreak. J Autoimmun. 2020; 109: 102433. PubMed: https://pubmed.ncbi.nlm.nih.gov/32113704/
28. Negro F. Is antibody-dependent enhancement playing a role in COVID-19 pathogenesis? Swiss Med Wkly. 2020; 150: w20249. PubMed: https://pubmed.ncbi.nlm.nih.gov/32298458/
29. Li H, Liu L, Zhang D, Xu J, Dai H, et al.SARS-CoV-2 and viral sepsis: observations and hypotheses. Lancet. 2020; 395: 1517-1520. PubMed: https://pubmed.ncbi.nlm.nih.gov/32311318/
30. Prompetchara E, Ketloy C, Palaga T. Immune responses in COVID-19 and potential vaccines: Lessons learned from SARS and MERS epidemic. Asian Pac J Allergy Immunol. 2020; 38: 1-9. PubMed: https://pubmed.ncbi.nlm.nih.gov/32105090/
31. Geng YJ, Wei ZY, Qian HY, Huang J, Lodato R, et al. Pathophysiological characteristics and therapeutic approaches for pulmonary injury and cardiovascular complications of coronavirus disease 2019. Cardiovasc Pathol. 2020; 47: 107228. PubMed: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7162778/
32. Zheng YY, Ma YT, Zhang JY, Xie X. COVID-19 and the cardiovascular system. Nat Rev Cardiol. 2020; 17: 259‐260. PubMed: https://pubmed.ncbi.nlm.nih.gov/32139904/
33. Guzik TJ, Mohiddin SA, Dimarco A, Patel V, Savvatis K, et al. COVID-19 and the cardiovascular system: implications for risk assessment, diagnosis, and treatment options. Cardiovasc Res. 2020; cvaa106. PubMed:
34. Mozzini C, Girelli D. The role of neutrophil extracellular traps in COVID-19: Only an hypothesis or a potential new field. Thrombosis Res. 2020; 26-27. PubMed: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7184981/
35. Taghizadeh-Hesary F, Akbari H. The powerful immune system against powerful COVID-19: A hypothesis. Med Hypotheses. 2020; 140: 109762. PubMed: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7175888/  
36. Yuki K, Fujiogi M, Koutsogiannaki S. COVID-19 pathophysiology: A review. Clin Immunol. 2020: 108427. Doi: 10.1016/j.clim.2020.108427. Epub ahead of print. PubMed: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7169933/
37. Zuo Y, Yalavarthi S, Shi H, Gockman K, Zuo M, et al. Neutrophil extracellular traps in COVID-19. JCI Insight. 2020. pii: 138999. Doi: 10. 1172/jci.insight.138999. Epub ahead of print. PubMed: https://pubmed.ncbi.nlm.nih.gov/32329756/
38. Kanda M, Nagai T, Takahashi T, Liu ML, Kondou N, et al. Leukemia inhibitory factor enhances endogenous cardiomyocyte regeneration after myocardial infarction. PLoS One. 2016; 11: e0156562. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/27227407
39. Slater H. FDA accepts IND for NK cell therapy CYNK-001 to treat patients with COVID-19. Immuno-Oncology News. April 3, 2020. PubMed:
40. Rameshrad M, Ghafoori M, Mohammadpour AH, Nayeri MJD, Hosseinzadeh H. A comprehensive review on drug repositioning against coronavirus disease 2019 (COVID19). Naunyn Schmiedebergs Arch Pharmacol. 2020; 1‐16. PubMed: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7235439/
41. Pandey A, Nikam AN, Shreya AB, Mutalik SP, Gopalan D, et al. Potential therapeutic targets for combating SARS-CoV-2: Drug repurposing, clinical trials and recent advancements. Life Sci. 2020; 117883. PubMed: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7263255/
42. Al-Anazi KA, Al-Jasser AM. Mesenchymal stem cells-their antimicrobial effects and their promising future role as novel therapies of infectious complications in high risk patients. In: Progress in stem cell transplantation. Edited by: Demirer T. Intech Open. 2015. PubMed:
43. Auletta JJ, Deans RJ, Bartholomew AM. Emerging roles for multipotent, bone marrow-derived stromal cells in host defense. Blood. 2012; 119: 1801-1809. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/22228625
44. Squillaro T, Peluso G, Galderisi U. Clinical trials with mesenchymal stem cells: An update. Cell Transplant. 2016; 25: 829-848. PubMed: https://pubmed.ncbi.nlm.nih.gov/26423725/
45. Thanunchai M, Hongeng S, Thitithanyanont A. Mesenchymal stromal cells and viral infection. Stem Cells Int. 2015; 2015: 860950. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/26294919
46. Yang K, Wang J, Wu M, Li M, Wang Y, et al. Mesenchymal stem cells detect and defend against gammaherpesvirus infection via the cGAS-STING pathway. Sci Rep. 2015; 5: 7820. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/25592282
47. Walter J, Ware LB, Matthay MA. Mesenchymal stem cells: Mechanisms of potential therapeutic benefit in ARDS and sepsis. Lancet Respir Med. 2014 Dec; 2: 1016-1026. PubMed: https://pubmed.ncbi.nlm.nih.gov/25465643/
48. Wilson JG, Liu KD, Zhuo H, Caballero L, McMillan M, et al. Mesenchymal stem (stromal) cells for treatment of ARDS: A phase 1 clinical trial. Lancet Respir Med. 2015; 3: 24-32. PubMed: https://pubmed.ncbi.nlm.nih.gov/25529339/
49. Chan MC, Kuok DI, Leung CY, Hui KPY, Valkenburg SA, et al. Human mesenchymal stromal cells reduce influenza A H5N1-associated acute lung injury in vitro and in vivo. Proc Natl Acad Sci USA. 2016; 113: 3621‐3626. PubMed: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4822574/
    
50. Rossetti D, Di Angelo Antonio S, Lukanović D, Kunic T, Certelli C, et al. Human umbilical cord-derived mesenchymal stem cells: Current trends and future perspectives. Asian Pac J Reprod 2019; 8: 93-101. PubMed:
51. Horie S, Masterson C, Brady J, Loftus P, Horan E, et al. Umbilical cord-derived CD362+ mesenchymal stromal cells for E. coli pneumonia: Impact of dose regimen, passage, cryopreservation, and antibiotic therapy. Stem Cell Res Ther. 2020; 11: 116. PubMed: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7071745/
52. Loy H, Kuok DIT, Hui KPY, Choi MHL, Yuen W, et al.et al. Therapeutic implications of human umbilical cord mesenchymal stromal cells in attenuating influenza A (H5N1) virus-associated acute lung injury. J Infect Dis. 2019; 219: 186-196. PubMed: https://pubmed.ncbi.nlm.nih.gov/30085072/
53. Atluri S, Manchikanti L, Hirsch JA.. Expanded umbilical cord mesenchymal stem cells (UC-MSCs) as a therapeutic strategy in managing critically ill COVID-19 patients: The case for compassionate use. Pain Physician. 2020; 23: E71-E83. PubMed: https://pubmed.ncbi.nlm.nih.gov/32214286/
54. Rogers CJ, Harman RJ, Bunnell BA, Schreiber MA, Xiang C, et al. Rationale for the clinical use of adipose-derived mesenchymal stem cells for COVID-19 patients. J Transl Med. 2020; 18: 203. PubMed: https://pubmed.ncbi.nlm.nih.gov/32423449/
55. Shin S, Kim Y, Jeong S, Hong S, Kim I, et al. The therapeutic effect of human adult stem cells derived from adipose tissue in endotoxemic rat model. Int J Med Sci. 2013; 10: 8-18. PubMed: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3534872/ v
56. Al-Anazi KA, Al-Anazi WK, Al-Jasser AM. The Rising role of mesenchymal stem cells in the treatment of various infectious complications. In: Update on mesenchymal and induced pluripotent stem cells. Edited by Al-Anazi KA. Intech Open. 2019. PubMed:
57. Golchin A, Seyedjafari E, Ardeshirylajimi A. Mesenchymal stem cell therapy for COVID-19: Present or future. Stem Cell Rev Rep. 2020; 1‐7. PubMed: https://pubmed.ncbi.nlm.nih.gov/32281052/
58. Barminko J, Gray A, Maguire T, Schloss R, Yarmush ML. Mesenchymal stromal cell mechanisms of immunomodulation and homing. In: Chase L, Vemuri M (eds) Mesenchymal Stem Cell Therapy. Stem Cell Biology and Regenerative Medicine 2013. Humana Press, Totowa, NJ.
59. Bari E, Ferrarotti I, Saracino L, Perteghella S, Torre ML, et al. Mesenchymal stromal cell secretome for severe COVID-19 infections: Premises for the therapeutic use. Cells. 2020; 9. pii: E924. PubMed: https://pubmed.ncbi.nlm.nih.gov/32283815/
60. Harrell CR, Fellabaum C, Jovicic N, Djonov V, Arsenijevic N, et al. Molecular mechanisms responsible for therapeutic potential of mesenchymal stem cell-derived secretome. Cells. 2019; 8. pii: E467. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/31100966
61. Vizoso FJ, Eiro N, Cid S, Schneider J,Perez-Fernandez R. Mesenchymal stem cell secretome: Toward cell-free therapeutic strategies in regenerative medicine. Int J Mol Sci. 2017; 18. pii: E1852. PubMed: https://pubmed.ncbi.nlm.nih.gov/28841158/
62. Mohammadipoor A, Antebi B, Batchinsky AI, Cancio LC. Therapeutic potential of products derived from mesenchymal stem/stromal cells in pulmonary disease. Respir Res. 2018; 19: 218. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/30413158
63. Konala VB, Mamidi MK, Bhonde R, Das AK, Pochampally R, et al. The current landscape of the mesenchymal stromal cell secretome: A new paradigm for cell-free regeneration. Cytotherapy. 2016; 18: 13-24. PubMed: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4924535/
64. Bari E, Ferrarotti I, Torre ML, Corsico AG, Perteghella S. Mesenchymal stem/stromal cell secretome for lung regeneration: The long way through "pharmaceuticalization" for the best formulation. J Control Release. 2019; 309: 11-24. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/31326462
65. Leng Z, Zhu R, Hou W, Fing Y, Yang Y, et al. Transplantation of ACE2- Mesenchymal stem cells improves the outcome of patients with COVID-19 pneumonia. Aging Dis. 2020; 11: 216‐228. Published 2020 Mar 9. PubMed: https://pubmed.ncbi.nlm.nih.gov/32257537/
66. Liang B, Chen J, Li T, Wu H, Yang W, et al. Clinical remission of a critically ill COVID-19 patient treated by human umbilical cord mesenchymal stem cells. China Xiv: 202002.00084v1 PubMed:
67. Khoury M, Rocco PRM, Phinney DG, Krampera M, Martin I, et al. Cell-based therapies for COVID-19: Proper clinical investigations are essential. Cytotherapy. 2020. PubMed: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7163352/
68. Metcalfe SM. Mesenchymal stem cells and management of COVID-19 pneumonia. Med Drug Discov. 2020; 5: 100019. PubMed: https://pubmed.ncbi.nlm.nih.gov/32296777
69. Pluristem. Pluristem reports preliminary data from its COVID-19 compassionate use program, treating seven patients with acute respiratory failure 2020. Clinical Study Results.
    https://www.pluristem.com/wp-content/uploads/2020/04/PSTI-PR-Follow-up-on-Covid-19-treatments. Final-For-Release.pdf
70. Sami T. Mesoblast reports 83% survival in ventilator-dependent COVID-19 patients following stem cell therapy: BioWorld; 2020. Preliminary Clinical Trial Results. https://www.bioworld.com/articles/434640-mesoblast-reports-83-survival-in-ventilator-dependent-covid-19-patients-following-stem-cell-therapy  
71. Tu YF, Chien CS, Yarmishyn AA, Lin YY, Luo YH, et al. A review of SARS-CoV-2 and the ongoing clinical trials. Int J Mol Sci. 2020; 21: 2657. PubMed: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7177898/
72. Lythgoe MP, Middleton P. Ongoing clinical trials for the management of the COVID-19 pandemic. Trends Pharmacol Sci. 2020; 41: 363‐382. PubMed: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7144665/
73. Moll G, Hoogduijn MJ, Ankrum JA. Editorial: Safety, efficacy and mechanisms of action of mesenchymal stem cell therapies. Front Immunol. 2020; 11: 243. PubMed: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7040069/
74. Zhao RC. Stem cell-based therapy for coronavirus disease 2019. Stem Cells Dev. 2020; 29: 679‐681. PubMed: https://pubmed.ncbi.nlm.nih.gov/32292113/
75. Liu S, Peng D, Qiu H, Yang K, Fu Z, et al. Mesenchymal stem cells as a potential therapy for COVID-19. Stem Cell Res Ther. 2020; 11, 169.  PubMed: https://stemcellres.biomedcentral.com/articles/10.1186/s13287-020-01678-8
76. Basil MC, Katzen J, Engler AE, Guo M, Herrigeset MJ, et al. The cellular and physiological basis for lung repair and regeneration: Past, present, and future. Cell Stem Cell. 2020; 26: 482‐502. PubMed:   https://www.ncbi.nlm.nih.gov/pubmed/32243808
77. Börger V, Weiss DJ, Anderson JD, Borràs FE, Bussolati B, et al. ISEV and ISCT statement on EVs from MSCs and other cells: considerations for potential therapeutic agents to suppress COVID-19. Cytotherapy. 2020. PubMed: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7229942/
78. Rajarshi K, Chatterjee A, Ray S. Combating COVID-19 with Mesenchymal Stem Cell therapy. Biotechnol Rep (Amst). 2020; e00467. PubMed: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7224671/
79. Ankrum J, Carver RJ. Can cell therapies halt cytokine storm in severe COVID-19 patients? Sci Transl Med. 2020; 12: eabb5673. PubMed:
80. Shetty AK. Mesenchymal stem cell infusion shows promise for combating coronavirus (COVID-19) - induced pneumonia. Aging Dis. 2020; 11: 462‐464. PubMed: https://pubmed.ncbi.nlm.nih.gov/32257554/
81. Zumla A, Wang FS, Ippolito G, Petrosillo N, Agratiet C, et al. Reducing mortality and morbidity in patients with severe COVID-19 disease by advancing ongoing trials of mesenchymal stromal (stem) cell (MSC) therapy - achieving global consensus and visibility for cellular host-directed therapies. Int J Infect Dis. 2020; 96: 431-439. PubMed: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7231497/
82. Gentile P, Sterodimas A. Adipose-derived stromal stem cells (ASCs) as a new regenerative immediate therapy combating coronavirus (COVID-19)-induced pneumonia. Expert Opin Biol Ther. 2020; 1‐6. PubMed: https://pubmed.ncbi.nlm.nih.gov/32329380/
83. Taghavi-Farahabadi M, Mahmoudi M, Soudi S, Hashemi SM. Hypothesis for the management and treatment of the COVID-19-induced acute respiratory distress syndrome and lung injury using mesenchymal stem cell-derived exosomes. Med Hypotheses. 2020; 144: 109865. PubMed: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7242964/  
84. Rao Us V, Thakur S, Rao J, Arakeri G, Brennanet BA, et al. Mesenchymal stem cells-bridge catalyst between innate and adaptive immunity in Covid 19. Med Hypotheses. 2020; 109845. PubMed: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7232064/
85. O'Driscoll L. Extracellular vesicles from mesenchymal stem cells as a Covid-19 treatment. Drug Discov Today. 2020; S1359-6446(20)30170-7. PubMed: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7202814/
86. Sengupta V, Sengupta S, Lazo A, Woods P, Nolan A, et al. Exosomes derived from bone marrow mesenchymal stem cells as treatment for severe COVID-19. Stem Cells Dev. 2020; 29: 747-754. PubMed: https://pubmed.ncbi.nlm.nih.gov/32380908/