COVID-19 Tedavisinde Mezenkimal Kök Hücrelerin Potansiyel Kullanımı Üzerine Kapsamlı Bir İnceleme

Yıl 2021, Cilt: 4 Sayı: 3, 31 - 65, 31.12.2021

Tugce Kurt , Isa Sevinc , Feyza Uysal , Elif Demiray , Hilal Yılmaz , Yavuz Emre Arslan

https://doi.org/10.54537/tusebdergisi.983736

Öz

İlk olarak Çin’in Wuhan kentinde tespit edildiği düşünülen yeni tip koronavirüs (SARS-CoV-2), raporlandığı ilk vakadan bu yana kısa süre içinde tüm dünyayı etkisi altına alarak bir salgına dönüşmüştür. Virüs, COVID-19 adı verilen bulaşıcı bir hastalığa neden olarak 150 milyondan fazla kişiyi etkilemiştir. Ayrıca yoğun virüs yükü ile enfekte olmuş bireylerde oluşan sitokin fırtınasının hastalarda akut solunum yolu bozukluğu (ARDS), pulmoner fibrozis ve hatta çoklu organ yetmezliği gibi durumlara neden olabildiği görülmüştür. Yapılan in vitro ve preklinik çalışmalarda mezenkimal kök hücrelerin (MKH) rejeneratif özelliklerinin yanında anti-enflamatuar ve immünmodülatör etkilerinin olduğu belirlenmiştir. Bu nedenle bilim insanları, rejeneratif bir umut olarak COVID-19 tedavisinde konvansiyonel ilaç veya plazma temelli tedavilere alternatif olarak MKH’leri kullanmayı önermektedir. Böylece hastalarda yoğun ilaç kullanımına bağlı yan etkilerin görülmeden MKH terapisi ile immünmodülasyon ve anti-enflamatuar etkilerin sağlanabileceği ve ARDS, pulmoner fibrosiz, sepsis ve çoklu organ yetmezliği gibi olumsuz senaryoların önüne geçileceği düşünülmektedir. Ayrıca MKH'lerin rejenerasyon özelliği sayesinde hasarlı doku tamirinin de sağlanabileceği öngörülmektedir. Ancak klinik uygulamalardaki tedavinin başarısı ve hasta güvenliği için yapılacak detaylı çalışmalarla COVID-19 tedavisi için MKH uygulamalarının standardize edilmesi gerekmektedir. Bu derlemede temel olarak COVID-19 tedavisi için yapılan MKH uygulamaları incelenmiştir. Metin içerisinde sırasıyla SARS-CoV-2 ve COVID-19 hastalığı kısaca açıklandıktan sonra yapılan aşı çalışmaları ile enfeksiyon sonrası uygulanan terapiler özetlenerek COVID-19 tedavisi için geliştirilen ve umut vaat eden MKH uygulamaları, MKH'lerin tedavideki rolü, hareket mekanizması, uygulama güvenliği ve etik konusu tartışılmıştır.

Anahtar Kelimeler

SARS-CoV-2, COVID-19, Mezenkimal kök hücre (MKH), İmmünomodulasyon, Anti-enflamatuar

Kaynakça

• 1. Nations U. World Population Prospects 2019. https://population.un.org/wpp/Maps/
• 2. Marco Galaverni, Gianfranco Bologna RD. DOĞANIN YOK OLUŞU VE PANDEMİLERİN YÜKSELİŞİ. WWF INTERNATIONAL. Published 2020. https://wwftr.awsassets.panda.org/downloads/doann_yok_oluu_ve_pandemilerin_yukselii_25_04_20.pdf?9920/Doganin-Yok-Olusu-ve
• 3. Huremović D. Brief History of Pandemics (Pandemics Throughout History). Psychiatry of Pandemics. Published online 2019:7-35. doi:10.1007/978-3-030-15346-5_2
• 4. DeWitte SN. Mortality Risk and Survival in the Aftermath of the Medieval Black Death. Noymer A, ed. PLoS One. 2014;9(5):e96513. doi:10.1371/journal.pone.0096513
• 5. Britannica TE of E. Influenza pandemic of 1918–19.
• 6. Kindhauser MK, Allen T, Frank V, Santhana S, Dye C. Zika : the origin and spread of a mosquito-borne virus. 2016;(February):675-686.
• 7. Wu D, Wu T, Liu Q, Yang Z. The SARS-CoV-2 outbreak: What we know. Int J Infect Dis. 2020;94:44-48. doi:10.1016/j.ijid.2020.03.004
• 8. Amanat F, Krammer F. SARS-CoV-2 Vaccines: Status Report. Immunity. 2020;52(4):583-589. doi:10.1016/j.immuni.2020.03.007
• 9. Coronavirus disease 2019 (COVID-19) Situation Report-94 HIGHLIGHTS. Published online 2020.
• 10. WHO. WHO Coronavirus (COVID-19) Dashboard. Published 2021. https://covid19.who.int/
• 11. CDC. Basics of COVID-19 | CDC. Centers for Disease Control adn Prevention, CDC. Published 2021. https://www.cdc.gov/coronavirus/2019-ncov/your-health/about-covid-19/basics-covid-19.html#:~:text=COVID-19 is a dangerous,other parts of the body.
• 12. Philip Ball AM. The epic battle against coronavirus misinformation and conspiracy theories. Nature. Published 2020. https://www.nature.com/articles/d41586-020-01452-z
• 13. Coronavirus: Outcry after Trump suggests injecting disinfectant as treatment - BBC News.
• 14. Worldometer. COVID-19 CORONAVIRUS PANDEMIC CORONAVIRUS CASES. Worldometer. Published 2021. https://www.worldometers.info/coronavirus/
• 15. PubMed. COVID-19 treatment. US National Library of Medicine. Published 2021. https://pubmed.ncbi.nlm.nih.gov/?term=COVID-19+treatment
• 16. Shi Y, Su J, Roberts AI, Shou P, Rabson AB, Ren G. How mesenchymal stem cells interact with tissue immune responses. Trends Immunol. 2012;33(3):136-143. doi:10.1016/j.it.2011.11.004
• 17. Harrell CR, Sadikot R, Pascual J, et al. Mesenchymal Stem Cell-Based Therapy of Inflammatory Lung Diseases: Current Understanding and Future Perspectives. Stem Cells Int. 2019;2019. doi:10.1155/2019/4236973
• 18. Rajarshi K, Chatterjee A, Ray S. Combating COVID-19 with mesenchymal stem cell therapy. Biotechnol Reports. 2020;26:e00467. doi:10.1016/j.btre.2020.e00467
• 19. Cui J, Li F, Shi Z-L. Origin and evolution of pathogenic coronaviruses. Nat Rev Microbiol 2018 173. 2018;17(3):181-192. doi:10.1038/s41579-018-0118-9
• 20. Pedersen SF, Ho YC. SARS-CoV-2: A storm is raging. J Clin Invest. 2020;130(5):2202-2205. doi:10.1172/JCI137647
• 21. Hu B, Guo H, Zhou P, Shi Z-L. Characteristics of SARS-CoV-2 and COVID-19. Nat Rev Microbiol. 2021;19(3):141-154. doi:10.1038/s41579-020-00459-7
• 22. Lau SKP, Woo PCY, Yip CCY, et al. Isolation and Characterization of a Novel Betacoronavirus Subgroup A Coronavirus, Rabbit Coronavirus HKU14, from Domestic Rabbits. J Virol. 2012;86(10):5481-5496. doi:10.1128/jvi.06927-11
• 23. Ludwig S, Zarbock A. Coronaviruses and SARS-CoV-2: A Brief Overview. Anesth Analg. 2020;131(1):93-96. doi:10.1213/ANE.0000000000004845
• 24. Monto AS, Cowling BJ, Peiris JSM. Coronaviruses. Viral Infect Humans Epidemiol Control. Published online June 2014:199-223. doi:10.1007/978-1-4899-7448-8_10
• 25. Akkoc T. COVID-19 and mesenchymal stem cell treatment; mystery or not. Adv Exp Med Biol. 2020;1298:167-176. doi:10.1007/5584_2020_557
• 26. Lai CC, Shih TP, Ko WC, Tang HJ, Hsueh PR. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus disease-2019 (COVID-19): The epidemic and the challenges. Int J Antimicrob Agents. 2020;55(3). doi:10.1016/j.ijantimicag.2020.105924
• 27. Shang J, Wan Y, Luo C, et al. Cell entry mechanisms of SARS-CoV-2. Proc Natl Acad Sci U S A. 2020;117(21):1-8. doi:10.1073/pnas.2003138117
• 28. Hoffmann M, Kleine-Weber H, Schroeder S, et al. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell. 2020;181(2):271-280.e8. doi:10.1016/j.cell.2020.02.052
• 29. Alanagreh L, Alzoughool F, Atoum M. The Human Coronavirus Disease COVID-19: Its Origin, Characteristics, and Insights into Potential Drugs and Its Mechanisms. Pathog 2020, Vol 9, Page 331. 2020;9(5):331. doi:10.3390/PATHOGENS9050331
• 30. Yao D, Ye H, Huo Z, Wu L, Wei S. Mesenchymal stem cell research progress for the treatment of COVID-19: https://doi.org/101177/0300060520955063. 2020;48(9). doi:10.1177/0300060520955063
• 31. Rogers CJ, Harman RJ, Bunnell BA, et al. Rationale for the clinical use of adipose-derived mesenchymal stem cells for COVID-19 patients. J Transl Med. 2020;18(1):1-20. doi:10.1186/s12967-020-02380-2
• 32. Irmak DK, Darıcı H, Karaöz E, Irmak DK, Darıcı H, Karaöz E. Stem Cell Based Therapy Option in COVID-19: Is It Really Promising? Aging Dis. 2020;11(5):1174-1191. doi:10.14336/AD.2020.0608
• 33. Brave H, MacLoughlin R. State of the Art Review of Cell Therapy in the Treatment of Lung Disease, and the Potential for Aerosol Delivery. Int J Mol Sci. 2020;21(17):6435. doi:10.3390/ijms21176435
• 34. Song P, Li W, Xie J, Hou Y, You C. Cytokine storm induced by SARS-CoV-2. Clin Chim Acta. 2020;509:280-287. doi:10.1016/j.cca.2020.06.017
• 35. Bhaskar S, Sinha A, Banach M, et al. Cytokine Storm in COVID-19—Immunopathological Mechanisms, Clinical Considerations, and Therapeutic Approaches: The REPROGRAM Consortium Position Paper. Front Immunol. 2020;11. doi:10.3389/fimmu.2020.01648
• 36. Alnefaie A, Albogami S. Current approaches used in treating COVID-19 from a molecular mechanisms and immune response perspective. Saudi Pharm J. 2020;28(11):1333-1352. doi:10.1016/j.jsps.2020.08.024
• 37. Rothan HA, Byrareddy SN. The epidemiology and pathogenesis of coronavirus disease (COVID-19) outbreak. J Autoimmun. 2020;109:102433. doi:10.1016/J.JAUT.2020.102433
• 38. WHO. Coronavirus disease (COVID-19) advice for the public. WHO. Published 2021. https://www.who.int/emergencies/diseases/novel-coronavirus-2019/advice-for-public
• 39. Kampf G, Todt D, Pfaender S, Steinmann E. Persistence of coronaviruses on inanimate surfaces and their inactivation with biocidal agents. J Hosp Infect. 2020;104(3):246-251. doi:10.1016/J.JHIN.2020.01.022
• 40. Hosseini SA, Zahedipour F, Mirzaei H, Kazemi Oskuee R. Potential SARS-CoV-2 vaccines: Concept, progress, and challenges. Int Immunopharmacol. 2021;97(March):107622. doi:10.1016/j.intimp.2021.107622
• 41. Khuroo MS, Khuroo M, Khuroo MS, Sofi AA, Khuroo NS. COVID-19 Vaccines: A Race Against Time in the Middle of Death and Devastation! J Clin Exp Hepatol. 2020;10(6):610-621. doi:10.1016/J.JCEH.2020.06.003
• 42. WHO. COVID-19 vaccine tracker and landscape. World Health Organization. Published 2021. https://www.who.int/publications/m/item/draft-landscape-of-covid-19-candidate-vaccines
• 43. SPUTNIK. GENERAL INFORMATION SPUTNIK V. SPUTNIK. Published 2021. https://sputnikvaccine.com/about-vaccine/
• 44. CanSinoBIO. CanSinoBIO. CanSino Biologics Inc. Published 2021. http://www.cansinotech.com/html/1/179/180/651.html
• 45. Li T, Zhang T, Gu Y, Li S, Xia N. Current progress and challenges in the design and development of a successful COVID-19 vaccine. Fundam Res. 2021;1(2):139-150. doi:10.1016/j.fmre.2021.01.011
• 46. Gumel AB, Iboi EA, Ngonghala CN, Elbasha EH. A primer on using mathematics to understand COVID-19 dynamics: Modeling, analysis and simulations. Infect Dis Model. 2021;6(August 2020):148-168. doi:10.1016/j.idm.2020.11.005
• 47. Martonosi SE, Behzad B, Cummings K. Pricing the COVID-19 vaccine: A mathematical approach. Omega. 2021;103:102451. doi:10.1016/J.OMEGA.2021.102451
• 48. Forman R, Shah S, Jeurissen P, Jit M, Mossialos E. COVID-19 vaccine challenges: What have we learned so far and what remains to be done? Health Policy (New York). 2021;125(5):553-567. doi:10.1016/j.healthpol.2021.03.013
• 49. Carneiro DC, Sousa JD, Monteiro-Cunha JP. The COVID-19 vaccine development: A pandemic paradigm. Virus Res. 2021;301:198454. doi:10.1016/j.virusres.2021.198454
• 50. Jhaveri R. The Next Set of COVID-19 Vaccines: Leveraging New Development Platforms to Increase Access for More People Around the World. Clin Ther. 2021;43(4):702-710. doi:10.1016/j.clinthera.2021.03.007
• 51. Berkley S. COVAX explained. GAVI. Published 2021. https://www.gavi.org/vaccineswork/covax-explained
• 52. Wouters OJ, Shadlen KC, Salcher-Konrad M, et al. Challenges in ensuring global access to COVID-19 vaccines: production, affordability, allocation, and deployment. Lancet. 2021;397(10278):1023-1034. doi:10.1016/S0140-6736(21)00306-8
• 53. Chukwu OA, Nnogo CC. Surmounting inherent challenges in healthcare service delivery for effective procurement and distribution of COVID-19 vaccines; A developing country context. Heal Policy Technol. 2021;10(2):100518. doi:10.1016/j.hlpt.2021.100518
• 54. Baden LR, El Sahly HM, Essink B, et al. Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine. N Engl J Med. 2021;384(5):403-416. doi:10.1056/NEJMoa2035389
• 55. Wentzell E, Racila AM. The social experience of participation in a COVID-19 vaccine trial: Subjects’ motivations, others’ concerns, and insights for vaccine promotion. Vaccine. 2021;39(17):2445-2451. doi:10.1016/J.VACCINE.2021.03.036
• 56. Munitz A, Yechezkel M, Dickstein Y, Yamin D, Gerlic M. BNT162b2 vaccination effectively prevents the rapid rise of SARS-CoV-2 variant B.1.1.7 in high-risk populations in Israel. Cell Reports Med. 2021;2(5):100264. doi:10.1016/j.xcrm.2021.100264
• 57. Altuntas F, Ata N, Yigenoglu TN, et al. Convalescent plasma therapy in patients with COVID-19. Transfus Apher Sci. 2021;60(1). doi:10.1016/J.TRANSCI.2020.102955
• 58. Dassarma B, Tripathy S, Matsabisa M. Emergence of ancient convalescent plasma (CP) therapy: To manage COVID-19 pandemic. Transfus Clin Biol. 2021;28(1):123-127. doi:10.1016/J.TRACLI.2020.11.004
• 59. FDA. Recommendations for Investigational COVID-19 Convalescent Plasma. FDA. Published 2021. https://www.fda.gov/vaccines-blood-biologics/investigational-new-drug-applications-inds-cber-regulated-products/recommendations-investigational-covid-19-convalescent-plasma
• 60. Nagoba B, Gavkare A, Jamadar N, Mumbre S, Selkar S. Positive aspects, negative aspects and limitations of plasma therapy with special reference to COVID-19. J Infect Public Health. 2020;13(12):1818-1822. doi:10.1016/j.jiph.2020.08.011
• 61. Noreen S, Maqbool I, Madni A. Dexamethasone: Therapeutic potential, risks, and future projection during COVID-19 pandemic. Eur J Pharmacol. 2021;894:173854. doi:10.1016/j.ejphar.2021.173854
• 62. Kumar R, Yeni CM, Utami NA, et al. SARS-CoV-2 infection during pregnancy and pregnancy-related conditions: Concerns, challenges, management and mitigation strategies–a narrative review. J Infect Public Health. 2021;14(7):863-875. doi:10.1016/j.jiph.2021.04.005
• 63. Shariare MH, Parvez MAK, Karikas GA, Kazi M. The growing complexity of COVID-19 drug and vaccine candidates: challenges and critical transitions. J Infect Public Health. 2021;14(2):214-220. doi:10.1016/j.jiph.2020.12.009
• 64. Aygün İ, Kaya M, Alhajj R. Identifying side effects of commonly used drugs in the treatment of Covid 19. Sci Rep. 2020;10(1):21508. doi:10.1038/s41598-020-78697-1
• 65. Basiri A, Pazhouhnia Z, Beheshtizadeh N, Hoseinpour M, Saghazadeh A, Rezaei N. Regenerative Medicine in COVID-19 Treatment: Real Opportunities and Range of Promises. Stem Cell Rev Reports. 2021;17(1):163-175. doi:10.1007/s12015-020-09994-5
• 66. El-Hashash AHK. Mesenchymal Stem Cells in Regenerative Medicine and Diseases: Hope for Better Human Health. Elsevier Inc.; 2020. doi:10.1016/B978-0-12-819713-4.00001-3
• 67. Burgess R. Introduction to stem cells. Stem Cells Handb Second Ed. Published online January 2013:1-27. doi:10.1007/978-1-4614-7696-2_1
• 68. Joyce N, Annett G, Wirthlin L, Olson S, Bauer G, Nolta JA. Mesenchymal stem cells for the treatment of neurodegenerative disease. http://dx.doi.org/102217/rme1072. 2010;5(6):933-946. doi:10.2217/RME.10.72
• 69. Andrzejewska A, Dabrowska S, Lukomska B, Janowski M. Mesenchymal Stem Cells for Neurological Disorders. Adv Sci. 2021;8(7):1-27. doi:10.1002/advs.202002944
• 70. Patel DM, Shah J, Srivastava AS. Therapeutic potential of mesenchymal stem cells in regenerative medicine. Stem Cells Int. 2013;2013. doi:10.1155/2013/496218
• 71. Coelho A, Alvites RD, Branquinho MV, Guerreiro SG, Maurício AC. Mesenchymal Stem Cells (MSCs) as a Potential Therapeutic Strategy in COVID-19 Patients: Literature Research. Front Cell Dev Biol. 2020;8(November):1-13. doi:10.3389/fcell.2020.602647
• 72. Golchin A, Seyedjafari E, Ardeshirylajimi A. Mesenchymal Stem Cell Therapy for COVID-19: Present or Future. Stem Cell Rev Reports. 2020;16(3):427-433. doi:10.1007/s12015-020-09973-w
• 73. Newman RE, Yoo D, LeRoux MA, Danilkovitch-Miagkova A. Treatment of inflammatory diseases with mesenchymal stem cells. Inflamm Allergy - Drug Targets. 2009;8(2):110-123. doi:10.2174/187152809788462635
• 74. ClinicalTrials.gov. Mesenchymal Stem Cells for the Treatment of COVID-19. US National Library of Medicine. Published 2021. https://clinicaltrials.gov/ct2/show/NCT04573270
• 75. Thanunchai M, Hongeng S, Thitithanyanont A. Mesenchymal Stromal cells and viral infection. Stem Cells Int. 2015;2015. doi:10.1155/2015/860950
• 76. Zengin R, Beyaz O, Koc ES, et al. Mesenchymal stem cell treatment in a critically ill COVID-19 patient: a case report. Stem Cell Investig. 2020;7:17-17. doi:10.21037/sci-2020-024
• 77. Griffin MD, Elliman SJ, Cahill E, English K, Ceredig R, Ritter T. Concise review: Adult mesenchymal stromal cell therapy for inflammatory diseases: How well are we joining the dots? Stem Cells. 2013;31(10):2033-2041. doi:10.1002/stem.1452
• 78. Jimenez-Puerta GJ, Marchal JA, López-Ruiz E, Gálvez-Martín P. Role of Mesenchymal Stromal Cells as Therapeutic Agents: Potential Mechanisms of Action and Implications in Their Clinical Use. J Clin Med. 2020;9(2):445. doi:10.3390/jcm9020445
• 79. Moll G, Hoogduijn MJ, Ankrum JA. Editorial: Safety, Efficacy and Mechanisms of Action of Mesenchymal Stem Cell Therapies. Front Immunol. 2020;11(February):1-4. doi:10.3389/fimmu.2020.00243
• 80. Vx M, John A, Koshy S, et al. Fostering mesenchymal stem cell therapy to halt cytokine storm in COVID-19. Biochim Biophys Acta - Mol Basis Dis. 2021;1867(2):166014. doi:10.1016/j.bbadis.2020.166014
• 81. Wang M, Yang Y, Yang D, et al. The immunomodulatory activity of human umbilical cord blood-derived mesenchymal stem cells in vitro. Immunology. 2009;126(2):220-232. doi:10.1111/j.1365-2567.2008.02891.x
• 82. Zhao Q, Ren H, Han Z. Mesenchymal stem cells: Immunomodulatory capability and clinical potential in immune diseases. J Cell Immunother. 2016;2(1):3-20. doi:10.1016/j.jocit.2014.12.001
• 83. Gao F, Chiu SM, Motan DAL, et al. Mesenchymal stem cells and immunomodulation: Current status and future prospects. Cell Death Dis. 2016;7(1). doi:10.1038/cddis.2015.327
• 84. Squillaro T, Peluso G, Galderisi U. Clinical Trials with Mesenchymal Stem Cells: An Update: http://dx.doi.org/103727/096368915X689622. 2016;25(5):829-848. doi:10.3727/096368915X689622
• 85. Yadav P, Vats R, Bano A, Bhardwaj R. Mesenchymal stem cell immunomodulation and regeneration therapeutics as an ameliorative approach for COVID-19 pandemics. Life Sci. 2020;263(August):118588. doi:10.1016/j.lfs.2020.118588
• 86. Lee SH, Kwon J ye, Kim S-Y, Jung K, Cho M-L. Interferon-gamma regulates inflammatory cell death by targeting necroptosis in experimental autoimmune arthritis. Sci Rep. 2017;7(1):10133. doi:10.1038/s41598-017-09767-0
• 87. Yan L, Zheng D, Xu R-H. Critical Role of Tumor Necrosis Factor Signaling in Mesenchymal Stem Cell-Based Therapy for Autoimmune and Inflammatory Diseases. Front Immunol. 2018;9(JUL):1658. doi:10.3389/FIMMU.2018.01658
• 88. Andrukhov O, Behm C, Blufstein A, Rausch-Fan X. Immunomodulatory Properties of Dental-Derived Mesenchymal Stem Cells. In: Periodontology and Dental Implantology. IntechOpen; 2019. doi:10.5772/intechopen.78049
• 89. Trinchieri G. Biology of Natural Killer Cells. Adv Immunol. 1989;47(C):187-376. doi:10.1016/S0065-2776(08)60664-1
• 90. Mundra V, Gerling IC, Mahato RI. Mesenchymal stem cell-based therapy. Mol Pharm. 2013;10(1):77-89. doi:10.1021/mp3005148
• 91. van Eeden C, Khan L, Osman MS, Tervaert JWC. Natural killer cell dysfunction and its role in covid-19. Int J Mol Sci. 2020;21(17):1-17. doi:10.3390/ijms21176351
• 92. Qin C, Zhou L, Hu Z, et al. Dysregulation of Immune Response in Patients With Coronavirus 2019 (COVID-19) in Wuhan, China. Clin Infect Dis. 2020;71(15):762-768. doi:10.1093/CID/CIAA248
• 93. Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395(10223):497-506. doi:10.1016/S0140-6736(20)30183-5
• 94. Spaggiari GM, Capobianco A, Becchetti S, Mingari MC, Moretta L. Mesenchymal stem cell-natural killer cell interactions: Evidence that activated NK cells are capable of killing MSCs, whereas MSCs can inhibit IL-2-induced NK-cell proliferation. Blood. 2006;107(4):1484-1490. doi:10.1182/blood-2005-07-2775
• 95. Weiss ARR, Dahlke MH. Immunomodulation by Mesenchymal Stem Cells (MSCs): Mechanisms of action of living, apoptotic, and dead MSCs. Front Immunol. 2019;10(JUN):1-10. doi:10.3389/fimmu.2019.01191
• 96. Lambrecht BN, Prins J-;B., Hoogsteden HC. Lung dendritic cells and host immunity to infection. Eur Respir J. 2001;18(4).
• 97. Borges RC, Hohmann MS, Borghi SM. Dendritic cells in COVID-19 immunopathogenesis: insights for a possible role in determining disease outcome. https://doi.org/101080/0883018520201844195. 2020;40(1-2):108-125. doi:10.1080/08830185.2020.1844195
• 98. Zhou R, To KK-W, Wong Y-C, et al. Acute SARS-CoV-2 Infection Impairs Dendritic Cell and T Cell Responses. Immunity. 2020;53(4):864-877.e5. doi:10.1016/J.IMMUNI.2020.07.026
• 99. Liu J, Li S, Liu J, et al. Longitudinal characteristics of lymphocyte responses and cytokine profiles in the peripheral blood of SARS-CoV-2 infected patients. EBioMedicine. 2020;55:102763. doi:10.1016/J.EBIOM.2020.102763
• 100. Blanco-Melo D, Nilsson-Payant BE, Liu W-C, et al. Imbalanced Host Response to SARS-CoV-2 Drives Development of COVID-19. Cell. 2020;181(5):1036-1045.e9. doi:10.1016/J.CELL.2020.04.026
• 101. Agrawal A, Agrawal S, Gupta S. Role of dendritic cells in inflammation and loss of tolerance in the elderly. Front Immunol. 2017;8(JUL):1-8. doi:10.3389/fimmu.2017.00896
• 102. Leng Z, Zhu R, Hou W, et al. Transplantation of ACE2- Mesenchymal stem cells improves the outcome of patients with covid-19 pneumonia. Aging Dis. 2020;11(2):216-228. doi:10.14336/AD.2020.0228
• 103. Wada N, Gronthos S, Bartold PM. Immunomodulatory effects of stem cells. Periodontol 2000. 2013;63(1):198-216. doi:10.1111/prd.12024
• 104. Johnston RB. Monocytes and Macrophages. N Engl J Med. 1988;318(12):747-752. doi:10.1056/NEJM198803243181205
• 105. Gómez-rial J, Rivero-calle I, Salas A. Role of Monocytes / Macrophages in Covid-19 Pathogenesis : Implications for Therapy. Published online 2020.
• 106. Feng Z, Diao B, Wang R, et al. The Novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Directly Decimates Human Spleens and Lymph Nodes. 2020;2:1-18. doi:10.1101/2020.03.27.20045427
• 107. Eggenhofer E, Hoogduijn MJ. Mesenchymal stem cell-educated macrophages. Published online 2012:1-5.
• 108. Kumar B V., Connors TJ, Farber DL. Human T Cell Development, Localization, and Function throughout Life. Immunity. 2018;48(2):202-213. doi:10.1016/j.immuni.2018.01.007
• 109. Ye Q, Wang B, Mao J. The pathogenesis and treatment of the ‘Cytokine Storm’’ in COVID-19.’ J Infect. 2020;80(6):607-613. doi:10.1016/j.jinf.2020.03.037
• 110. Pistoia V. Production of cytokines by human B cells in health and disease. Immunol Today. 1997;18(7):343-350. doi:10.1016/S0167-5699(97)01080-3
• 111. Mauri C, Bosma A. Immune regulatory function of B cells. Annu Rev Immunol. 2012;30:221-241. doi:10.1146/annurev-immunol-020711-074934
• 112. Cañete PF, Vinuesa CG. COVID-19 Makes B Cells Forget, but T Cells Remember. Cell. 2020;183(1):13-15. doi:10.1016/j.cell.2020.09.013
• 113. CO O, NE S, PW B, et al. Durable SARS-CoV-2 B cell immunity after mild or severe disease. J Clin Invest. 2021;131(7). doi:10.1172/JCI145516
• 114. Carreras-Planella L, Monguió-Tortajada M, Borràs FE, Franquesa M. Immunomodulatory Effect of MSC on B Cells Is Independent of Secreted Extracellular Vesicles. Front Immunol. 2019;10(JUN):1-8. doi:10.3389/fimmu.2019.01288
• 115. Corcione A, Benvenuto F, Ferretti E, et al. Human mesenchymal stem cells modulate B-cell functions. Blood. 2006;107(1):367-372. doi:10.1182/blood-2005-07-2657
• 116. Rasmusson I, Le Blanc K, Sundberg B, Ringdén O. Mesenchymal stem cells stimulate antibody secretion in human B cells. Scand J Immunol. 2007;65(4):336-343. doi:10.1111/j.1365-3083.2007.01905.x
• 117. Iyer SS, Rojas M. Anti-infl ammatory effects of mesenchymal stem cells : novel. Expert Opin Biol Ther. 2008;8(5):569-582.
• 118. Liang B, Chen J, Li T, et al. Clinical remission of a critically ill COVID-19 patient treated by human umbilical cord mesenchymal stem cells: A case report. Medicine (Baltimore). 2020;99(31):e21429. doi:10.1097/MD.0000000000021429
• 119. 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(July):11-24. doi:10.1016/j.jconrel.2019.07.022
• 120. Fu Y, Karbaat L, Wu L, Leijten J, Both SK, Karperien M. Trophic Effects of Mesenchymal Stem Cells in Tissue Regeneration. Tissue Eng - Part B Rev. 2017;23(6):515-528. doi:10.1089/ten.teb.2016.0365
• 121. Chen Y, Shao JZ, Xiang LX, Dong XJ, Zhang GR. Mesenchymal stem cells: A promising candidate in regenerative medicine. Int J Biochem Cell Biol. 2008;40(5):815-820. doi:10.1016/j.biocel.2008.01.007
• 122. Zhu Y, Geng S, Li Q, Jiang H. Transplantation of Mesenchymal Stem Cells: A Potential Adjuvant Therapy for COVID-19. Front Bioeng Biotechnol. 2020;8(November):1-9. doi:10.3389/fbioe.2020.557652
• 123. Chambers E, Rounds S, Lu Q. Pulmonary endothelial cell apoptosis in emphysema and acute lung injury. Adv Anat Embryol Cell Biol. 2018;228:63-86. doi:10.1007/978-3-319-68483-3_4
• 124. Lee KH, Tseng WC, Yang CY, Tarng DC. The Anti-Inflammatory, Anti-Oxidative, and Anti-Apoptotic Benefits of Stem Cells in Acute Ischemic Kidney Injury. Int J Mol Sci. 2019;20(14). doi:10.3390/ijms20143529
• 125. Bernard O, Jeny F, Uzunhan Y, et al. Mesenchymal stem cells reduce hypoxia-induced apoptosis in alveolar epithelial cells by modulating HIF and ROS hypoxic signaling. Am J Physiol - Lung Cell Mol Physiol. 2018;314(3):L360-L371. doi:10.1152/ajplung.00153.2017
• 126. Di Rocco G, Baldari S, Toietta G. Towards Therapeutic Delivery of Extracellular Vesicles: Strategies for In Vivo Tracking and Biodistribution Analysis. Stem Cells Int. 2016;2016. doi:10.1155/2016/5029619
• 127. Zheng M, Gao Y, Wang G, et al. Functional exhaustion of antiviral lymphocytes in COVID-19 patients. Cell Mol Immunol. 2020;17(5):533-535. doi:10.1038/s41423-020-0402-2
• 128. Sadeghi S, Soudi S, Shafiee A, Hashemi SM. Mesenchymal stem cell therapies for COVID-19: Current status and mechanism of action. Life Sci. 2020;262:118493. doi:10.1016/j.lfs.2020.118493
• 129. Klimczak A. Perspectives on mesenchymal stem/progenitor cells and their derivates as potential therapies for lung damage caused by COVID-19. World J Stem Cells. 2020;12(9):1013-1022. doi:10.4252/wjsc.v12.i9.1013
• 130. Mias C, Trouche E, Seguelas M-H, et al. Ex Vivo Pretreatment with Melatonin Improves Survival, Proangiogenic/Mitogenic Activity, and Efficiency of Mesenchymal Stem Cells Injected into Ischemic Kidney. Stem Cells. 2008;26(7):1749-1757. doi:10.1634/stemcells.2007-1000
• 131. Rohban R, Pieber TR. Mesenchymal stem and progenitor cells in regeneration: Tissue specificity and regenerative potential. Stem Cells Int. 2017;2017. doi:10.1155/2017/5173732
• 132. Khatri M, Richardson LA, Meulia T. Mesenchymal stem cell-derived extracellular vesicles attenuate influenza virus-induced acute lung injury in a pig model. Stem Cell Res Ther. 2018;9(1):1-13. doi:10.1186/s13287-018-0774-8
• 133. Krasnodembskaya A, Song Y, Fang X, et al. Antibacterial effect of human mesenchymal stem cells is mediated in part from secretion of the antimicrobial peptide LL-37. Stem Cells. 2010;28(12):2229-2238. doi:10.1002/stem.544
• 134. Gentile P, Sterodimas A, Pizzicannella J, Calabrese C, Garcovich S. Research progress on Mesenchymal Stem Cells (MSCs), adipose-derived mesenchymal stem cells (AD-MSCs), drugs, and vaccines in inhibiting COVID-19 disease. Aging Dis. 2020;11(5):1191-1201. doi:10.14336/AD.2020.0711
• 135. Alcayaga-Miranda F, Cuenca J, Khoury M. Antimicrobial activity of mesenchymal stem cells: Current status and new perspectives of antimicrobial peptide-based therapies. Front Immunol. 2017;8(MAR):1-15. doi:10.3389/fimmu.2017.00339
• 136. Muraca M, Pessina A, Pozzobon M, et al. Mesenchymal stromal cells and their secreted extracellular vesicles as therapeutic tools for COVID-19 pneumonia? J Control Release. 2020;325:135-140. doi:10.1016/j.jconrel.2020.06.036
• 137. Sinclair K, Yerkovich ST, Chambers DC. Mesenchymal stem cells and the lung. Respirology. 2013;18(3):397-411. doi:10.1111/RESP.12050
• 138. Basil MC, Katzen J, Engler AE, et al. The Cellular and Physiological Basis for Lung Repair and Regeneration: Past, Present, and Future. Cell Stem Cell. 2020;26(4):482-502. doi:10.1016/j.stem.2020.03.009
• 139. Noronha NDC, Mizukami A, Caliári-Oliveira C, et al. Correction to: Priming approaches to improve the efficacy of mesenchymal stromal cell-based therapies (Stem Cell Research and Therapy (2019) 10 (131) DOI: 10.1186/s13287-019-1224-y). Stem Cell Res Ther. 2019;10(1):1-21. doi:10.1186/s13287-019-1259-0
• 140. De Santis MM, Bölükbas DA, Lindstedt S, Wagner DE. How to build a lung: Latest advances and emerging themes in lung bioengineering. Eur Respir J. 2018;52(1). doi:10.1183/13993003.01355-2016
• 141. Chambers DC, Enever D, Ilic N, et al. A phase 1b study of placenta-derived mesenchymal stromal cells in patients with idiopathic pulmonary fibrosis. Respirology. 2014;19(7):1013-1018. doi:10.1111/resp.12343
• 142. Song L, Guan XJ, Chen X, et al. Mesenchymal stem cells reduce cigarette smoke-induced inflammation and airflow obstruction in rats via TGF-β1 signaling. COPD J Chronic Obstr Pulm Dis. 2014;11(5):582-590. doi:10.3109/15412555.2014.898032
• 143. Foronjy RF, Majka SM. The Potential for Resident Lung Mesenchymal Stem Cells to Promote Functional Tissue Regeneration: Understanding Microenvironmental Cues. Cells. 2012;1(4):874-885. doi:10.3390/cells1040874
• 144. Gupta N, Su X, Popov B, Lee JW, Serikov V, Matthay MA. Intrapulmonary Delivery of Bone Marrow-Derived Mesenchymal Stem Cells Improves Survival and Attenuates Endotoxin-Induced Acute Lung Injury in Mice. J Immunol. 2007;179(3):1855-1863. doi:10.4049/jimmunol.179.3.1855
• 145. Geiger S, Hirsch D, Hermann FG. Cell therapy for lung disease. Eur Respir Rev. 2017;26(144). doi:10.1183/16000617.0044-2017
• 146. Rojas M, Xu J, Woods CR, et al. Bone marrow-derived mesenchymal stem cells in repair of the injured lung. Am J Respir Cell Mol Biol. 2005;33(2):145-152. doi:10.1165/rcmb.2004-0330OC
• 147. Mei SHJ, Haitsma JJ, Dos Santos CC, et al. Mesenchymal stem cells reduce inflammation while enhancing bacterial clearance and improving survival in sepsis. Am J Respir Crit Care Med. 2010;182(8):1047-1057. doi:10.1164/rccm.201001-0010OC
• 148. Kennelly H, Mahon BP, English K. Human mesenchymal stromal cells exert HGF dependent cytoprotective effects in a human relevant pre-clinical model of COPD. Sci Rep. 2016;6(April):1-11. doi:10.1038/srep38207
• 149. De Oliveira HG, Cruz FF, Antunes MA, et al. Combined bone marrow-derived mesenchymal stromal cell therapy and one-way endobronchial valve placement in patients with pulmonary emphysema: A phase i clinical trial. Stem Cells Transl Med. 2017;6(3):962-969. doi:10.1002/sctm.16-0315
• 150. McIntyre LA, Moher D, Fergusson DA, et al. Efficacy of mesenchymal stromal cell therapy for acute lung injury in preclinical animal models: A systematic review. PLoS One. 2016;11(1):1-16. doi:10.1371/journal.pone.0147170
• 151. Cai SX, Liu AR, Chen S, et al. The orphan receptor tyrosine kinase ROR2 facilitates MSCs to repair lung injury in ARDS animal model. Cell Transplant. 2016;25(8):1561-1574. doi:10.3727/096368915X689776
• 152. Thannickal VJ, Toews GB, White ES, Lynch JP, Martinez FJ. Mechanisms of pulmonary fibrosis. Annu Rev Med. 2004;55:395-417. doi:10.1146/annurev.med.55.091902.103810
• 153. Chen X, Shi C, Cao H, et al. The hedgehog and Wnt/β-catenin system machinery mediate myofibroblast differentiation of LR-MSCs in pulmonary. Cell Death Dis. 2018;9(6). doi:10.1038/s41419-018-0692-9
• 154. Kotton DN, Morrisey EE. Lung regeneration: Mechanisms, applications and emerging stem cell populations. Nat Med. 2014;20(8):822-832. doi:10.1038/nm.3642
• 155. Abraham A, Krasnodembskaya A. Mesenchymal stem cell-derived extracellular vesicles for the treatment of acute respiratory distress syndrome. Stem Cells Transl Med. 2020;9(1):28-38. doi:10.1002/sctm.19-0205
• 156. PubMed. mesenchymal stem cell and COVID-19. US National Library of Medicine. Published 2021. https://pubmed.ncbi.nlm.nih.gov/?term=mesenchymal+stem+cell+and+COVID-19&filter=pubt.journalarticle
• 157. Shi L, Huang H, Lu X, et al. Effect of human umbilical cord-derived mesenchymal stem cells on lung damage in severe COVID-19 patients: a randomized, double-blind, placebo-controlled phase 2 trial. Signal Transduct Target Ther. 2021;6(1). doi:10.1038/s41392-021-00488-5
• 158. ClinicalTrials N. Evaluation of Safety and Efficiency of Method of Exosome Inhalation in SARS-CoV-2 Associated Pneumonia. (COVID-19EXO). US National Library of Medicine. Published 2020. https://clinicaltrials.gov/ct2/show/study/NCT04491240?term=nct04276987&draw=2&rank=3
• 159. ClinicalTrials N. Therapeutic Study to Evaluate the Safety and Efficacy of DW-MSC in COVID-19 Patients (DW-MSC). US National Library of Medicine. Published 2021. https://clinicaltrials.gov/ct2/show/NCT04535856?draw=2
• 160. Musiał-Wysocka A, Kot M, Majka M. The Pros and Cons of Mesenchymal Stem Cell-Based Therapies. Cell Transplant. 2019;28(7):801-812. doi:10.1177/0963689719837897
• 161. Moll G, Ankrum JA, Kamhieh-Milz J, et al. Intravascular Mesenchymal Stromal/Stem Cell Therapy Product Diversification: Time for New Clinical Guidelines. Trends Mol Med. 2019;25(2):149-163. doi:10.1016/j.molmed.2018.12.006
• 162. Pittenger MF, Discher DE, Péault BM, Phinney DG, Hare JM, Caplan AI. Mesenchymal stem cell perspective: cell biology to clinical progress. npj Regen Med. 2019;4(1). doi:10.1038/s41536-019-0083-6
• 163. Lanzoni G, Linetsky E, Correa D, et al. Umbilical cord mesenchymal stem cells for COVID-19 acute respiratory distress syndrome: A double-blind, phase 1/2a, randomized controlled trial. Stem Cells Transl Med. 2021;10(5):660-673. doi:10.1002/sctm.20-0472
• 164. Hashemian SMR, Aliannejad R, Zarrabi M, et al. Mesenchymal stem cells derived from perinatal tissues for treatment of critically ill COVID-19-induced ARDS patients: a case series. Stem Cell Res Ther. 2021;12(1):1-12. doi:10.1186/s13287-021-02165-4
• 165. Sharma D, Zhao F. Updates on clinical trials evaluating the regenerative potential of allogenic mesenchymal stem cells in COVID-19. npj Regen Med. 2021;6(1). doi:10.1038/s41536-021-00147-x
• 166. Xiao K, Hou F, Huang X, Li B, Qian ZR, Xie L. Mesenchymal stem cells: Current clinical progress in ARDS and COVID-19. Stem Cell Res Ther. 2020;11(1):1-7. doi:10.1186/s13287-020-01804-6
• 167. Gonzalez-Rey E, Anderson P, Gonzalez MA, Rico L, Buscher D, Delgado M. Human adult stem cells derived from adipose tissue protect against experimental colitis and sepsis. Gut. 2009;58(7):929-939. doi:10.1136/gut.2008.168534
• 168. Horak J, Nalos L, Martinkova V, et al. Evaluation of Mesenchymal Stem Cell Therapy for Sepsis: A Randomized Controlled Porcine Study. Front Immunol. 2020;11(February):1-13. doi:10.3389/fimmu.2020.00126
• 169. Laroye C, Lemarié J, Boufenzer A, et al. Clinical-grade mesenchymal stem cells derived from umbilical cord improve septic shock in pigs. Intensive Care Med Exp. 2018;6(1):24. doi:10.1186/s40635-018-0194-1
• 170. Lukomska B, Stanaszek L, Zuba-Surma E, Legosz P, Sarzynska S, Drela K. Challenges and Controversies in Human Mesenchymal Stem Cell Therapy. Stem Cells Int. 2019;2019. doi:10.1155/2019/9628536
• 171. Ankrum JA, Ong JF, Karp JM. Mesenchymal stem cells: immune evasive, not immune privileged. Nat Biotechnol. 2014;32(3):252-260. doi:10.1038/nbt.2816
• 172. Codinach M, Blanco M, Ortega I, et al. Design and validation of a consistent and reproducible manufacture process for the production of clinical-grade bone marrow–derived multipotent mesenchymal stromal cells. Cytotherapy. 2016;18(9):1197-1208. doi:10.1016/j.jcyt.2016.05.012
• 173. Levy O, Kuai R, Siren EMJ, et al. Shattering barriers toward clinically meaningful MSC therapies. Sci Adv. 2020;6(30):1-19. doi:10.1126/sciadv.aba6884
• 174. Ding DC, Shyu WC, Lin SZ. Mesenchymal stem cells. Cell Transplant. 2011;20(1):5-14. doi:10.3727/096368910X
• 175. de Miguel-Beriain I. The ethics of stem cells revisited. Adv Drug Deliv Rev. 2015;82:176-180. doi:10.1016/j.addr.2014.11.011
• 176. Volarevic V, Markovic BS, Gazdic M, et al. Ethical and Safety Issues of Stem Cell-Based Therapy. Int J Med Sci. 2018;15(1):36-45. doi:10.7150/ijms.21666
• 177. Zhao YX, Chen SR, Su PP, et al. Using Mesenchymal Stem Cells to Treat Female Infertility: An Update on Female Reproductive Diseases. Stem Cells Int. 2019;2019. doi:10.1155/2019/9071720
• 178. Verfaillie CM. Adult stem cells: Assessing the case for pluripotency. Trends Cell Biol. 2002;12(11):502-508. doi:10.1016/S0962-8924(02)02386-3
• 179. Dzierzak E, Bigas A. Blood Development: Hematopoietic Stem Cell Dependence and Independence. Cell Stem Cell. 2018;22(5):639-651. doi:10.1016/j.stem.2018.04.015
• 180. Tuan RS, Boland G, Tuli R. Adult mesenchymal stem cells and cell-based tissue engineering. Arthritis Res Ther 2003 51. 2002;5(1):1-14. doi:10.1186/AR614
• 181. Pellegrini G, Ardigò D, Milazzo G, et al. Navigating Market Authorization: The Path Holoclar Took to Become the First Stem Cell Product Approved in the European Union. Stem Cells Transl Med. 2018;7(1):146-154. doi:10.1002/sctm.17-0003
• 182. Jeyaraman M, Somasundaram R, Anudeep TC, et al. Mesenchymal Stem Cells (MSCs) as a Novel Therapeutic Option for nCOVID-19—A Review. Open J Regen Med. 2020;09(02):20-35. doi:10.4236/ojrm.2020.92004
• 183. Berebichez-Fridman R, Montero-Olvera PR. Sources and clinical applications of mesenchymal stem cells state-of-the-art review. Sultan Qaboos Univ Med J. 2018;18(3):e264-e277. doi:10.18295/squmj.2018.18.03.002
• 184. Berenson JR, Yellin O, Blumenstein B, et al. Using a Powered Bone Marrow Biopsy System Results in Shorter Procedures, Causes Less Residual Pain to Adult Patients, and Yields Larger Specimens. Diagn Pathol. 2011;6(1):23. doi:10.1186/1746-1596-6-23
• 185. Strioga M, Viswanathan S, Darinskas A, Slaby O, Michalek J. Same or Not the Same? Comparison of Adipose Tissue-Derived Versus Bone Marrow-Derived Mesenchymal Stem and Stromal Cells. Stem Cells Dev. 2012;21(14):2724-2752. doi:10.1089/scd.2011.0722
• 186. Drela K, Stanaszek L, Nowakowski A, Kuczynska Z, Lukomska B. Experimental Strategies of Mesenchymal Stem Cell Propagation: Adverse Events and Potential Risk of Functional Changes. Stem Cells Int. 2019;2019:1-10. doi:10.1155/2019/7012692
• 187. NIH. A Pilot Clinical Study on Inhalation of Mesenchymal Stem Cells Exosomes Treating Severe Novel Coronavirus Pneumonia, NCT04276987.; 2020. https://clinicaltrials.gov/ct2/show/study/NCT04276987?id=NCT04276987&draw=2&rank=1
• 188. Fuente R De, Rubio D, Garcia-castro J, Cigudosa JC, Lloyd AC, Bernad A. AC gu st AC Au st. 2005;(8):3035-3039.
• 189. Aponte PM, Caicedo A. Stemness in cancer: Stem cells, cancer stem cells, and their microenvironment. Stem Cells Int. 2017;2017. doi:10.1155/2017/5619472
• 190. Herberts CA, Kwa MSG, Hermsen HPH. Risk factors in the development of stem cell therapy. J Transl Med. 2011;9:1-14. doi:10.1186/1479-5876-9-29
• 191. Liu XB, Chen H, Chen HQ, et al. Angiopoietin-1 preconditioning enhances survival and functional recovery of mesenchymal stem cell transplantation. J Zhejiang Univ Sci B. 2012;13(8):616-623. doi:10.1631/jzus.B1201004
• 192. Kim HJ, Park J-S. Usage of Human Mesenchymal Stem Cells in Cell-based Therapy: Advantages and Disadvantages. Dev Reprod. 2017;21(1):1-10. doi:10.12717/dr.2017.21.1.001
• 193. Durand N, Mallea J, Zubair AC. Insights into the use of mesenchymal stem cells in COVID-19 mediated acute respiratory failure. npj Regen Med. 2020;5(1). doi:10.1038/s41536-020-00105-z
• 194. Zhang Y, Ding J, Ren S, et al. Intravenous infusion of human umbilical cord Wharton’s jelly-derived mesenchymal stem cells as a potential treatment for patients with COVID-19 pneumonia. Stem Cell Res Ther. 2020;11(1):4-9. doi:10.1186/s13287-020-01725-4
• 195. Mahajan A, Bhattacharyya S. A brief review on potential application of mesenchymal stem cell and secretome in combating mortality and morbidity in COVID-19 patients. Biomed J. 2021;44(1):63-73. doi:10.1016/j.bj.2020.09.003