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White Paper by Soumyaa Thakur

Reviewed by Vi Lam, Dr. Prasad Pethe


The SARS-CoV-2 outbreak left everyone shocked as to what a tiny little virus can do to the entire world. It has taken the lives of a large group of individuals, and many have also been able to defeat the virus. Although there is no definite treatment or preventive medicine yet, there are many strong contenders in the race to find a cure or vaccine. One such contender is stem cells. Recently noticed worldwide, stem cells are on the cutting edge of modern medicine and are used as therapeutics in vast areas of medicine such as in the treatment of ALS (amyotrophic lateral sclerosis), GVHD (graft versus host disease), liver cirrhosis, and AMI (acute myocardial infarction). Stem cells have also shown promising results in fields of neurodegenerative diseases, diabetes, dental ailments, ocular treatment, cardiac repair, and gene therapy. Stem cells have also displayed their ability in organ engineering.

Particularly mesenchymal stem cells (Fig.1) are being researched for the use as a therapeutic for COVID-19. Mesenchymal stem cells (MSC) are a type of multipotent stem cells and can differentiate and self-renew into a specific range of cells such as osteoblasts (a type of bone cells), myocytes (muscle cells), chondrocytes (cartilage cells), and adipocytes (fat cells). MSC can be isolated from both human and animal sources; when obtained from humans, are of the non- hematopoietic type. They possess immunomodulatory effects, secrete immune receptors and cytokines that help in the regulation of the host microenvironment

 
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Why Mesenchymal Stem Cells?

The fundamental question is why Mesenchymal Stem Cells? MSEs have eminent anti- inflammatory and immunomodulatory properties, due to which they have been used in the treatment of various auto-immune diseases such as multiple sclerosis and rheumatoid arthritis, or to inhibit rejection of transplanted organs. In the COVID-19 pandemic, they can help by normalizing the immune system function. Specifically, these cells help increase the level of the anti-inflammatory protein IL-10 which in turn helps curb mild to severe inflammation caused in the target organs. MSEs, once in action, also reduce the levels of the pro-inflammatory protein TNF-α and the inflammation marker C-reactive protein. Research suggests that Mesenchymal Stem Cells also help increase the number of lymphocytes and regulatory dendritic cells in infected patients which in turn activates anti-viral properties that can help combat the virus. The MSE can also help restrain the cytokine storm induced by the SARS-CoV-2 indicating that they can be used as a promising therapy in patients who develop ARDS as a result of SARS-CoV-2 infection. MSE therapy has also shown promising results in elderly infected individuals. For COVID-19 patients, research has been restricted to Mesenchymal Stem Cells obtained from the placenta and umbilical cord for unknown reasons. (“Exploring the Utility of Stem Cell Therapy for COVID-19 | Technology Networks,” n.d.; “How stem cells combat coronavirus,” n.d.) Clinical trials dedicated to testing the use of Mesenchymal Stem Cells in COVID-19 patients have already begun in many countries such as Europe, Canada, and The United States of America where, doctors expect to have a footfall of 300 hospitalized patients for this randomized, placebo-controlled trial; wherein, few patients shall receive the drug remestemcel-L and few shall receive the placebo in addition to the standard of care. (“Experimental stem cell therapy trial for COVID-19 initiated,” n.d.)

Mode of Action

Mesenchymal Stem Cells have the potential to be the strongest competitors in the race to find a treatment for COVID-19. Clinical grade MSCs are injected intravenously into infected patients that showed symptoms such as high fever, dyspnea, reduced oxygen saturation, and pneumonia at the dose of 1 × 106 MSCs per kilogram body weight. The patients were observed for a period of 14 days. These patients showed resolved symptoms in almost 2-4 days. Fig. 2 shows the steps that occur in the course of MSC therapy for COVID-19.

 
 
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Some of these injected Mesenchymal Stem Cells get entrapped in the lungs and release a wide variety of soluble mediators such as extracellular vesicles, anti-inflammatory cytokines, antimicrobial-peptides, and angiogenic growth factors. The release of these mediators is specific to each individual and depends on the lung environment; this pattern is strongly regulated by the differential activation of the pathogen-associated molecular pathogen receptors (PAMPS) that are expressed on the surface of MSCs. The PAMPS also involved Toll-Like receptors which are strongly activated by viral unmethylated CpF-DNA and viral RNA that leads to the activation of

subsequent cellular signaling pathways followed by activation of MSCs. The injected stem cells also release Keratinocyte Growth Factor (KGF) and angiopoietin -1 (Ang-1) that help restore the distorted alveolar-capillary barriers, a common symptom of patients with ARDS. The secreted extracellular vessels contain inhibitory mRNA and miRNA that are known to regulate the positive effects of MSCs in the case of lung tissue damage. In the case of any underlying ailments in COVID-19 patients, the immunomodulatory effects of the MSCs are known to improve organ function due to the secretion of paracrine factors that interact with active immune cells.

It has been observed that after the injection of stem cells, the levels of peripheral lymphocytes, and regulatory dendritic cells in infected patients increased drastically whereas, the levels of C-reactive protein and TNF-α decreased. The cytokine storm induced by the SARS-CoV-2 virus was observed to reduce radically almost 6 days after infusion. Furthermore, elucidation of the underlying mechanisms carried out by the MSC on the SARS-CoV-2 virus was performed using the technique by 10X RNA sequencing which indicated that the injected population of Mesenchymal Stem Cells was free from viral infection. The fact the Mesenchymal Stem Cells have to ability to be resistant to viral infections gives them an upper hand when compared to other under research treatment modalities. This resistance is assumed to be induced by the presence of intrinsic interferon stimulating factors.

It can be concluded that the pulmonary microenvironment can be repaired with the help of Mesenchymal Stem Cell therapy thereby preventing the everlasting effects of COVID-19 such as pulmonary fibrosis (Chrzanowski, Kim, & McClements, 2020; Golchin, Seyedjafari, & Ardeshirylajimi, 2020; Leng et al., 2020; Liu et al., 2020; Rajarshi, Chatterjee, & Ray, 2020)

References:

  1. Experimental stem cell therapy trial for COVID-19 initiated. (n.d.). Retrieved July 3, 2020, from https://www.europeanpharmaceuticalreview.com/news/120258/experimental-stem-cell-th erapy-trial-for-covid-19-initiated/

  2. How stem cells combat coronavirus. (n.d.). Retrieved July 3, 2020, from https://cryobank.ua/en/news-en/how-stem-cells-combat-coronavirus/

  3. Exploring the Utility of Stem Cell Therapy for COVID-19 | Technology Networks. (n.d.). Retrieved July 3, 2020, from https://www.technologynetworks.com/biopharma/articles/exploring-the-utility-of-stem-ce ll-therapy-for-covid-19-334068

  4. Chrzanowski, W., Kim, S. Y., & McClements, L. (2020). Can Stem Cells Beat COVID-19: Advancing Stem Cells and Extracellular Vesicles Toward Mainstream Medicine for Lung Injuries Associated With SARS-CoV-2 Infections. ​Frontiers in Bioengineering and Biotechnology​, ​8(​May), 1–8. https://doi.org/10.3389/fbioe.2020.00554

  5. Golchin, A., Seyedjafari, E., & Ardeshirylajimi, A. (2020). Mesenchymal Stem Cell Therapy for COVID-19: Present or Future. ​Stem Cell Reviews and Reports​, ​16​(3), 427–433. https://doi.org/10.1007/s12015-020-09973-w

  6. Leng, Z., Zhu, R., Hou, W., Feng, Y., Yang, Y., Han, Q., ... Zhao, R. C. (2020). Transplantation of ACE2- Mesenchymal stem cells improves the outcome of patients with covid-19 pneumonia. ​Aging and Disease,​ ​11(​2), 216–228. https://doi.org/10.14336/AD.2020.0228

  7. Liu, S., Peng, D., Qiu, H., Yang, K., Fu, Z., & Zou, L. (2020). Mesenchymal stem cells asapotentialtherapyforCOVID-19.​StemCellResearchandTherapy,​​11(​1),8–11. https://doi.org/10.1186/s13287-020-01678-8

  8. Rajarshi, K., Chatterjee, A., & Ray, S. (2020). Combating COVID-19 with mesenchymal stem cell therapy. ​Biotechnology Reports,​ ​26,​ e00467. https://doi.org/10.1016/j.btre.2020.e00467

  9. Ludwig, S., & Zarbock, A. (2020). Coronaviruses and SARS-CoV-2: A Brief Overview. Anesthesia and Analgesia​, ​131​(1), 93–96. https://doi.org/10.1213/ANE.0000000000004845

  10. Saldanha-Araujo, F., Melgaço Garcez, E., Silva-Carvalho, A. E., & Carvalho, J. L. (2020). Mesenchymal Stem Cells: A New Piece in the Puzzle of COVID-19 Treatment. Frontiers in Immunology​, ​11​(July), 1–10. ​https://doi.org/10.3389/fimmu.2020.01563

  11. Shu, L., Niu, C., Li, R., Huang, T., Wang, Y., Huang, M., ... Feng, G. (2020). Treatment of severe COVID-19 with human umbilical cord mesenchymal stem cells. ​Stem Cell Research & Therapy​, ​11​(1), 361. ​https://doi.org/10.1186/s13287-020-01875-5

  12. Esquivel, D., Mishra, R., Soni, P., Seetharaman, R., Mahmood, A., & Srivastava, A. (2020). Stem Cells Therapy as a Possible Therapeutic Option in Treating COVID-19 Patients. ​Stem Cell Reviews and Reports​. ​https://doi.org/10.1007/s12015-020-10017-6

  13. Majolo, F., da Silva, G. L., Vieira, L., Timmers, L. F. S. M., Laufer, S., & Goettert, M. I. (2020). Review of Trials Currently Testing Stem Cells for Treatment of Respiratory Diseases: Facts Known to Date and Possible Applications to COVID-19. ​Stem Cell Reviews and Reports​. ​https://doi.org/10.1007/s12015-020-10033-6

  14. Tsuchiya, A., Takeuchi, S., Iwasawa, T., Kumagai, M., Sato, T., Motegi, S., ... Terai, S. (2020). Therapeutic potential of mesenchymal stem cells and their exosomes in severe novel coronavirus disease 2019 (COVID-19) cases. ​Inflammation and Regeneration,​ 40​(1), 10–15. ​https://doi.org/10.1186/s41232-020-00121-y

  15. Can, A., & Coskun, H. (2020). The rationale of using mesenchymal stem cells in patients with COVID-19-related acute respiratory distress syndrome: What to expect. ​Stem Cells Translational Medicine,​ (June), 1–16. ​https://doi.org/10.1002/sctm.20-0164

  16. Sahu, K. K., Siddiqui, A. D., & Cerny, J. (2020). Mesenchymal Stem Cells in COVID-19: A Journey from Bench to Bedside. ​Laboratory Medicine.​ https://doi.org/10.1093/labmed/lmaa049

  17. Lu, Z., Chang, W., Meng, S., Xu, X., Xie, J., Guo, F., ... Liu, L. (2019). Mesenchymal stem cells induce dendritic cell immune tolerance via paracrine hepatocyte growth factor toalleviateacutelunginjury.​StemCellResearchandTherapy,​​10(​1),1–16. https://doi.org/10.1186/s13287-019-1488-2

  18. Tang, L., Jiang, Y., Zhu, M., Chen, L., Zhou, X., Zhou, C., ... Li, L. (2020). Clinical study using mesenchymal stem cells for the treatment of patients with severe COVID-19. Frontiers of Medicine.​ ​https://doi.org/10.1007/s11684-020-0810-9

  19. Xiao, K., Hou, F., Huang, X., Li, B., Qian, Z. R., & Xie, L. (2020). Mesenchymal stem cells: Current clinical progress in ARDS and COVID-19. ​Stem Cell Research and Therapy​, ​11​(1), 1–7. ​https://doi.org/10.1186/s13287-020-01804-6

  20. Atluri, S., Manchikanti, L., & Hirsch, J. A. (2020). 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,​ ​23(​ 2), E71–E84.

  21. Copcu, H. E. (2020). Potential Using of Fat-derived Stromal Cells in the Treatment of Active Disease, and also, in Both Pre- and Post-Periods in COVID-19. ​Aging and Disease,​ ​11(​ 4), 730. ​https://doi.org/10.14336/ad.2020.0621

  22. He, J. G., Li, H. R., Li, B. B., Xie, Q. L., Yan, D., & Wang, X. J. (2019). Bone marrow mesenchymal stem cells overexpressing GATA-4 improve cardiac function following myocardial infarction. ​Perfusion (United Kingdom)​, ​34​(8), 696–704. https://doi.org/10.1177/0267659119847442

  23. Chalphin, A. V., Tracy, S. A., Lazow, S. P., Kycia, I., Zurakowski, D., & Fauza, D. O. (2020). A comparison between placental and amniotic mesenchymal stem cells in transamniotic stem cell therapy for experimental gastroschisis. ​Journal of Pediatric Surgery,​ ​55(​ 1), 49–53. ​https://doi.org/10.1016/j.jpedsurg.2019.09.049

  24. Vellas, C., Delobel, P., De Souto Barreto, P., & Izopet, J. (2020). COVID-19, Virology and Geroscience: A Perspective. ​Journal of Nutrition, Health and Aging​, ​24​(7), 685–691. https://doi.org/10.1007/s12603-020-1416-2

  25. Esakandari, H., Nabi-Afjadi, M., Fakkari-Afjadi, J., Farahmandian, N., Miresmaeili, S.-M., & Bahreini, E. (2020). A comprehensive review of COVID-19 characteristics. Biological Procedures Online​, ​22​(1), 1–10. ​https://doi.org/10.1186/s12575-020-00128-2

  26. Baig, A. M. (2020). Computing the Effects of SARS-CoV-2 on Respiration Regulatory Mechanisms in COVID-19. ​ACS Chemical Neuroscience,​ ​11(​16), 2416–2421. https://doi.org/10.1021/acschemneuro.0c00349

  27. Pascarella, G., Strumia, A., Piliego, C., Bruno, F., Del Buono, R., Costa, F., ... Agrò, F. E. (2020). COVID-19 diagnosis and management: a comprehensive review. ​Journal of Internal Medicine​, ​288​(2), 192–206. ​https://doi.org/10.1111/joim.13091

  28. Naserghandi, A., Allameh, S. F., & Saffarpour, R. (2020). All about COVID-19 in brief. New Microbes and New Infections,​ ​35,​ 100678. https://doi.org/10.1016/j.nmni.2020.100678

  29. Taghavi-Farahabadi, M., Mahmoudi, M., Soudi, S., & Hashemi, S. M. (2020). Hypothesis for the management and treatment of the COVID-19-induced acute respiratory distress syndrome and lung injury using mesenchymal stem cell-derived exosomes. ​Medical Hypotheses,​ ​144(​May), 109865. https://doi.org/10.1016/j.mehy.2020.109865

  30. Fitzgerald, P. J. (2020). Noradrenergic and serotonergic drugs may have opposing effects on COVID-19 cytokine storm and associated psychological effects. ​Medical Hypotheses​, 144​(May), 109985. ​https://doi.org/10.1016/j.mehy.2020.109985

  31. Rao, V., Thakur, S., Rao, J., Arakeri, G., Brennan, P. A., Jadhav, S., ... Rao, G. (2020). Mesenchymal stem cells-bridge catalyst between innate and adaptive immunity in COVID 19. ​Medical Hypotheses,​ ​143(​May), 109845. https://doi.org/10.1016/j.mehy.2020.109845

  32. Metcalfe, S. M. (2020). Mesenchymal stem cells and management of COVID-19 pneumonia. ​Medicine in Drug Discovery​, ​5​, 100019. https://doi.org/10.1016/j.medidd.2020.100019

  33. Chen, J., Hu, C., Chen, L., Tang, L., Zhu, Y., Xu, X., ... Li, L. (2020). Clinical Study of Mesenchymal Stem Cell Treatment for Acute Respiratory Distress Syndrome Induced by Epidemic Influenza A (H7N9) Infection: A Hint for COVID-19 Treatment. ​Engineering,​ (xxxx). https://doi.org/10.1016/j.eng.2020.02.006

  34. Zumla, A., Wang, F. S., Chang, C., Ippolito, G., Petrosillo, N., Agrati, C., ... Maeurer, M. (2020). 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. International Journal of Infectious Diseases​, ​96​, 431–439. https://doi.org/10.1016/j.ijid.2020.05.040

  35. Karaahmet, F., & Kocaman, S. A. (2020). Endothelial progenitor cells and mesenchymal stem cells to overcome vascular deterioration and cytokine storm in critical patients with COVID-19. ​Medical Hypotheses,​ ​144(​May), 109973. https://doi.org/10.1016/j.mehy.2020.109973

  36. Deffune, E., Prudenciatti, A., & Moroz, A. (2020). Mesenchymal stem cell (MSc) secretome: A possible therapeutic strategy for intensive-care COVID-19 patients. Medical Hypotheses,​ ​142,​ 109769. https://doi.org/10.1016/j.mehy.2020.109769

  37. Khorshidi, M., Zarezadeh, M., Emami, M., Olang, B., & Moghaddam, O. M. (2020). Promising impacts of mesenchymal stem cell therapy in treatment of SARS-CoV-2 (COVID-19). ​Heart & Lung​, ​2​. https://doi.org/10.1016/j.hrtlng.2020.08.007

  38. Hamdan, H., Hashmi, S. K., Lazarus, H., Gale, R. P., Qu, W., & El Fakih, R. (2020). Promising role for mesenchymal stromal cells in coronavirus infectious disease-19 (COVID-19)-related severe acute respiratory syndrome? ​Blood Reviews​, (xxxx), 100742. https://doi.org/10.1016/j.blre.2020.100742

  39. O’Driscoll, L. (2020). Extracellular vesicles from mesenchymal stem cells as a Covid-19 treatment. ​Drug Discovery Today,​ ​25(​7), 1124–1125. https://doi.org/10.1016/j.drudis.2020.04.022

  40. Chen, X., Shan, Y., Wen, Y., Sun, J., & Du, H. (2020). Mesenchymal stem cell therapy in severe COVID-19: A retrospective study of short-term treatment efficacy and side effects. ​Journal of Infection,​ (xxxx), 5–7. https://doi.org/10.1016/j.jinf.2020.05.020

  41. Muraca, M., Pessina, A., Pozzobon, M., Dominici, M., Galderisi, U., Lazzari, L., ... Baraldi, E. (2020). Mesenchymal stromal cells and their secreted extracellular vesicles as therapeutic tools for COVID-19 pneumonia? ​Journal of Controlled Release​, ​325​(June), 135–140. https://doi.org/10.1016/j.jconrel.2020.06.036

  42. Razmi, M., Hashemi, F., Gheytanchi, E., & Dehghan, M. (2020). International Immunopharmacology Immunomodulatory-based therapy as a potential promising treatment strategy against severe COVID-19 patients : A systematic review. ​International Immunopharmacology,​ ​88(​August), 106942. https://doi.org/10.1016/j.intimp.2020.106942

  43. Sleem, A., & Saleh, F. (2020). Mesenchymal stem cells in the fight against viruses: Face to face with the invisible enemy. ​Current Research in Translational Medicine​, ​68​(3), 105–110. https://doi.org/10.1016/j.retram.2020.04.003

  44. Mansourabadi, A. H., Sadeghalvad, M., Mohammadi-Motlagh, H. R., & Rezaei, N. (2020). The immune system as a target for therapy of SARS-CoV-2: A systematic review of the current immunotherapies for COVID-19. ​Life Sciences​, ​258​(August), 118185. https://doi.org/10.1016/j.lfs.2020.118185

  45. Wang, D., Li, Z., & Liu, Y. (2020). An overview of the safety, clinical application and antiviral research of the COVID-19 therapeutics. ​Journal of Infection and Public Health.​ https://doi.org/10.1016/j.jiph.2020.07.004

  46. Li, Y., Liu, S., Zhang, S., Ju, Q., Zhang, S., Yang, Y., & Wang, H. (2020). Current treatment approaches for COVID-19 and the clinical value of transfusion-related technologies. ​Transfusion and Apheresis Science,​ (May), 102839. https://doi.org/10.1016/j.transci.2020.102839

  47. Hassanpour, M., Rezaie, J., Nouri, M., & Panahi, Y. (2020). The role of extracellular vesicles in COVID-19 virus infection. ​Infection, Genetics and Evolution​, ​85​(May), 104422. https://doi.org/10.1016/j.meegid.2020.104422

  48. Turner, L. (2020). Preying on Public Fears and Anxieties in a Pandemic: Businesses Selling Unproven and Unlicensed “Stem Cell Treatments” for COVID-19. ​Cell Stem Cell,​ ​26(​ 6), 806–810. https://doi.org/10.1016/j.stem.2020.05.003

  49. Zhang, Y., Zeng, X., Jiao, Y., Li, Z., Liu, Q., Yang, M., & Ye, J. (2020). Mechanisms involved in the development of thrombocytopenia in patients with COVID-19. Thrombosis Research,​ ​193(​May), 110–115. https://doi.org/10.1016/j.thromres.2020.06.008

  50. Algwaiz, G., Aljurf, M., Koh, M., Horowitz, M. M., Ljungman, P., Weisdorf, D., ... Hashmi, S. K. (2020). Real-World Issues and Potential Solutions in Hematopoietic Cell Transplantation during the COVID-19 Pandemic: Perspectives from the Worldwide Network for Blood and Marrow Transplantation and Center for International Blood and Marrow Transplant Research Health Services and International Studies Committee. Biology of Blood and Marrow Transplantation​, ​000​, 1–9. https://doi.org/10.1016/j.bbmt.2020.07.021

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