COVID-19: A premise for MSCs?

The recent COVID-19 outbreak was declared a pandemic on March 11, 2020 by the World Health Organization (WHO)¹. Since then, countries have gone into “lockdown”, including South Africa who declared a National State of Disaster². The media is overrun with daily reports of new cases or mortalities, healthcare systems are buckling under the pressure and researchers are racing against the clock to find a cure. Apart from addressing the primary viral infection, the related complications pose an even greater threat as the infection may progress to viral pneumonia and organ failure.  Researches have therefor started to investigate novel therapies using stem cells to manage these secondary complications ^{3, 4, 5, 6}. Various studies have reported on the efficiency of mesenchymal stromal cells (MSC) to protect and repair induced lung injury in rodent models including enhanced oxygenation and lung compliance, decreased lung inflammation and restored lung structure⁷. In addition, the MSC secretome has also been shown to be effective in reducing the levels of inflammatory cytokines and interleukins,⁸ which may also prove beneficial in COVID-19 related pneumonia.

The premise for using MSCs in the treatment of COVID-19 was substantiated by the treatment of a 65-year-old female patient in Kunming Hospital³. Researchers administered three doses of umbilical cord derived MSCs at different intervals and reported improvements within four days after her first treatment. Similar findings were reported in consecutive studies performed in China. Various studies have also been performed using MSCs derived from different sources including bone marrow, adipose tissue and menstrual blood^{9, 10, 11}.

In order to implement a stem cell-based treatment regime as supportive care for patients infected with the COVID-19 virus, a well-defined, characterised stem cell line would have to be available. MSCs are naïve cells that can differentiate into a variety of adult cell types dependant on its surrounding niche. Research has shown that MSCs possess immune-modulating properties and can home to damaged tissues, promoting the regeneration and repair thereof. MSCs also have the capacity to suppress the regular processes of allogeneic rejection, which subsequently allows the use of donor cells without prior histocompatibility testing. Although MSCs derived from different tissue sources vary in certain biological aspects, the International Society for Cell Therapy (ISCT) has identified a minimum criterion that needs to be met for stem cells to be classified as MSC. These criteria were derived from the properties of MSCs and the biological mediators required to initiate their functions. These criteria are¹³:

• MSCs must be plastic-adherent when maintained in standard culture conditions.
• MSC must express CD105, CD73 and CD90, and lack expression of CD45, CD34, CD14 or CD11b, CD79α or CD19 and HLA-DR surface molecules.
• MSC must differentiate into osteoblasts (bone), adipocytes (fat) and chondroblasts (cartilage) in vitro

Furthermore, data and dose-related responses and possible adverse events would be required to ensure the safe and effective use of these cells. No such case studies or clinical trials have been reported on in South Africa as of yet, despite Africa being identified as most at risk for COVID-19 spread due to high population densities, frequent traffic between Africa and China and limited resources¹².

Currently, South Africa has little to no developed infrastructure that could sustain the use and investigation of MSCs for respiratory distress apart from smaller clinics that rely on private funding. Regardless of the limitations that we face, SASCI is committed to promoting the safe and effective use of cell derived products and is currently liaising with various industry partners to address this hiatus.  We hope to report back soon and until then, be vigilant, be safe and be responsible.

1. Ducharme, J. World Health Organization Declares COVID-19 a ‘Pandemic.’ Here’s What That Means. Time [newspaper on the Internet]. 2020 March 11 [cited 07 Apr 2020];Covid-19. Available from: https://time.com/5791661/who-coronavirus-pandemic-declaration/
2. Tandwa, L. Coronavirus in SA: Ramaphosa declares national ‘state of disaster’, imposes travel bans. News24. 2020 March 15 [cited 07 April 2020];News. Available from: https://www.news24.com/SouthAfrica/News/coronavirus-in-sa-ramaphosa-declares-national-state-of-disaster-imposes-travel-bans-20200315
3. Liang B, Chen J, Li T, Wu H, Yang W, Li Y et al. Clinical remission of a critically ill COVID-19 patient treated by human umbilical cord mesenchymal stem cells. ChinaXiv [Internet]. 2020 FEB [cited 2020 Mar 24]. Available from: http://psych.chinaxiv.org/user/download.htm?id=30285&filetype=pdf.
   DOI: chinaXiv:202002.00084v1
4. Sairam 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 [Internet]. 2020 MAR0; 23:E71-E83 [cited 2020 Apr 07]. Available from: https://asipp.worldsecuresystems.com/COVID-19/DRAFT-COVID%20Article.pdf. ISSN 2150-1149.
5. clinicaltrials.gov. Mesenchymal Stem Cell Treatment for Pneumonia Patients Infected with 2019 Novel Coronavirus. U.S National Library of Medicine. 2020. [cited 2020 February 24]. Available from: https://clinicaltrials.gov/ct2/show/NCT04252118
6. clinicaltrials.gov. Umbilical Cord(UC)-Derived Mesenchymal Stem Cells(MSCs) Treatment for the 2019-novel Coronavirus(nCOV) Pneumonia. U.S National Library of Medicine. [cited 2020 Apr 07] Available from: https://clinicaltrials.gov/ct2/show/NCT04269525?term=stem+cells&cond=Corona+Virus+Infection&draw=2
7. Curley GF, Hayes M, Ansari B, et al. Mesenchymal stem cells enhance recovery and repair following ventilator-induced lung injury in the rat. Thorax. 2012;67:496-501.
8. Hayes, M., Curley, G.F., Masterson, C. et al. Mesenchymal stromal cells are more effective than the MSC secretome in diminishing injury and enhancing recovery following ventilator-induced lung injury. ICMx 3, 29 (2015). https://doi.org/10.1186/s40635-015-0065-y
9. Chen J, Hu C, Chen L, Tang L, Zhu Y, Xu X et al. 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. 2020. ISSN 2095-8099, https://doi.org/10.1016/j.eng.2020.02.006.
10. Antoniou KM, Papadaki HA, Soufla G, Kastrinaki MC, Damianaki A, Koutala H et al. Investigation of bone marrow mesenchymal stem cells (BM MSCs) involvement in idiopathic pulmonary fibrosis (IPF). Respiratory Medicine. 2010:104(10):1535-1542.
11. Zheng G, Huang L, Tong H et al. Treatment of acute respiratory distress syndrome with allogeneic adipose-derived mesenchymal stem cells: a randomized, placebo-controlled pilot study. Respir Res. 2014:15(39). https://doi.org/10.1186/1465-9921-15-39
12. Velavan TP and Meyer CG. The COVID-19 epidemic. Tropical Medicine and International Health. FEB 2020. [cited 2020 MAR 23]. doi:10.1111/tmi.13383. Available from: https://www.researchgate.net/profile/Thirumalaisamy_Velavan3/publication/339232865_The_Covid-19_epidemic/links/5e4c5bbc92851c7f7f456773/The-Covid-19-epidemic.pdf
13. M Dominici, K Le Blanc, I Mueller, I Slaper-Cortenbach, Fc Marini, Ds Krause et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. 2006: 8:4, 315-317, DOI: 10.1080/14653240600855905