Mesenchymal stem cells and COVID-19: the process of discovery and of translation

BMT

Biomaterials Translational

TBA2096-112X

Biomaterials Translational

10.12336/biomatertransl.2021.04.006

Review

Mesenchymal stem cells and COVID-19: the process of discovery and of translationhttps://artdesignp.com/journal/BMT/2/4/10.12336/biomatertransl.2021.04.006CaplanArnold I.

2021

2021-12-28

Mesenchymal stem cells were developed as a cell-based therapeutic in the 1990’s. The translation of culture expanded mesenchymal stem cells from a basic science focus into a modern therapeutic has taken 30 years. The current state of the basic science information argues that mesenchymal stem cells may be curative for coronavirus disease 2019 (COVID-19). Indeed, early small-scale clinical trials have shown positive results. The issue raised is how to assemble the resources to get this cell-based therapy approved for clinical use. The technology is complex, the COVID-19 viral infections are life threatening, the cost is high, but human life is precious. What will it take to perfect this potentially curative technology?COVID-19 ; discovery research ; mesenchymal stem cell ; translation

1. Caplan, A. I. Mesenchymal stem cells. J Orthop Res. 1991, 9, 641-650.  2. Guimarães-Camboa, N.; Cattaneo, P.; Sun, Y.; Moore-Morris, T.; Gu, Y.; Dalton, N. D.; Rockenstein, E.; Masliah, E.; Peterson, K. L.; Stallcup, W. B.; Chen, J.; Evans, S. M. Pericytes of multiple organs do not behave as mesenchymal stem cells in vivo. Cell Stem Cell. 2017, 20:345-359.e5.  3. Levy, O.; Kuai, R.; Siren, E. M. J.; Bhere, D.; Milton, Y.; Nissar, N.; De Biasio, M.; Heinelt, M.; Reeve, B.; Abdi, R.; Alturki, M.; Fallatah, M.; Almalik, A.; Alhasan, A. H.; Shah, K.; Karp, J. M. Shattering barriers toward clinically meaningful MSC therapies. Sci Adv. 2020, 6, eaba6884.  4. Dominici, M.; Le Blanc, K.; Mueller, I.; Slaper-Cortenbach, I.; Marini, F.; Krause, D.; Deans, R.; Keating, A.; Prockop, D.; Horwitz, E. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. 2006, 8, 315-317.  5. Caplan, A. I. What’s in a name? Tissue Eng Part A. 2010, 16, 2415-2417.  6. Crisan, M.; Yap, S.; Casteilla, L.; Chen, C. W.; Corselli, M.; Park, T. S.; Andriolo, G.; Sun, B.; Zheng, B.; Zhang, L.; Norotte, C.; Teng, P. N.; Traas, J.; Schugar, R.; Deasy, B. M.; Badylak, S.; Buhring, H. J.; Giacobino, J. P.; Lazzari, L.; Huard, J.; Péault, B. A perivascular origin for mesenchymal stem cells in multiple human organs. Cell Stem Cell. 2008, 3, 301-313.  7. Caplan, A. I. All MSCs are pericytes? Cell Stem Cell. 2008, 3, 229-230.  8. Bernardo, M. E.; Fibbe, W. E. Mesenchymal stromal cells: sensors and switchers of inflammation. Cell Stem Cell. 2013, 13, 392-402.  9. de Witte, S. F. H.; Luk, F.; Sierra Parraga, J. M.; Gargesha, M.; Merino, A.; Korevaar, S. S.; Shankar, A. S.; O’Flynn, L.; Elliman, S. J.; Roy, D.; Betjes, M. G. H.; Newsome, P. N.; Baan, C. C.; Hoogduijn, M. J. Immunomodulation by therapeutic mesenchymal stromal cells (MSC) is triggered through phagocytosis of MSC by monocytic cells. Stem Cells. 2018, 36, 602-615.  10. Vasandan, A. B.; Jahnavi, S.; Shashank, C.; Prasad, P.; Kumar, A.; Prasanna, S. J. Human Mesenchymal stem cells program macrophage plasticity by altering their metabolic status via a PGE(2)-dependent mechanism. Sci Rep. 2016, 6, 38308.  11. Lin, P.; Correa, D.; Kean, T. J.; Awadallah, A.; Dennis, J. E.; Caplan, A. I. Serial transplantation and long-term engraftment of intra-arterially delivered clonally derived mesenchymal stem cells to injured bone marrow. Mol Ther. 2014, 22, 160-168.  12. Caplan, A. I.; Dennis, J. E. Mesenchymal stem cells as trophic mediators. J Cell Biochem. 2006, 98, 1076-1084.  13. Guo, W.; Wang, H.; Zou, S.; Gu, M.; Watanabe, M.; Wei, F.; Dubner, R.; Huang, G. T.; Ren, K. Bone marrow stromal cells produce long-term pain relief in rat models of persistent pain. Stem Cells. 2011, 29, 1294-1303.  14. Bonfield, T. L.; Koloze, M.; Lennon, D. P.; Zuchowski, B.; Yang, S. E.; Caplan, A. I. Human mesenchymal stem cells suppress chronic airway inflammation in the murine ovalbumin asthma model. Am J Physiol Lung Cell Mol Physiol. 2010, 299, L760-770.  15. Meirelles Lda, S.; Fontes, A. M.; Covas, D. T.; Caplan, A. I. Mechanisms involved in the therapeutic properties of mesenchymal stem cells. Cytokine Growth Factor Rev. 2009, 20, 419-427.  16. Krasnodembskaya, A.; Song, Y.; Fang, X.; Gupta, N.; Serikov, V.; Lee, J. W.; Matthay, M. A. Antibacterial effect of human mesenchymal stem cells is mediated in part from secretion of the antimicrobial peptide LL-37. Stem Cells. 2010, 28, 2229-2238.  17. Sutton, M. T.; Fletcher, D.; Ghosh, S. K.; Weinberg, A.; van Heeckeren, R.; Kaur, S.; Sadeghi, Z.; Hijaz, A.; Reese, J.; Lazarus, H. M.; Lennon, D. P.; Caplan, A. I.; Bonfield, T. L. Antimicrobial properties of mesenchymal stem cells: therapeutic potential for cystic fibrosis infection, and treatment. Stem Cells Int. 2016, 2016, 5303048.  18. Mascharak, S.; desJardins-Park, H. E.; Davitt, M. F.; Griffin, M.; Borrelli, M. R.; Moore, A. L.; Chen, K.; Duoto, B.; Chinta, M.; Foster, D. S.; Shen, A. H.; Januszyk, M.; Kwon, S. H.; Wernig, G.; Wan, D. C.; Lorenz, H. P.; Gurtner, G. C.; Longaker, M. T. Preventing Engrailed-1 activation in fibroblasts yields wound regeneration without scarring. Science. 2021, 372, eaba2374.  19. Zhang, L.; Ghosh, S. K.; Basavarajappa, S. C.; Muller-Greven, J.; Penfield, J.; Brewer, A.; Ramakrishnan, P.; Buck, M.; Weinberg, A. Molecular dynamics simulations and functional studies reveal that hBD-2 binds SARS-CoV-2 spike RBD and blocks viral entry into ACE2 expressing cells. bioRxiv. 2021. doi: 10.1101/2021.01.07.425621.  20. Wang, C.; Wang, S.; Li, D.; Chen, P.; Han, S.; Zhao, G.; Chen, Y.; Zhao, J.; Xiong, J.; Qiu, J.; Wei, D. Q.; Zhao, J.; Wang, J. Human cathelicidin inhibits SARS-CoV-2 infection: killing two birds with one stone. ACS Infect Dis. 2021, 7, 1545-1554.  21. Caplan, A. I. Cell-based therapies: the nonresponder. Stem Cells Transl Med. 2018, 7, 762-766.  22. Becker, A. J.; Mc, C. E.; Till, J. E. Cytological demonstration of the clonal nature of spleen colonies derived from transplanted mouse marrow cells. Nature. 1963, 197, 452-454.  23. Hosoda, T.; Zheng, H.; Cabral-da-Silva, M.; Sanada, F.; Ide-Iwata, N.; Ogorek, B.; Ferreira-Martins, J.; Arranto, C.; D’Amario, D.; del Monte, F.; Urbanek, K.; D’Alessandro, D. A.; Michler, R. E.; Anversa, P.; Rota, M.; Kajstura, J.; Leri, A. Human cardiac stem cell differentiation is regulated by a mircrine mechanism. Circulation. 2011, 123, 1287-1296.  24. Retraction of: Human Cardiac Stem Cell Differentiation Is Regulated by a Mircrine Mechanism. Circulation. 2019, 139, e38.  25. Singh, S.; Chakravarty, T.; Chen, P.; Akhmerov, A.; Falk, J.; Friedman, O.; Zaman, T.; Ebinger, J. E.; Gheorghiu, M.; Marbán, L.; Marbán, E.; Makkar, R. R. Allogeneic cardiosphere-derived cells (CAP-1002) in critically ill COVID-19 patients: compassionate-use case series. Basic Res Cardiol. 2020, 115, 36.  26. Caplan, A. I. Medicinal signalling cells: they work, so use them. Nature. 2019, 566, 39.  27. Caplan, A. I. There is no “stem cell mess”. Tissue Eng Part B Rev. 2019, 25, 291-293.  28. Leng, Z.; Zhu, R.; Hou, W.; Feng, Y.; Yang, Y.; Han, Q.; Shan, G.; Meng, F.; Du, D.; Wang, S.; Fan, J.; Wang, W.; Deng, L.; Shi, H.; Li, H.; Hu, Z.; Zhang, F.; Gao, J.; Liu, H.; Li, X.; Zhao, Y.; Yin, K.; He, X.; Gao, Z.; Wang, Y.; Yang, B.; Jin, R.; Stambler, I.; Lim, L. W.; Su, H.; Moskalev, A.; Cano, A.; Chakrabarti, S.; Min, K. J.; Ellison-Hughes, G.; Caruso, C.; Jin, K.; Zhao, R. C. Transplantation of ACE2(-) mesenchymal stem cells improves the outcome of patients with COVID-19 pneumonia. Aging Dis. 2020, 11, 216-228.  29. Lanzoni, G.; Linetsky, E.; Correa, D.; Messinger Cayetano, S.; Alvarez, R. A.; Kouroupis, D.; Alvarez Gil, A.; Poggioli, R.; Ruiz, P.; Marttos, A. C.; Hirani, K.; Bell, C. A.; Kusack, H.; Rafkin, L.; Baidal, D.; Pastewski, A.; Gawri, K.; Leñero, C.; Mantero, A. M. A.; Metalonis, S. W.; Wang, X.; Roque, L.; Masters, B.; Kenyon, N. S.; Ginzburg, E.; Xu, X.; Tan, J.; Caplan, A. I.; Glassberg, M. K.; Alejandro, R.; Ricordi, C. 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, 660-673.  30. Kaushal, S.; Khan, A.; Deatrick, K.; Ng, D. K.; Snyder, A.; Shah, A.; Caceres, L. V.; Bacallao, K.; Bembea, M.; Everett, A.; Zhu, J.; Kaczorowski, D.; Madathil, R.; Tabatabai, A.; Rosenthal, G.; Brooks, A.; Longsomboon, B.; Mishra, R.; Saha, P.; Desire, Y.; Saltzman, R.; Hankey, K. G.; Arias, S. A.; Ayoade, F.; Tovar, J. A.; Lamazares, R.; Gershengorn, H. B.; Fontaine, M. J.; Klein, M.; Mullins, K.; Gunasekaran, M.; Loebe, M.; Karakeshishyan, V.; Jayaweera, D. T.; Atala, A.; Ghodsizad, A.; Hare, J. M. Intravenous mesenchymal stem cells in extracorporeal oxygenation patients with severe COVID-19 acute respiratory distress syndrome. medRxiv. 2020. doi:10.1101/2020.10.15.20122523.