Allogeneic Mesenchymal Stem Cells and Its Conditioned Medium as a Potential Adjuvant Therapy for COVID-19

Wahyu Widowati, Ahmad Faried, Hanna Sari Widya Kusuma, Yulius Hermanto, Ali Budi Harsono, Tono Djuwantono


Recent research has demonstrated that mesenchymal stem cells (MSCs) potentially benefit and enhance coronavirus disease (COVID-19) recovery. This benefit occurs via a mechanism that promotes viral clearance by phagocytes and macrophages. This action occurs through the innate (increase in IL-10 production and decrease in TNF-α and IL-12 production) and the adaptive immune system (decrease in IL-17 production, promote regulatory T cell proliferation and inhibit effectors T cell proliferation). MSCs are expected to act as an anti-inflammatory in the hyper-inflammatory state of COVID-19. MSCs enhance immune cell replacement that have been overwhelmed or have been lost due to cytokine storm. Although vaccines are the answer to this pandemic, MSCs can improve COVID-19 patients, especially in patients with chronic illnesses. The focus on keeping death-rates low is a great opportunity for MSCs-based therapy for severe or critically ill patients. MSCs and conditioned medium have the potential to serve as adjunctive therapy in preventing the body's overactive defense response or the so-called cytokine storm caused by COVID-19.

Keywords: adjuvant therapy, COVID-19, mesenchymal stem cells, secretome

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Xu Z, Shi L, Wang Y, Zhang J, Huang L, Zhang C, et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med. 2020; 8(4): 420-2, CrossRef.

Leng Z, Zhu R, Hou W, Feng Y, Yang Y, Han Q, et al. Transplantation of ACE2-mesenchymal stem cells improves the outcome of patients with COVID-19 pneumonia. Aging Dis. 2020; 11(2): 216-28, CrossRef.

Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, et al. A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med. 2020; 382(8): 727-33, CrossRef.

McAleavy M, Zhang Q, Ehmann PJ, Xu J, Wipperman MF, Ajithdoss D, et al. The activin/FLRG pathway associates with poor COVID-19 outcomes in hospitalized patients. Mol Cell Biol. 2022; 42(1): e0046721, CrossRef.

Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020; 395(10223): 497-506, CrossRef.

Chouw A, Triana R, Dewi NM, Darmayanti S, Rahman MN, Susanto A, et al. Ischemic stroke: New neuron recovery approach with mesenchymal and neural stem cells. Mol Cell Biomed Sci. 2018; 2(2): 48-54, CrossRef.

Marlina M, Rahmadian R, Armenia A, Widowati W, Rizal R, Kusuma HSW, et al. Isolation, characterization, proliferation and differentiation of synovial membrane-derived mesenchymal stem cells (SM-MSCs) from osteoarthritis patients. Mol Cell Biomed Sci. 2020; 4(2): 76-82, CrossRef.

Feter Y, Afiana NS, Chandra JN, Abdullah JK, Shafira J, Sandra F. Dental mesenchymal stem cell: Its role in tooth development types, surface antigens and differentiation potential. Mol Cell Biomed Sci. 2017; 1(2): 50-7, CrossRef.

Chouw A, Putra BW, Sartika CR, Diantini A. Positive correlation between very small embryonic stem cell, hematopoietic stem cell, and endothelial progenitor cell in umbilical cord blood unit. Indones Biomed J. 2018; 10(3): 231-5, CrossRef.

Khoury M, Cuenca J, Cruz FF, Figueroa FE, Rocco PRM, Weiss DJ. Current status of cell-based therapies for respiratory virus infections: Applicability to COVID-19. Eur Respir J. 2020; 55(6): 2000858, CrossRef.

Jin Y, Yang H, Ji W, Wu W, Chen S, Zhang W, et al. Virology, epidemiology, pathogenesis, and control of COVID-19. Viruses. 2020; 12(4): 372, CrossRef.

Peiris JS, Guan Y, Yuen KY. Severe acute respiratory syndrome. Nat Med. 2004; 10(12 Suppl): S88-97, CrossRef.

Zhou P, Yang XL, Wang XG, Hu B, Zhang L, Zhang W, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 2020; 579(7798): 270-3, CrossRef.

Masters PS, Perlman S. Coronaviridae. In: Knipe DM, Howley PM, editors. Fields Virology. 6th ed. Philadelphia: Wolters Kluwer Health; 2013. p. 825-58, article.

Masters PS. The molecular biology of coronaviruses. Adv Virus Res. 2006; 66: 193-292, CrossRef.

Hamming I, Timens W, Bulthuis ML, Lely AT, Navis G, van Goor H. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J Pathol. 2004; 203(2): 631-7, CrossRef.

Iwata-Yoshikawa N, Okamura T, Shimizu Y, Hasegawa H, Takeda M, Nagata N. TMPRSS2 contributes to virus spread and immunopathology in the airways of murine models after coronavirus infection. J Virol. 2019; 93(6): e01815-18, CrossRef.

Mahase E. Coronavirus covid-19 has killed more people than SARS and MERS combined, despite lower case fatality rate. BMJ. 2020; 368: m641, CrossRef.

Kembuan MAHN, Mawuntu AHP, Yohanna Y, Feliana F, Tumboimbela MJ. Lower GCS is related to poor outcome among acute stroke patients with COVID-19 in a tertiary referral hospital in Indonesia. Indones Biomed J. 2021; 13(4): 409-17, CrossRef.

Sheahan TP, Sims AC, Leist SR, Schäfer A, Won J, Brown AJ, et al. Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV. Nat Commun. 2020; 11(1): 222, CrossRef.

Boulware DR, Pullen MF, Bangdiwala AS, Pastick KA, Lofgren SM, Okafor EC, et al. A randomized trial of hydroxychloroquine as postexposure prophylaxis for Covid-19. N Engl J Med. 2020; 383(6): 517-25, CrossRef.

Bellani G, Laffey JG, Pham T, Fan E, Brochard L, Esteban A, et al. Epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in 50 countries. JAMA. 2016; 315(8): 788-800, CrossRef.

Gibson PG, Qin L, Puah SH. COVID-19 acute respiratory distress syndrome (ARDS): Clinical features and differences from typical pre-COVID-19 ARDS. Med J Aust. 2020; 213(2): 54-56.e1, CrossRef.

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: A case report. Medicine. 2020; 99(31): e21429, CrossRef.

Metcalfe SM. Mesenchymal stem cells and management of COVID-19 pneumonia. Med Drug Discov. 2020; 5: 100019, CrossRef.

Tian S, Xiong Y, Liu H, Niu L, Guo J, Liao M, et al. Pathological study of the 2019 novel coronavirus disease (COVID-19) through postmortem core biopsies. Mod Pathol. 2020; 33(6): 1007-14, CrossRef.

Shang L, Zhao J, Hu Y, Du R, Cao B. On the use of corticosteroids for 2019-nCoV pneumonia. Lancet. 2020; 395(10225): 683-4, CrossRef.

Kim N, Cho SG. Clinical applications of mesenchymal stem cells. Korean J Intern Med. 2013; 28(4): 387-402, CrossRef.

Lindroos B. Characterization and Optimization of in vitro Culture Conditions of Adult Stem Cells for Clinical Therapy [Dissertation]. Tampere: University of Tampere; 2009, article.

Gjorgieva D, Zaidman N, Bosnakovski D. Mesenchymal stem cells for anti-cancer drug delivery. Recent Pat Anticancer Drug Discov. 2013; 8(3): 310-8, CrossRef.

Caplan AI, Dennis JE. Mesenchymal stem cells as trophic mediators. J Cell Biochem. 2006; 98(5): 1076-84, CrossRef.

Bongso A, Fong CY, Gauthaman K. Taking stem cells to the clinic: Major challenges. J Cell Biochem. 2008; 105(6): 1352-60, CrossRef.

Widowati W, Wijaya L, Bachtiar I, Gunanegara RF, Sugeng SU, Irawan YA, et al. Effect of oxygen tension on proliferation and characteristics of Wharton’s jelly-derived mesenchymal stem cells. Biomark Genom Med. 2014; 6: 43-8, CrossRef.

Yang J, Jia Z. Cell-based therapy in lung regenerative medicine. Regen Med Res. 2014; 2(1): 7, CrossRef.

Gao F, Chiu SM, Motan DA, Zhang Z, Chen L, Ji HL, et al. Mesenchymal stem cells and immunomodulation: Current status and future prospects. Cell Death Dis. 2016; 7(1): e2062, CrossRef.

Lee JW, Gupta N, Serikov V, Matthay MA. Potential application of mesenchymal stem cells in acute lung injury. Expert Opin Biol Ther. 2009; 9(10): 1259-70, CrossRef.

Zheng G, Ge M, Qiu G, Shu Q, Xu J. Mesenchymal stromal cells affect disease outcomes via macrophage polarization. Stem Cells Int. 2015; 2015: 989473, CrossRef.

Mao YX, Xu JF, Seeley EJ, Tang XD, Xu LL, Zhu YG, et al. Adipose tissue-derived mesenchymal stem cells attenuate pulmonary infection caused by Pseudomonas aeruginosa via inhibiting overproduction of prostaglandin E2. Stem Cells. 2015; 33(7): 2331-42, CrossRef.

Zheng Y, Cai W, Zhou S, Xu L, Jiang C. Protective effect of bone marrow derived mesenchymal stem cells in lipopolysaccharide-induced acute lung injury mediated by claudin-4 in a rat model. Am J Transl Res. 2016; 8(9): 3769-79, article.

Golchin A, Seyedjafari E, Ardeshirylajimi A. Mesenchymal stem cell therapy for COVID-19: Present or future. Stem Cell Rev Rep. 2020; 16(3): 427-33, CrossRef.

Widowati W, Wargasetia TL, Rahardja F, Gunanegara RF, Handayani T, Kusuma HSW, et al. Potential of human Wharton’s jelly mesenchymal stem cells (hWJMSCs) secretome for COVID-19 adjuvant therapy candidate. IEEE International Conference on Health, Instrumentation & Measurement, and Natural Sciences 2021 Jul 14-16, Medan. Manhattan: IEEE; 2021. p. 1-6, CrossRef.

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): 1855-63, CrossRef.

Curley GF, Hayes M, Ansari B, Shaw G, Ryan A, Barry F, et al. Mesenchymal stem cells enhance recovery and repair following ventilator-induced lung injury in the rat. Thorax. 2012; 67(6): 496-501, CrossRef.

Lee JW, Fang X, Gupta N, Serikov V, Matthay MA. Allogeneic human mesenchymal stem cells for treatment of E. coli endotoxin-induced acute lung injury in the ex vivo perfused human lung. Proc Natl Acad Sci U S A. 2009; 106(38): 16357-62, CrossRef.

Lee JW, Fang X, Krasnodembskaya A, Howard JP, Matthay MA. Concise review: Mesenchymal stem cells for acute lung injury: Role of paracrine soluble factors. Stem Cells. 2011; 29(6): 913-9, CrossRef.

Hayes M, Masterson C, Devaney J, Barry F, Elliman S, O'Brien T, et al. Therapeutic efficacy of human mesenchymal stromal cells in the repair of established ventilator-induced lung injury in the rat. Anesthesiology. 2015; 122(2): 363-73, CrossRef.

Lee JW, Rocco PR, Pelosi P. Mesenchymal stem cell therapy for acute respiratory distress syndrome: A light at the end of the tunnel? Anesthesiology. 2015; 122(2): 238-40, CrossRef.

Lee JW, Krasnodembskaya A, McKenna DH, Song Y, Abbott J, Matthay MA. Therapeutic effects of human mesenchymal stem cells in ex vivo human lungs injured with live bacteria. Am J Respir Crit Care Med. 2013; 187(7): 751-60, CrossRef.

Monsel A, Zhu YG, Gennai S, Hao Q, Hu S, Rouby JJ, et al. Therapeutic effects of human mesenchymal stem cell-derived microvesicles in severe pneumonia in mice. Am J Respir Crit Care Med. 2015; 192(3): 324-36, CrossRef.

Mei SH, McCarter SD, Deng Y, Parker CH, Liles WC, Stewart DJ. Prevention of LPS-induced acute lung injury in mice by mesenchymal stem cells overexpressing angiopoietin 1. PLoS Med. 2007; 4(9): e269, CrossRef.

Yang Y, Hu S, Xu X, Li J, Liu A, Han J, et al. The vascular endothelial growth factors-expressing character of mesenchymal stem cells plays a positive role in treatment of acute lung injury in vivo. Mediators Inflamm. 2016; 2016: 2347938, CrossRef.

Németh K, Leelahavanichkul A, Yuen PS, Mayer B, Parmelee A, Doi K, et al. Bone marrow stromal cells attenuate sepsis via prostaglandin E(2)-dependent reprogramming of host macrophages to increase their interleukin-10 production. Nat Med. 2009; 15(1): 42-9, CrossRef.

Harrell CR, Sadikot R, Pascual J, Fellabaum C, Jankovic MG, Jovicic N, et al. Mesenchymal stem cell-based therapy of inflammatory lung diseases: Current understanding and future perspectives. Stem Cells Int. 2019; 2019: 4236973, CrossRef.

Fang X, Abbott J, Cheng L, Colby JK, Lee JW, Levy BD, et al. Human mesenchymal stem (stromal) cells promote the resolution of acute lung injury in part through lipoxin A4. J Immunol. 2015; 195(3): 875-81, CrossRef.

Li Y, Xu J, Shi W, Chen C, Shao Y, Zhu L, et al. Mesenchymal stromal cell treatment prevents H9N2 avian influenza virus-induced acute lung injury in mice. Stem Cell Res Ther. 2016; 7(1): 159, CrossRef.

Gupta N, Krasnodembskaya A, Kapetanaki M, Mouded M, Tan X, Serikov V, et al. Mesenchymal stem cells enhance survival and bacterial clearance in murine Escherichia coli pneumonia. Thorax. 2012; 67(6): 533-9, CrossRef.

Yang BX, El Farran CA, Guo HC, Yu T, Fang HT, Wang HF, et al. Systematic identification of factors for provirus silencing in embryonic stem cells. Cell. 2015; 163(1): 230-45, CrossRef.

Simonson OE, Mougiakakos D, Heldring N, Bassi G, Johansson HJ, Dalén M, et al. In vivo effects of mesenchymal stromal cells in two patients with severe acute respiratory distress syndrome. Stem Cells Transl Med. 2015; 4(10): 1199-213, CrossRef.

Zheng G, Huang L, Tong H, Shu Q, Hu Y, Ge M, 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(1): 39, CrossRef.

Han J, Liu Y, Liu H, Li Y. Genetically modified mesenchymal stem cell therapy for acute respiratory distress syndrome. Stem Cell Res Ther. 2019; 10(1): 386, CrossRef.

Amable PR, Teixeira MV, Carias RB, Granjeiro JM, Borojevic R. Protein synthesis and secretion in human mesenchymal cells derived from bone marrow, adipose tissue and Wharton's jelly. Stem Cell Res Ther. 2014; 5(2): 53, CrossRef.

Bernard O, Jeny F, Uzunhan Y, Dondi E, Terfous R, Label R, 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): L360-71, CrossRef.

Behnke J, Kremer S, Shahzad T, Chao CM, Böttcher-Friebertshäuser E, Morty RE, et al. MSC based therapies - New perspectives for the injured lung. J Clin Med. 2020; 9(3): 682, CrossRef.

Abreu SC, Weiss DJ, Rocco PR. Extracellular vesicles derived from mesenchymal stromal cells: A therapeutic option in respiratory diseases? Stem Cell Res Ther. 2016; 7(1): 53, CrossRef.

Phelps J, Sanati-Nezhad A, Ungrin M, Duncan NA, Sen A. Bioprocessing of mesenchymal stem cells and their derivatives: Toward cell-free therapeutics. Stem Cells Int. 2018; 2018: 9415367, CrossRef.

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): 17, CrossRef.

Emukah C, Dittmar E, Naqvi R, Martinez J, Corral A, Moreira A, et al. Mesenchymal stromal cell conditioned media for lung disease: A systematic review and meta-analysis of preclinical studies. Respir Res. 2019; 20(1): 239, CrossRef.

Ghannam S, Bouffi C, Djouad F, Jorgensen C, Noël D. Immunosuppression by mesenchymal stem cells: Mechanisms and clinical applications. Stem Cell Res Ther. 2010; 1(1): 2, CrossRef.

Yao W, Shi L, Zhang Y, Dong H, Zhang Y. Mesenchymal stem/stromal cell therapy for COVID-19 pneumonia: Potential mechanisms, current clinical evidence, and future perspectives. Stem Cell Res Ther. 2022; 13(1): 124, CrossRef.

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; 6(10): 1153-61, CrossRef.

Wilson JG, Liu KD, Zhuo H, Caballero L, McMillan M, Fang X, et al. Mesenchymal stem (stromal) cells for treatment of ARDS: A phase 1 clinical trial. Lancet Respir Med. 2015; 3(1): 24-32, CrossRef.

Chen Y, Liang W, Yang S, Wu N, Gao H, Sheng J, et al. Human infections with the emerging avian influenza A H7N9 virus from wet market poultry: Clinical analysis and characterisation of viral genome. Lancet. 2013; 381(9881): 1916-25, CrossRef.

Matthay MA, Calfee CS, Zhuo H, Thompson BT, Wilson JG, Levitt JE, et al. Treatment with allogeneic mesenchymal stromal cells for moderate to severe acute respiratory distress syndrome (START study): A randomised phase 2a safety trial. Lancet Respir Med. 2019; 7(2): 154-62, CrossRef.

Dilogo IH, Aditianingsih D, Sugiarto A, Burhan E, Damayanti T, Sitompul PA, et al. Umbilical cord mesenchymal stromal cells as critical COVID-19 adjuvant therapy: A randomized controlled trial. Stem Cells Transl Med. 2021; 10(9): 1279-87, CrossRef.


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