Clinical study using mesenchymal stem cells for the treatment of patients with severe COVID-19

Abstract

The coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 was identified in December 2019. The symptoms include fever, cough, dyspnea, early symptom of sputum, and acute respiratory distress syndrome (ARDS). Mesenchymal stem cell (MSC) therapy is the immediate treatment used for patients with severe cases of COVID-19. Herein, we describe two confirmed cases of COVID-19 in Wuhan to explore the role of MSC in the treatment of COVID-19. MSC transplantation increases the immune indicators (including CD4 and lymphocytes) and decreases the inflammation indicators (interleukin-6 and C-reactive protein). High-flow nasal cannula can be used as an initial support strategy for patients with ARDS. With MSC transplantation, the fraction of inspired O₂ (FiO₂) of the two patients gradually decreased while the oxygen saturation (SaO₂) and partial pressure of oxygen (PO₂) improved. Additionally, the patients’ chest computed tomography showed that bilateral lung exudate lesions were adsorbed after MSC infusion. Results indicated that MSC transplantation provides clinical data on the treatment of COVID-19 and may serve as an alternative method for treating COVID-19, particularly in patients with ARDS.

Keywords

coronavirus disease 2019 (COVID-19) / mesenchymal stem cell / acute respiratory distress syndrome / stem cell therapeutics

References

[1] Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, Zhang L, Fan G, Xu J, Gu X, Cheng Z, Yu T, Xia J, Wei Y, Wu W, Xie X, Yin W, Li H, Liu M, Xiao Y, Gao H, Guo L, Xie J, Wang G, Jiang R, Gao Z, Jin Q, Wang J, Cao B. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020; 395(10223): 497–506

[2] Li Q, Guan X, Wu P, Wang X, Zhou L, Tong Y, Ren R, Leung KSM, Lau EHY, Wong JY, Xing X, Xiang N, Wu Y, Li C, Chen Q, Li D, Liu T, Zhao J, Liu M, Tu W, Chen C, Jin L, Yang R, Wang Q, Zhou S, Wang R, Liu H, Luo Y, Liu Y, Shao G, Li H, Tao Z, Yang Y, Deng Z, Liu B, Ma Z, Zhang Y, Shi G, Lam TTY, Wu JT, Gao GF, Cowling BJ, Yang B, Leung GM, Feng Z. Early transmission dynamics in Wuhan, China, of novel coronavirus-infected pneumonia. N Engl J Med 2020; 382(13): 1199–1207

[3] Xu XW, Wu XX, Jiang XG, Xu KJ, Ying LJ, Ma CL, Li SB, Wang HY, Zhang S, Gao HN, Sheng JF, Cai HL, Qiu YQ, Li LJ. Clinical findings in a group of patients infected with the 2019 novel coronavirus (SARS-CoV-2) outside of Wuhan, China: retrospective case series. BMJ 2020; 368: m606

[4] Holshue ML, DeBolt C, Lindquist S, Lofy KH, Wiesman J, Bruce H, Spitters C, Ericson K, Wilkerson S, Tural A, Diaz G, Cohn A, Fox L, Patel A, Gerber SI, Kim L, Tong S, Lu X, Lindstrom S, Pallansch MA, Weldon WC, Biggs HM, Uyeki TM, Pillai SK;Washington State 2019-nCoV Case Investigation Team. First case of 2019 novel coronavirus in the United States. N Engl J Med 2020; 382(10): 929–936

[5] Xia S, Liu M, Wang C, Xu W, Lan Q, Feng S, Qi F, Bao L, Du L, Liu S, Qin C, Sun F, Shi Z, Zhu Y, Jiang S, Lu L. Inhibition of SARS-CoV-2 (previously 2019-nCoV) infection by a highly potent pan-coronavirus fusion inhibitor targeting its spike protein that harbors a high capacity to mediate membrane fusion. Cell Res 2020; 30: 343–355

[6] Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, Liu L, Shan H, Lei CL, Hui DSC, Du B, Li LJ, Zeng G, Yuen KY, Chen RC, Tang CL, Wang T, Chen PY, Xiang J, Li SY, Wang JL, Liang ZJ, Peng YX, Wei L, Liu Y, Hu YH, Peng P, Wang JM, Liu JY, Chen Z, Li G, Zheng ZJ, Qiu SQ, Luo J, Ye CJ, Zhu SY, Zhong NS; China Medical Treatment Expert Group for COVID-19. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med 2020; 382(18): 1708–1720

[7] Zhou M, Zhang X, Qu J. Coronavirus disease 2019 (COVID-19): a clinical update. Front Med 2020; 14(2): 126–135

[8] Zhou P, Yang XL, Wang XG, Hu B, Zhang L, Zhang W, Si HR, Zhu Y, Li B, Huang CL, Chen HD, Chen J, Luo Y, Guo H, Jiang RD, Liu MQ, Chen Y, Shen XR, Wang X, Zheng XS, Zhao K, Chen QJ, Deng F, Liu LL, Yan B, Zhan FX, Wang YY, Xiao GF, Shi ZL. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 2020; 579(7798): 270–273

[9] Lu H, Stratton CW, Tang YW. Outbreak of pneumonia of unknown etiology in Wuhan, China: the mystery and the miracle. J Med Virol 2020; 92(4): 401–402

[10] Lu R, Zhao X, Li J, Niu P, Yang B, Wu H, Wang W, Song H, Huang B, Zhu N, Bi Y, Ma X, Zhan F, Wang L, Hu T, Zhou H, Hu Z, Zhou W, Zhao L, Chen J, Meng Y, Wang J, Lin Y, Yuan J, Xie Z, Ma J, Liu WJ, Wang D, Xu W, Holmes EC, Gao GF, Wu G, Chen W, Shi W, Tan W. Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding. Lancet 2020; 395(10224): 565–574

[11] Zhang Q, Wang Y, Qi C, Shen L, Li J. Clinical trial analysis of 2019-nCoV therapy registered in China. J Med Virol 2020; 92(6): 540–545

[12] Rothan HA, Byrareddy SN. The epidemiology and pathogenesis of coronavirus disease (COVID-19) outbreak. J Autoimmun 2020; 109: 102433

[13] Wang C, Horby PW, Hayden FG, Gao GF. A novel coronavirus outbreak of global health concern. Lancet 2020; 395(10223): 470–473

[14] Xu Z, Shi L, Wang Y, Zhang J, Huang L, Zhang C, Liu S, Zhao P, Liu H, Zhu L, Tai Y, Bai C, Gao T, Song J, Xia P, Dong J, Zhao J, Wang FS. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med 2020; 8(4): 420–422

[15] Han Y, Li X, Zhang Y, Han Y, Chang F, Ding J. Mesenchymal stem cells for regenerative medicine. Cells 2019; 8(8): E886

[16] Le Blanc K, Davies LC. MSCs-cells with many sides. Cytotherapy 2018; 20(3): 273–278

[17] Shi M, Liu Z, Wang Y, Xu R, Sun Y, Zhang M, Yu X, Wang H, Meng L, Su H, Jin L, Wang FS. A pilot study of mesenchymal stem cell therapy for acute liver allograft rejection. Stem Cells Transl Med 2017; 6(12): 2053–2061

[18] Weiss ARR, Dahlke MH. Immunomodulation by mesenchymal stem cells (MSCs): mechanisms of action of living, apoptotic, and dead MSCs. Front Immunol 2019; 10: 1191

[19] Samsonraj RM, Raghunath M, Nurcombe V, Hui JH, van Wijnen AJ, Cool SM. Concise review: multifaceted characterization of human mesenchymal stem cells for use in regenerative medicine. Stem Cells Transl Med 2017; 6(12): 2173–2185

[20] Hashmi S, Ahmed M, Murad MH, Litzow MR, Adams RH, Ball LM, Prasad VK, Kebriaei P, Ringden O. Survival after mesenchymal stromal cell therapy in steroid-refractory acute graft-versus-host disease: systematic review and meta-analysis. Lancet Haematol 2016; 3(1): e45–e52

[21] Liang J, Zhang H, Kong W, Deng W, Wang D, Feng X, Zhao C, Hua B, Wang H, Sun L. Safety analysis in patients with autoimmune disease receiving allogeneic mesenchymal stem cells infusion: a long-term retrospective study. Stem Cell Res Ther 2018; 9(1): 312

[22] Gao F, Chiu SM, Motan DA, Zhang Z, Chen L, Ji HL, Tse HF, Fu QL, Lian Q. Mesenchymal stem cells and immunomodulation: current status and future prospects. Cell Death Dis 2016; 7(1): e2062

[23] de Castro LL, Lopes-Pacheco M, Weiss DJ, Cruz FF, Rocco PRM. Current understanding of the immunosuppressive properties of mesenchymal stromal cells. J Mol Med (Berl) 2019; 97(5): 605–618

[24] Saldaña L, Bensiamar F, Vallés G, Mancebo FJ, García-Rey E, Vilaboa N. Immunoregulatory potential of mesenchymal stem cells following activation by macrophage-derived soluble factors. Stem Cell Res Ther 2019; 10(1): 58

[25] Khoury M, Rocco PRM, Phinney DG, Krampera M, Martin I, Viswanathan S, Nolta JA, LeBlanc K, Galipeau J, Weiss DJ. Cell-based therapies for COVID-19: proper clinical investigations are essential. Cytotherapy 2020; [Epub ahead of print] doi: 10.1016/j.jcyt.2020.04.089

[26] Wilson JG, Liu KD, Zhuo H, Caballero L, McMillan M, Fang X, Cosgrove K, Vojnik R, Calfee CS, Lee JW, Rogers AJ, Levitt J, Wiener-Kronish J, Bajwa EK, Leavitt A, McKenna D, Thompson BT, Matthay MA. Mesenchymal stem (stromal) cells for treatment of ARDS: a phase 1 clinical trial. Lancet Respir Med 2015; 3(1): 24–32

[27] Meng X, Ichim TE, Zhong J, Rogers A, Yin Z, Jackson J, Wang H, Ge W, Bogin V, Chan KW, Thébaud B, Riordan NH. Endometrial regenerative cells: a novel stem cell population. J Transl Med 2007; 5(1): 57

[28] Zuo W, Xie B, Li C, Yan Y, Zhang Y, Liu W, Huang J, Chen D. The clinical applications of endometrial mesenchymal stem cells. Biopreserv Biobank 2018; 16(2): 158–164

[29] Chen L, Qu J, Xiang C. The multi-functional roles of menstrual blood-derived stem cells in regenerative medicine. Stem Cell Res Ther 2019; 10(1): 1

[30] Yan Z, Guo F, Yuan Q, Shao Y, Zhang Y, Wang H, Hao S, Du X. Endometrial mesenchymal stem cells isolated from menstrual blood repaired epirubicin-induced damage to human ovarian granulosa cells by inhibiting the expression of Gadd45b in cell cycle pathway. Stem Cell Res Ther 2019; 10(1): 4

[31] Chen L, Zhang C, Chen L, Wang X, Xiang B, Wu X, Guo Y, Mou X, Yuan L, Chen B, Wang J, Xiang C. Human menstrual blood-derived stem cells ameliorate liver fibrosis in mice by targeting hepatic stellate cells via paracrine mediators. Stem Cells Transl Med 2017; 6(1): 272–284

[32] Khanmohammadi M, Khanjani S, Edalatkhah H, Zarnani AH, Heidari-Vala H, Soleimani M, Alimoghaddam K, Kazemnejad S. Modified protocol for improvement of differentiation potential of menstrual blood-derived stem cells into adipogenic lineage. Cell Prolif 2014; 47(6): 615–623

[33] Chen L, Qu J, Cheng T, Chen X, Xiang C. Menstrual blood-derived stem cells: toward therapeutic mechanisms, novel strategies, and future perspectives in the treatment of diseases. Stem Cell Res Ther 2019; 10(1): 406

[34] Chen J, Hu C, Chen L, Tang L, Zhu Y, Xu X, Chen L, Gao H, Lu X, Yu L, Dai X, Xiang C, Li L. Clinical study of mesenchymal stem cell treating acute respiratory distress syndrome induced by epidemic influenza A (H7N9) infection, a hint for COVID-19 treatment. Engineering (Beijing) 2020; [Epub ahead of print] doi: 10.1016/j.eng.2020.02.006

[35] Wu X, Luo Y, Chen J, Pan R, Xiang B, Du X, Xiang L, Shao J, Xiang C. Transplantation of human menstrual blood progenitor cells improves hyperglycemia by promoting endogenous progenitor differentiation in type 1 diabetic mice. Stem Cells Dev 2014; 23(11): 1245–1257

[36] Wu Y, Chen X, Zhao Y, Wang Y, Li Y, Xiang C. Genome-wide DNA methylation and hydroxymethylation analysis reveal human menstrual blood-derived stem cells inhibit hepatocellular carcinoma growth through oncogenic pathway suppression via regulating 5-hmC in enhancer elements. Stem Cell Res Ther 2019; 10(1): 151

[37] Li YH, Hu CY, Wu NP, Yao HP, Li LJ. Molecular characteristics, functions, and related pathogenicity of MERS-CoV proteins. Engineering (Beijing) 2019; 5(5): 940–947

[38] Bosch BJ, Martina BE, Van Der Zee R, Lepault J, Haijema BJ, Versluis C, Heck AJ, De Groot R, Osterhaus AD, Rottier PJ. Severe acute respiratory syndrome coronavirus (SARS-CoV) infection inhibition using spike protein heptad repeat-derived peptides. Proc Natl Acad Sci USA 2004; 101(22): 8455–8460

[39] Chen G, Wu D, Guo W, Cao Y, Huang D, Wang H, Wang T, Zhang X, Chen H, Yu H, Zhang X, Zhang M, Wu S, Song J, Chen T, Han M, Li S, Luo X, Zhao J, Ning Q. Clinical and immunological features of severe and moderate coronavirus disease 2019. J Clin Invest 2020; 130(5): 2620–2629

[40] The Lancet. Emerging understandings of 2019-nCoV. Lancet 2020; 395(10221): 311

[41] Cohen J, Normile D. New SARS-like virus in China triggers alarm. Science 2020; 367(6475): 234–235

[42] Lorusso A, Calistri P, Petrini A, Savini G, Decaro N. Novel coronavirus (SARS-CoV-2) epidemic: a veterinary perspective. Vet Ital 2020; 56(1): 5–10

[43] Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y, Qiu Y, Wang J, Liu Y, Wei Y, Xia J, Yu T, Zhang X, Zhang L. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet 2020; 395(10223): 507–513

[44] Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, Zhao X, Huang B, Shi W, Lu R, Niu P, Zhan F, Ma X, Wang D, Xu W, Wu G, Gao GF, Tan W; China Novel Coronavirus Investigating and Research Team. A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med 2020; 382(8): 727–733

[45] Chen S, Cui G, Peng C, Lavin MF, Sun X, Zhang E, Yang Y, Guan Y, Du Z, Shao H. Transplantation of adipose-derived mesenchymal stem cells attenuates pulmonary fibrosis of silicosis via anti-inflammatory and anti-apoptosis effects in rats. Stem Cell Res Ther 2018; 9(1): 110

[46] Liu D, Kong F, Yuan Y, Seth P, Xu W, Wang H, Xiao F, Wang L, Zhang Q, Yang Y, Wang H. Decorin-modified umbilical cord mesenchymal stem cells (MSCs) attenuate radiation-induced lung injuries via regulating inflammation, fibrotic factors, and immune responses. Int J Radiat Oncol Biol Phys 2018; 101(4): 945–956

[47] Marnell L, Mold C, Du Clos TW. C-reactive protein: ligands, receptors and role in inflammation. Clin Immunol 2005; 117(2): 104–111

[48] 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 LW, Su H, Moskalev A, Cano A, Chakrabarti S, Min KJ, Ellison-Hughes G, Caruso C, Jin K, Zhao RC. Transplantation of ACE2⁻ mesenchymal stem cells improves the outcome of patients with COVID-19 pneumonia. Aging Dis 2020; 11(2): 216–228

[49] Cahill EF, Kennelly H, Carty F, Mahon BP, English K. Hepatocyte growth factor is required for mesenchymal stromal cell protection against bleomycin-induced pulmonary fibrosis. Stem Cells Transl Med 2016; 5(10): 1307–1318

[50] Zheng G, Huang L, Tong H, Shu Q, Hu Y, Ge M, Deng K, Zhang L, Zou B, Cheng B, Xu J. 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

[51] Zhang Y, Ma ZF. Impact of the COVID-19 pandemic on mental health and quality of life among local residents in Liaoning Province, China: a cross-sectional study. Int J Environ Res Public Health 2020; 17(7): E2381

[52] Xiang B, Chen L, Wang X, Zhao Y, Wang Y, Xiang C. Transplantation of menstrual blood-derived mesenchymal stem cells promotes the repair of LPS-induced acute lung injury. Int J Mol Sci 2017; 18(4): 689

Acknowledgements

The authors thank Dr. Shusen Zheng and Dr. Tingbo Liang from The First Affiliated Hospital, College of Medicine, Zhejiang University for support of this work. This work was supported by the Technological Special Project for Significant New Drugs Development of China (No. 2018ZX09201002-005) and National Key R&D Program of China (No. 2017YFA0105701), the National Science and Technology Major Project (No. 2017ZX10204401), and the Emergency Research Fund for COVID-19 of Zhejiang Province (No. 2020C03125).

Compliance with ethics guidelines

Lingling Tang, Yingan Jiang, Mengfei Zhu, Lijun Chen, Xiaoyang Zhou, Chenliang Zhou, Peng Ye, Xiaobei Chen, Baohong Wang, Zhenyu Xu, Qiang Zhang, Xiaowei Xu, Hainv Gao, Xiaojun Wu, Dong Li, Wanli Jiang, Jingjing Qu, Charlie Xiang, and Lanjuan Li declare no conflicts of interest. This study was approved by the Ethics Committee of Shulan (Hangzhou) hospital, Hangzhou, China and the Ethics Committee of Renmin Hospital of Wuhan University (No. WDRY2020-K011), Wuhan, China. MSC administration in patients with SARS-CoV-2 induced ARDS was conducted in a multi-center and open-label clinical trial (No. ChiCTR2000029606).

RIGHTS & PERMISSIONS

2020 Higher Education Press