LETTER TO FRONTIERS OF MEDICINE |
|
|
|
Clinical study using mesenchymal stem cells for the treatment of patients with severe COVID-19 |
Lingling Tang1, Yingan Jiang2, Mengfei Zhu1, Lijun Chen3, Xiaoyang Zhou2, Chenliang Zhou2, Peng Ye2, Xiaobei Chen2, Baohong Wang3, Zhenyu Xu4, Qiang Zhang4, Xiaowei Xu3, Hainv Gao1, Xiaojun Wu2, Dong Li2, Wanli Jiang2, Jingjing Qu3, Charlie Xiang3(), Lanjuan Li1,3() |
1. The Shulan (Hangzhou) Hospital, Affiliated to Shulan International Medical College, Zhejiang Shuren University, Hangzhou 310022, China 2. Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan 430060, China 3. State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China 4. Innovative Precision Medicine (IPM) Group, Hangzhou 311215, China |
|
|
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
|
Corresponding Author(s):
Charlie Xiang,Lanjuan Li
|
Just Accepted Date: 28 June 2020
Online First Date: 06 August 2020
Issue Date: 12 October 2020
|
|
1 |
C Huang, Y Wang, X Li, L Ren, J Zhao, Y Hu, L Zhang, G Fan, J Xu, X Gu, Z Cheng, T Yu, J Xia, Y Wei, W Wu, X Xie, W Yin, H Li, M Liu, Y Xiao, H Gao, L Guo, J Xie, G Wang, R Jiang, Z Gao, Q Jin, J Wang, B Cao. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020; 395(10223): 497–506
https://doi.org/10.1016/S0140-6736(20)30183-5
pmid: 31986264
|
2 |
Q Li, X Guan, P Wu, X Wang, L Zhou, Y Tong, R Ren, KSM Leung, EHY Lau, JY Wong, X Xing, N Xiang, Y Wu, C Li, Q Chen, D Li, T Liu, J Zhao, M Liu, W Tu, C Chen, L Jin, R Yang, Q Wang, S Zhou, R Wang, H Liu, Y Luo, Y Liu, G Shao, H Li, Z Tao, Y Yang, Z Deng, B Liu, Z Ma, Y Zhang, G Shi, TTY Lam, JT Wu, GF Gao, BJ Cowling, B Yang, GM Leung, Z Feng. Early transmission dynamics in Wuhan, China, of novel coronavirus-infected pneumonia. N Engl J Med 2020; 382(13): 1199–1207
https://doi.org/10.1056/NEJMoa2001316
pmid: 31995857
|
3 |
XW Xu, XX Wu, XG Jiang, KJ Xu, LJ Ying, CL Ma, SB Li, HY Wang, S Zhang, HN Gao, JF Sheng, HL Cai, YQ Qiu, LJ Li. 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
https://doi.org/10.1136/bmj.m606
pmid: 32075786
|
4 |
ML Holshue, C DeBolt, S Lindquist, KH Lofy, J Wiesman, H Bruce, C Spitters, K Ericson, S Wilkerson, A Tural, G Diaz, A Cohn, L Fox, A Patel, SI Gerber, L Kim, S Tong, X Lu, S Lindstrom, MA Pallansch, WC Weldon, HM Biggs, TM Uyeki, SK; PillaiWashington 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
https://doi.org/10.1056/NEJMoa2001191
pmid: 32004427
|
5 |
S Xia, M Liu, C Wang, W Xu, Q Lan, S Feng, F Qi, L Bao, L Du, S Liu, C Qin, F Sun, Z Shi, Y Zhu, S Jiang, L Lu. 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
https://doi.org/10.1038/s41422-020-0305-x
pmid: 32231345
|
6 |
WJ Guan, ZY Ni, Y Hu, WH Liang, CQ Ou, JX He, L Liu, H Shan, CL Lei, DSC Hui, B Du, LJ Li, G Zeng, KY Yuen, RC Chen, CL Tang, T Wang, PY Chen, J Xiang, SY Li, JL Wang, ZJ Liang, YX Peng, L Wei, Y Liu, YH Hu, P Peng, JM Wang, JY Liu, Z Chen, G Li, ZJ Zheng, SQ Qiu, J Luo, CJ Ye, SY Zhu, NS; China Medical Treatment Expert Group for COVID-19 Zhong. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med 2020; 382(18): 1708–1720
https://doi.org/10.1056/NEJMoa2002032
pmid: 32109013
|
7 |
M Zhou, X, Zhang J Qu. Coronavirus disease 2019 (COVID-19): a clinical update. Front Med 2020; 14(2): 126–135
https://doi.org/10.1007/s11684-020-0767-8 PMID:32240462
|
8 |
P Zhou, XL Yang, XG Wang, B Hu, L Zhang, W Zhang, HR Si, Y Zhu, B Li, CL Huang, HD Chen, J Chen, Y Luo, H Guo, RD Jiang, MQ Liu, Y Chen, XR Shen, X Wang, XS Zheng, K Zhao, QJ Chen, F Deng, LL Liu, B Yan, FX Zhan, YY Wang, GF Xiao, ZL Shi. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 2020; 579(7798): 270–273
https://doi.org/10.1038/s41586-020-2012-7
pmid: 32015507
|
9 |
H Lu, CW Stratton, YW Tang. Outbreak of pneumonia of unknown etiology in Wuhan, China: the mystery and the miracle. J Med Virol 2020; 92(4): 401–402
https://doi.org/10.1002/jmv.25678
pmid: 31950516
|
10 |
R Lu, X Zhao, J Li, P Niu, B Yang, H Wu, W Wang, H Song, B Huang, N Zhu, Y Bi, X Ma, F Zhan, L Wang, T Hu, H Zhou, Z Hu, W Zhou, L Zhao, J Chen, Y Meng, J Wang, Y Lin, J Yuan, Z Xie, J Ma, WJ Liu, D Wang, W Xu, EC Holmes, GF Gao, G Wu, W Chen, W Shi, W Tan. Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding. Lancet 2020; 395(10224): 565–574
https://doi.org/10.1016/S0140-6736(20)30251-8
pmid: 32007145
|
11 |
Q Zhang, Y Wang, C Qi, L Shen, J Li. Clinical trial analysis of 2019-nCoV therapy registered in China. J Med Virol 2020; 92(6): 540–545
https://doi.org/10.1002/jmv.25733
|
12 |
HA Rothan, SN Byrareddy. The epidemiology and pathogenesis of coronavirus disease (COVID-19) outbreak. J Autoimmun 2020; 109: 102433
https://doi.org/10.1016/j.jaut.2020.102433
pmid: 32113704
|
13 |
C Wang, PW Horby, FG Hayden, GF Gao. A novel coronavirus outbreak of global health concern. Lancet 2020; 395(10223): 470–473
https://doi.org/10.1016/S0140-6736(20)30185-9
pmid: 31986257
|
14 |
Z Xu, L Shi, Y Wang, J Zhang, L Huang, C Zhang, S Liu, P Zhao, H Liu, L Zhu, Y Tai, C Bai, T Gao, J Song, P Xia, J Dong, J Zhao, FS Wang. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med 2020; 8(4): 420–422
https://doi.org/10.1016/S2213-2600(20)30076-X
pmid: 32085846
|
15 |
Y Han, X Li, Y Zhang, Y Han, F Chang, J Ding. Mesenchymal stem cells for regenerative medicine. Cells 2019; 8(8): E886
https://doi.org/10.3390/cells8080886
pmid: 31412678
|
16 |
K Le Blanc, LC Davies. MSCs-cells with many sides. Cytotherapy 2018; 20(3): 273–278
https://doi.org/10.1016/j.jcyt.2018.01.009
pmid: 29434007
|
17 |
M Shi, Z Liu, Y Wang, R Xu, Y Sun, M Zhang, X Yu, H Wang, L Meng, H Su, L Jin, FS Wang. A pilot study of mesenchymal stem cell therapy for acute liver allograft rejection. Stem Cells Transl Med 2017; 6(12): 2053–2061
https://doi.org/10.1002/sctm.17-0134
pmid: 29178564
|
18 |
ARR Weiss, MH Dahlke. Immunomodulation by mesenchymal stem cells (MSCs): mechanisms of action of living, apoptotic, and dead MSCs. Front Immunol 2019; 10: 1191
https://doi.org/10.3389/fimmu.2019.01191
pmid: 31214172
|
19 |
RM Samsonraj, M Raghunath, V Nurcombe, JH Hui, AJ van Wijnen, SM Cool. Concise review: multifaceted characterization of human mesenchymal stem cells for use in regenerative medicine. Stem Cells Transl Med 2017; 6(12): 2173–2185
https://doi.org/10.1002/sctm.17-0129
pmid: 29076267
|
20 |
S Hashmi, M Ahmed, MH Murad, MR Litzow, RH Adams, LM Ball, VK Prasad, P Kebriaei, O Ringden. 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
https://doi.org/10.1016/S2352-3026(15)00224-0
pmid: 26765648
|
21 |
J Liang, H Zhang, W Kong, W Deng, D Wang, X Feng, C Zhao, B Hua, H Wang, L Sun. 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
https://doi.org/10.1186/s13287-018-1053-4
pmid: 30428931
|
22 |
F Gao, SM Chiu, DA Motan, Z Zhang, L Chen, HL Ji, HF Tse, QL Fu, Q Lian. Mesenchymal stem cells and immunomodulation: current status and future prospects. Cell Death Dis 2016; 7(1): e2062
https://doi.org/10.1038/cddis.2015.327
pmid: 26794657
|
23 |
LL de Castro, M Lopes-Pacheco, DJ Weiss, FF Cruz, PRM Rocco. Current understanding of the immunosuppressive properties of mesenchymal stromal cells. J Mol Med (Berl) 2019; 97(5): 605–618
https://doi.org/10.1007/s00109-019-01776-y
pmid: 30903229
|
24 |
L Saldaña, F Bensiamar, G Vallés, FJ Mancebo, E García-Rey, N Vilaboa. Immunoregulatory potential of mesenchymal stem cells following activation by macrophage-derived soluble factors. Stem Cell Res Ther 2019; 10(1): 58
https://doi.org/10.1186/s13287-019-1156-6
pmid: 30760316
|
25 |
M Khoury, PRM Rocco, DG Phinney, M Krampera, I Martin, S Viswanathan, JA Nolta, K LeBlanc, J Galipeau, DJ Weiss. 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
https://doi.org/10.1016/j.jcyt.2020.04.089
|
26 |
JG Wilson, KD Liu, H Zhuo, L Caballero, M McMillan, X Fang, K Cosgrove, R Vojnik, CS Calfee, JW Lee, AJ Rogers, J Levitt, J Wiener-Kronish, EK Bajwa, A Leavitt, D McKenna, BT Thompson, MA Matthay. Mesenchymal stem (stromal) cells for treatment of ARDS: a phase 1 clinical trial. Lancet Respir Med 2015; 3(1): 24–32
https://doi.org/10.1016/S2213-2600(14)70291-7
pmid: 25529339
|
27 |
X Meng, TE Ichim, J Zhong, A Rogers, Z Yin, J Jackson, H Wang, W Ge, V Bogin, KW Chan, B Thébaud, NH Riordan. Endometrial regenerative cells: a novel stem cell population. J Transl Med 2007; 5(1): 57
https://doi.org/10.1186/1479-5876-5-57
pmid: 18005405
|
28 |
W Zuo, B Xie, C Li, Y Yan, Y Zhang, W Liu, J Huang, D Chen. The clinical applications of endometrial mesenchymal stem cells. Biopreserv Biobank 2018; 16(2): 158–164
https://doi.org/10.1089/bio.2017.0057
pmid: 29265881
|
29 |
L Chen, J Qu, C Xiang. The multi-functional roles of menstrual blood-derived stem cells in regenerative medicine. Stem Cell Res Ther 2019; 10(1): 1
https://doi.org/10.1186/s13287-018-1105-9
pmid: 30606242
|
30 |
Z Yan, F Guo, Q Yuan, Y Shao, Y Zhang, H Wang, S Hao, X Du. 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
https://doi.org/10.1186/s13287-018-1101-0
pmid: 30606243
|
31 |
L Chen, C Zhang, L Chen, X Wang, B Xiang, X Wu, Y Guo, X Mou, L Yuan, B Chen, J Wang, C Xiang. 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
https://doi.org/10.5966/sctm.2015-0265
pmid: 28170193
|
32 |
M Khanmohammadi, S Khanjani, H Edalatkhah, AH Zarnani, H Heidari-Vala, M Soleimani, K Alimoghaddam, S Kazemnejad. Modified protocol for improvement of differentiation potential of menstrual blood-derived stem cells into adipogenic lineage. Cell Prolif 2014; 47(6): 615–623
https://doi.org/10.1111/cpr.12133
pmid: 25252214
|
33 |
L Chen, J Qu, T Cheng, X Chen, C Xiang. 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
https://doi.org/10.1186/s13287-019-1503-7
pmid: 31864423
|
34 |
J Chen, C Hu, L Chen, L Tang, Y Zhu, X Xu, L Chen, H Gao, X Lu, L Yu, X Dai, C Xiang, L Li. 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
https://doi.org/10.1016/j.eng.2020.02.006
pmid: 32292627
|
35 |
X Wu, Y Luo, J Chen, R Pan, B Xiang, X Du, L Xiang, J Shao, C Xiang. 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
https://doi.org/10.1089/scd.2013.0390
pmid: 24499421
|
36 |
Y Wu, X Chen, Y Zhao, Y Wang, Y Li, C Xiang. 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
https://doi.org/10.1186/s13287-019-1243-8
pmid: 31151404
|
37 |
YH Li, CY Hu, NP Wu, HP Yao, LJ Li. Molecular characteristics, functions, and related pathogenicity of MERS-CoV proteins. Engineering (Beijing) 2019; 5(5): 940–947
https://doi.org/10.1016/j.eng.2018.11.035
pmid: 32288963
|
38 |
BJ Bosch, BE Martina, R Van Der Zee, J Lepault, BJ Haijema, C Versluis, AJ Heck, R De Groot, AD Osterhaus, PJ Rottier. 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
https://doi.org/10.1073/pnas.0400576101
pmid: 15150417
|
39 |
G Chen, D Wu, W Guo, Y Cao, D Huang, H Wang, T Wang, X Zhang, H Chen, H Yu, X Zhang, M Zhang, S Wu, J Song, T Chen, M Han, S Li, X Luo, J Zhao, Q Ning. Clinical and immunological features of severe and moderate coronavirus disease 2019. J Clin Invest 2020; 130(5): 2620–2629
https://doi.org/10.1172/JCI137244
pmid: 32217835
|
40 |
The Lancet. Emerging understandings of 2019-nCoV. Lancet 2020; 395(10221): 311
https://doi.org/10.1016/S0140-6736(20)30186-0
pmid: 31986259
|
41 |
J Cohen, D Normile. New SARS-like virus in China triggers alarm. Science 2020; 367(6475): 234–235
https://doi.org/10.1126/science.367.6475.234
pmid: 31949058
|
42 |
A Lorusso, P Calistri, A Petrini, G Savini, N Decaro. Novel coronavirus (SARS-CoV-2) epidemic: a veterinary perspective. Vet Ital 2020; 56(1): 5–10
pmid: 32048818
|
43 |
N Chen, M Zhou, X Dong, J Qu, F Gong, Y Han, Y Qiu, J Wang, Y Liu, Y Wei, J Xia, T Yu, X Zhang, L Zhang. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet 2020; 395(10223): 507–513
https://doi.org/10.1016/S0140-6736(20)30211-7
pmid: 32007143
|
44 |
N Zhu, D Zhang, W Wang, X Li, B Yang, J Song, X Zhao, B Huang, W Shi, R Lu, P Niu, F Zhan, X Ma, D Wang, W Xu, G Wu, GF Gao, W; China Novel Coronavirus Investigating and Research Team Tan. A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med 2020; 382(8): 727–733
https://doi.org/10.1056/NEJMoa2001017
pmid: 31978945
|
45 |
S Chen, G Cui, C Peng, MF Lavin, X Sun, E Zhang, Y Yang, Y Guan, Z Du, H Shao. 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
https://doi.org/10.1186/s13287-018-0846-9
pmid: 29673394
|
46 |
D Liu, F Kong, Y Yuan, P Seth, W Xu, H Wang, F Xiao, L Wang, Q Zhang, Y Yang, H Wang. 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
https://doi.org/10.1016/j.ijrobp.2018.04.007
pmid: 29976507
|
47 |
L Marnell, C Mold, TW Du Clos. C-reactive protein: ligands, receptors and role in inflammation. Clin Immunol 2005; 117(2): 104–111
https://doi.org/10.1016/j.clim.2005.08.004
pmid: 16214080
|
48 |
Z Leng, R Zhu, W Hou, Y Feng, Y Yang, Q Han, G Shan, F Meng, D Du, S Wang, J Fan, W Wang, L Deng, H Shi, H Li, Z Hu, F Zhang, J Gao, H Liu, X Li, Y Zhao, K Yin, X He, Z Gao, Y Wang, B Yang, R Jin, I Stambler, LW Lim, H Su, A Moskalev, A Cano, S Chakrabarti, KJ Min, G Ellison-Hughes, C Caruso, K Jin, RC Zhao. Transplantation of ACE2− mesenchymal stem cells improves the outcome of patients with COVID-19 pneumonia. Aging Dis 2020; 11(2): 216–228
https://doi.org/10.14336/AD.2020.0228
pmid: 32257537
|
49 |
EF Cahill, H Kennelly, F Carty, BP Mahon, K English. Hepatocyte growth factor is required for mesenchymal stromal cell protection against bleomycin-induced pulmonary fibrosis. Stem Cells Transl Med 2016; 5(10): 1307–1318
https://doi.org/10.5966/sctm.2015-0337
pmid: 27388243
|
50 |
G Zheng, L Huang, H Tong, Q Shu, Y Hu, M Ge, K Deng, L Zhang, B Zou, B Cheng, J Xu. 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
https://doi.org/10.1186/1465-9921-15-39
pmid: 24708472
|
51 |
Y Zhang, ZF Ma. 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
https://doi.org/10.3390/ijerph17072381
pmid: 32244498
|
52 |
B Xiang, L Chen, X Wang, Y Zhao, Y Wang, C Xiang. 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
https://doi.org/10.3390/ijms18040689
pmid: 28346367
|
|
Viewed |
|
|
|
Full text
|
|
|
|
|
Abstract
|
|
|
|
|
Cited |
|
|
|
|
|
Shared |
|
|
|
|
|
Discussed |
|
|
|
|