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Mesenchymal stem cell treatment improves outcome of COVID-19 patients via multiple immunomodulatory mechanisms
Zhu, Rongjia1; Yan, Tingdong2; Feng, Yingmei3; Liu, Yan4; Cao, Hongcui5,6; Peng, Gongxin7; Yang, Yanlei8; Xu, Zhen2,9; Liu, Jingqi5; Hou, Wei3; Wang, Xiaoyue7; Li, Zhe2; Deng, Luchan1; Wang, Shihua1; Li, Jing1; Han, Qin1; Li, Hongling1; Shan, Guangliang1; Cao, Yinghao7; An, Xingyan1; Yan, Jianshe2; Zhang, Zhonghui2; Li, Huafei2; Qu, Xuebin2; Zhu, Jiaqi5,6; Zhou, Shumin2; Wang, Jiao2; Zhang, Fengchun8; Gao, Jinming8; Jin, Ronghua3; Xu, Dayong4; Ma, Yan Qing9; Huang, Tao10; Peng, Shuang11; Zheng, Zhi1; Stambler, Ilia12,13; Gilson, Eric12,14,15; Lim, Lee Wei12,16; Moskalev, Alexey12,17,18; Cano, Antonio12,19; Chakrabarti, Sasanka12,20; Ulfhake, Brun12,21; Su, Huanxing12,22; Xu, Haoying1; Xu, Sihuan4; Wei, Feng23; Brown-Borg, Holly M.12,24; Min, Kyung Jin12,25; Ellison-Hughes, Georgina12,26; Caruso, Calogero12,27; Jin, Kunlin12,28; Zhao, Robert Chunhua1,2,12
2021-12-01
Source PublicationCell Research
ISSN1001-0602
Volume31Issue:12Pages:1244-1262
Abstract

The infusion of coronavirus disease 2019 (COVID-19) patients with mesenchymal stem cells (MSCs) potentially improves clinical symptoms, but the underlying mechanism remains unclear. We conducted a randomized, single-blind, placebo-controlled (29 patients/group) phase II clinical trial to validate previous findings and explore the potential mechanisms. Patients treated with umbilical cord-derived MSCs exhibited a shorter hospital stay (P = 0.0198) and less time required for symptoms remission (P = 0.0194) than those who received placebo. Based on chest images, both severe and critical patients treated with MSCs showed improvement by day 7 (P = 0.0099) and day 21 (P = 0.0084). MSC-treated patients had fewer adverse events. MSC infusion reduced the levels of C-reactive protein, proinflammatory cytokines, and neutrophil extracellular traps (NETs) and promoted the maintenance of SARS-CoV-2-specific antibodies. To explore how MSCs modulate the immune system, we employed single-cell RNA sequencing analysis on peripheral blood. Our analysis identified a novel subpopulation of VNN2 hematopoietic stem/progenitor-like (HSPC-like) cells expressing CSF3R and PTPRE that were mobilized following MSC infusion. Genes encoding chemotaxis factors — CX3CR1 and L-selectin — were upregulated in various immune cells. MSC treatment also regulated B cell subsets and increased the expression of costimulatory CD28 in T cells in vivo and in vitro. In addition, an in vivo mouse study confirmed that MSCs suppressed NET release and reduced venous thrombosis by upregulating kindlin-3 signaling. Together, our results underscore the role of MSCs in improving COVID-19 patient outcomes via maintenance of immune homeostasis.

DOI10.1038/s41422-021-00573-y
URLView the original
Indexed BySCIE
Language英語English
WOS Research AreaCell Biology
WOS SubjectCell Biology
WOS IDWOS:000711303100002
Scopus ID2-s2.0-85118151264
Fulltext Access
Citation statistics
Cited Times [WOS]:4   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionUniversity of Macau
Corresponding AuthorJin, Ronghua; Ma, Yan Qing; Zhao, Robert Chunhua
Affiliation1.Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China
2.School of Life Sciences, Shanghai University, Shanghai, China
3.You’an Hospital, Capital Medical University, Beijing, China
4.Puren Hospital Affiliated to Wuhan University of Science and Technology, Wuhan, China
5.State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
6.National Clinical Research Center for Infectious Diseases, Hangzhou, China
7.Center for Bioinformatics, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & School of Basic Medicine, Peking Union Medical College, Beijing, China
8.Department of Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
9.Versiti Blood Research Institute, Milwaukee, United States
10.Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, China
11.Qingdao Walson Standard Biopharmaceutical Co, Ltd, Qingdao, China
12.International Society on Aging and Disease, Bryan, United States
13.Department of Science, Technology and Society, Bar Ilan University, Ramat Gan, Israel
14.Université Côte d’Azur, CNRS, Inserm, IRCAN, Faculty of Medicine, Nice, France
15.Department of Medical Genetics, Centre Hospitalier Universitaire (CHU), Nice, France
16.School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong
17.Institute of Biology, Komi Science Center of Russian Academy of Sciences, Syktyvkar, Russian Federation
18.Russian Gerontological Research Clinical Center, Moscow, Russian Federation
19.Department of Pediatrics, Obstetrics and Gynecology, University of Valencia, Valencia, Spain
20.Maharishi Markandeshwar Deemed University, Mullana-Ambala, India
21.Karolinska University Hospital, Stockholm, Sweden
22.Institute of Chinese Medical Science, University of Macau, Taipa, Macao
23.State Key Laboratory of Advanced Materials for Smart Sensing, GRINM GROUP Co, Ltd, Beijing, China
24.Department of Biomedical Sciences, University of North Dakota, School of Medicine & Health Sciences, Grand Forks, United States
25.Department of Biological Sciences, Inha University, Incheon, South Korea
26.School of Basic and Medical Biosciences, Faculty of Life Sciences & Medicine, King’s College London, London, United Kingdom
27.Department of Biomedicine, Neuroscience and Advanced Diagnostics, University of Palermo, Palermo, Italy
28.University of North Texas Health Science Center, Bryan, United States
Recommended Citation
GB/T 7714
Zhu, Rongjia,Yan, Tingdong,Feng, Yingmei,et al. Mesenchymal stem cell treatment improves outcome of COVID-19 patients via multiple immunomodulatory mechanisms[J]. Cell Research,2021,31(12):1244-1262.
APA Zhu, Rongjia.,Yan, Tingdong.,Feng, Yingmei.,Liu, Yan.,Cao, Hongcui.,Peng, Gongxin.,Yang, Yanlei.,Xu, Zhen.,Liu, Jingqi.,Hou, Wei.,Wang, Xiaoyue.,Li, Zhe.,Deng, Luchan.,Wang, Shihua.,Li, Jing.,Han, Qin.,Li, Hongling.,Shan, Guangliang.,Cao, Yinghao.,...&Zhao, Robert Chunhua.(2021).Mesenchymal stem cell treatment improves outcome of COVID-19 patients via multiple immunomodulatory mechanisms.Cell Research,31(12),1244-1262.
MLA Zhu, Rongjia,et al."Mesenchymal stem cell treatment improves outcome of COVID-19 patients via multiple immunomodulatory mechanisms".Cell Research 31.12(2021):1244-1262.
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