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ORIGINAL ARTICLES

Mesenchymal stem cell treatment improves outcome of COVID-19 patients via multiple immunomodulatory mechanisms

Rongjia Zhu1,† , Tingdong Yan2,† , Yingmei Feng3,† , Yan Liu4,† , Hongcui Cao5,6,† , Gongxin Peng7,† , Yanlei Yang8 , Zhen Xu2,9 , Jingqi Liu5 , Wei Hou3 , Xiaoyue Wang7 , Zhe Li2 , Luchan Deng1 , Shihua Wang1 , Jing Li1 , Qin Han1 , Hongling Li1 , Guangliang Shan1 , Yinghao Cao7 , Xingyan An1 , Jianshe Yan2 , Zhonghui Zhang2 , Huafei Li2 , Xuebin Qu2 , Jiaqi Zhu5,6 , Shumin Zhou2 , Jiao Wang2 , Fengchun Zhang8 , Jinming Gao8 , Ronghua Jin3,* , Dayong Xu4 , Yan-Qing Ma9 , Tao Huang10 , Shuang Peng11 , Zhi Zheng1 , Ilia Stambler12,13 , Eric Gilson12,14,15 , Lee Wei Lim12,16 , Alexey Moskalev12,17,18 , Antonio Cano12,19 , Sasanka Chakrabarti12,20 , Brun Ulfhake12,21 , Huanxing Su12,22 , Haoying Xu1 , Sihuan Xu4 , Feng Wei23 , Holly M. Brown-Borg12,24 , Kyung-Jin Min12,25 , Georgina Ellison-Hughes12,26 , Calogero Caruso12,27 , Kunlin Jin12,28 , Robert Chunhua Zhao1,2,12,*

1Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China
2School of Life Sciences, Shanghai University, Shanghai, China
3You’an Hospital, Capital Medical University, Beijing, China
4Puren Hospital Affiliated to Wuhan University of Science and Technology, Wuhan, Hubei, China
5State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
6National Clinical Research Center for Infectious Diseases, Hangzhou, Zhejiang, China
7Center for Bioinformatics, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & School of Basic Medicine, Peking Union Medical College, Beijing, China
8Department of Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
9Versiti Blood Research Institute, Milwaukee, WI, USA
10Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, China
11Qingdao Walson Standard Biopharmaceutical Co, Ltd, Qingdao, Shangdong, China
12International Society on Aging and Disease, Bryan, TX, USA
13Department of Science, Technology and Society, Bar Ilan University, Ramat Gan, Israel
14Université Côte d’Azur, CNRS, Inserm, IRCAN, Faculty of Medicine, Nice, France
15Department of Medical Genetics, Centre Hospitalier Universitaire (CHU), Nice, France
16School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, China
17Institute of Biology, Komi Science Center of Russian Academy of Sciences, Syktyvkar, Russia
18Russian Gerontological Research Clinical Center, Moscow, Russia
19Department of Pediatrics, Obstetrics and Gynecology, University of Valencia, Valencia, Spain
20Maharishi Markandeshwar Deemed University, Mullana-Ambala, India
21Karolinska University Hospital, Stockholm, Sweden
22Institute of Chinese Medical Science, University of Macau, Taipa, Macau, China
23State Key Laboratory of Advanced Materials for Smart Sensing, GRINM GROUP Co, Ltd, Beijing, China
24Department of Biomedical Sciences, University of North Dakota, School of Medicine & Health Sciences, Grand Forks, ND, USA
25Department of Biological Sciences, Inha University, Incheon, Republic of Korea
26School of Basic and Medical Biosciences, Faculty of Life Sciences & Medicine, King’s College London, London, UK
27Department of Biomedicine, Neuroscience and Advanced Diagnostics, University of Palermo, Palermo, Italy
28University of North Texas Health Science Center, Bryan, TX, USA
These authors contributed equally: Rongjia Zhu, Tingdong Yan, Yingmei Feng, Yan Liu, Hongcui Cao, Gongxin Peng
* Correspondence: Ronghua Jin(jin_eagle@sina.com)Robert Chunhua Zhao(zhaochunhua@vip.163.com)

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.

https://doi.org/10.1038/s41422-021-00573-y

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