Volume 31, No 12, Dec 2021

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 31 Issue 12, December 2021: 1244-1262   |  Open Access

ORIGINAL ARTICLES

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

Rongjia Zhu^1,† , Tingdong Yan^2,† , Yingmei Feng^3,† , Yan Liu^4,† , Hongcui Cao^5,6,† , Gongxin Peng^7,† , Yanlei Yang⁸ , Zhen Xu^2,9 , 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 Zhu^5,6 , Shumin Zhou² , Jiao Wang² , Fengchun Zhang⁸ , Jinming Gao⁸ , Ronghua Jin^3,* , Dayong Xu⁴ , Yan-Qing Ma⁹ , Tao Huang¹⁰ , Shuang Peng¹¹ , Zhi Zheng¹ , Ilia Stambler^12,13 , Eric Gilson^12,14,15 , Lee Wei Lim^12,16 , Alexey Moskalev^12,17,18 , Antonio Cano^12,19 , Sasanka Chakrabarti^12,20 , Brun Ulfhake^12,21 , Huanxing Su^12,22 , Haoying Xu¹ , Sihuan Xu⁴ , Feng Wei²³ , Holly M. Brown-Borg^12,24 , Kyung-Jin Min^12,25 , Georgina Ellison-Hughes^12,26 , Calogero Caruso^12,27 , Kunlin Jin^12,28 , Robert Chunhua Zhao^1,2,12,*

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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