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

Rongjia Zhu, Tingdong Yan, Yingmei Feng, Yan Liu, Hongcui Cao, Gongxin Peng, Yanlei Yang, Zhen Xu, Jingqi Liu, Wei Hou, Xiaoyue Wang, Zhe Li, Luchan Deng, Shihua Wang, Jing Li, Qin Han, Hongling Li, Guangliang Shan, Yinghao Cao, Xingyan AnJianshe Yan, Zhonghui Zhang, Huafei Li, Xuebin Qu, Jiaqi Zhu, Shumin Zhou, Jiao Wang, Fengchun Zhang, Jinming Gao, Ronghua Jin, Dayong Xu, Yan Qing Ma, Tao Huang, Shuang Peng, Zhi Zheng, Ilia Stambler, Eric Gilson, Lee Wei Lim, Alexey Moskalev, Antonio Cano, Sasanka Chakrabarti, Brun Ulfhake, Huanxing Su, Haoying Xu, Sihuan Xu, Feng Wei, Holly M. Brown-Borg, Kyung Jin Min, Georgina Ellison-Hughes, Calogero Caruso, Kunlin Jin, Robert Chunhua Zhao*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

62 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)1244-1262
Number of pages19
Issue number12
Publication statusPublished - Dec 2021


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