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 Yang 8, Zhen Xu 2 9, Jingqi Liu 5, Wei Hou 3, Xiaoyue Wang 7, Zhe Li 2, Luchan Deng 1, Shihua Wang 1, Jing Li 1, Qin Han 1, Hongling Li 1, Guangliang Shan 1, Yinghao Cao 7, Xingyan An 1, Jianshe Yan 2, Zhonghui Zhang 2, Huafei Li 2, Xuebin Qu 2, Jiaqi Zhu 5 6, Shumin Zhou 2, Jiao Wang 2, Fengchun Zhang 8, Jinming Gao 8, Ronghua Jin 10, Dayong Xu 4, Yan-Qing Ma 11, Tao Huang 12, Shuang Peng 13, Zhi Zheng 1, Ilia Stambler 14 15, Eric Gilson 14 16 17, Lee Wei Lim 14 18, Alexey Moskalev 14 19 20, Antonio Cano 14 21, Sasanka Chakrabarti 14 22, Brun Ulfhake 14 23, Huanxing Su 14 24, Haoying Xu 1, Sihuan Xu 4, Feng Wei 25, Holly M Brown-Borg 14 26, Kyung-Jin Min 14 27, Georgina Ellison-Hughes 14 28, Calogero Caruso 14 29, Kunlin Jin 14 30, Robert Chunhua Zhao 31 32 33

 

Cell Res. 2021 Dec;31(12):1244-1262. doi: 10.1038/s41422-021-00573-y.

PMID: 34702946

 

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.