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

• Published in: Cell research Vol. 31; no. 12; pp. 1244 - 1262
• Main Authors: 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, An, Xingyan, Yan, Jianshe, Zhang, Zhonghui, Li, Huafei, Qu, Xuebin, Zhu, Jiaqi, Zhou, Shumin, Wang, Jiao, Zhang, Fengchun, Gao, Jinming, Jin, Ronghua, Xu, Dayong, Ma, Yan-Qing, Huang, Tao, Peng, Shuang, Zheng, Zhi, Stambler, Ilia, Gilson, Eric, Lim, Lee Wei, Moskalev, Alexey, Cano, Antonio, Chakrabarti, Sasanka, Ulfhake, Brun, Su, Huanxing, Xu, Haoying, Xu, Sihuan, Wei, Feng, Brown-Borg, Holly M., Min, Kyung-Jin, Ellison-Hughes, Georgina, Caruso, Calogero, Jin, Kunlin, Zhao, Robert Chunhua
• Format: Journal Article
• Language: English
• Published: Singapore Springer Singapore 01.12.2021; Nature Publishing Group
• Subjects: 13/1; 13/100; 13/21; 13/31; 13/51; 38; 38/39; 45; 631/532/2074; 631/80/304; Adverse events; Aged; Animals; Antibodies; Antibodies, Viral - blood; B-Lymphocyte Subsets - cytology; B-Lymphocyte Subsets - immunology; B-Lymphocyte Subsets - metabolism; Biomedical and Life Sciences; C-reactive protein; C-Reactive Protein - analysis; CD28 antigen; Cell Biology; Chemotaxis; Clinical trials; Coronaviruses; COVID-19; COVID-19 - immunology; COVID-19 - therapy; COVID-19 - virology; CX3CR1 protein; Cytokines; Cytokines - genetics; Cytokines - metabolism; Cytoskeletal Proteins - metabolism; Disease Models, Animal; Extracellular Traps - metabolism; Female; Gene sequencing; Health services; Hematopoietic stem cells; Homeostasis; Humans; Immune system; Immunomodulation; Immunomodulators; In vivo methods and tests; Inflammation; L-selectin; Leukocytes (neutrophilic); Leukocytes, Mononuclear - cytology; Leukocytes, Mononuclear - metabolism; Life Sciences; Lymphocytes; Lymphocytes T; Maintenance; Male; Mesenchymal Stem Cell Transplantation; Mesenchymal stem cells; Mice; Mice, Inbred C57BL; Middle Aged; Patients; Peripheral blood; Placebos; Remission; SARS-CoV-2 - isolation & purification; Severe acute respiratory syndrome coronavirus 2; Signs and symptoms; Stem cell transplantation; Stem cells; T-Lymphocytes - cytology; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; Thromboembolism; Thrombosis; Umbilical cord; Venous Thrombosis - metabolism; Venous Thrombosis - pathology; Viral diseases
• ISSN: 1001-0602; 1748-7838; 1748-7838
• DOI: 10.1038/s41422-021-00573-y

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.