tetano
Editor, Senior Moderator
Cell Res
. 2021 Oct 26.
doi: 10.1038/s41422-021-00573-y. Online ahead of print.
Mesenchymal stem cell treatment improves outcome of COVID-19 patients via multiple immunomodulatory mechanisms
Rongjia Zhu[SUP] #[/SUP][SUP] 1 [/SUP], Tingdong Yan[SUP] #[/SUP][SUP] 2 [/SUP], Yingmei Feng[SUP] #[/SUP][SUP] 3 [/SUP], Yan Liu[SUP] #[/SUP][SUP] 4 [/SUP], Hongcui Cao[SUP] #[/SUP][SUP] 5 6 [/SUP], Gongxin Peng[SUP] #[/SUP][SUP] 7 [/SUP], Yanlei Yang[SUP] 8 [/SUP], Zhen Xu[SUP] 2 9 [/SUP], Jingqi Liu[SUP] 5 [/SUP], Wei Hou[SUP] 3 [/SUP], Xiaoyue Wang[SUP] 7 [/SUP], Zhe Li[SUP] 2 [/SUP], Luchan Deng[SUP] 1 [/SUP], Shihua Wang[SUP] 1 [/SUP], Jing Li[SUP] 1 [/SUP], Qin Han[SUP] 1 [/SUP], Hongling Li[SUP] 1 [/SUP], Guangliang Shan[SUP] 1 [/SUP], Yinghao Cao[SUP] 7 [/SUP], Xingyan An[SUP] 1 [/SUP], Jianshe Yan[SUP] 2 [/SUP], Zhonghui Zhang[SUP] 2 [/SUP], Huafei Li[SUP] 2 [/SUP], Xuebin Qu[SUP] 2 [/SUP], Jiaqi Zhu[SUP] 5 6 [/SUP], Shumin Zhou[SUP] 2 [/SUP], Jiao Wang[SUP] 2 [/SUP], Fengchun Zhang[SUP] 8 [/SUP], Jinming Gao[SUP] 8 [/SUP], Ronghua Jin[SUP] 10 [/SUP], Dayong Xu[SUP] 4 [/SUP], Yan-Qing Ma[SUP] 11 [/SUP], Tao Huang[SUP] 12 [/SUP], Shuang Peng[SUP] 13 [/SUP], Zhi Zheng[SUP] 1 [/SUP], Ilia Stambler[SUP] 14 15 [/SUP], Eric Gilson[SUP] 14 16 17 [/SUP], Lee Wei Lim[SUP] 14 18 [/SUP], Alexey Moskalev[SUP] 14 19 20 [/SUP], Antonio Cano[SUP] 14 21 [/SUP], Sasanka Chakrabarti[SUP] 14 22 [/SUP], Brun Ulfhake[SUP] 14 23 [/SUP], Huanxing Su[SUP] 14 24 [/SUP], Haoying Xu[SUP] 1 [/SUP], Sihuan Xu[SUP] 4 [/SUP], Feng Wei[SUP] 25 [/SUP], Holly M Brown-Borg[SUP] 14 26 [/SUP], Kyung-Jin Min[SUP] 14 27 [/SUP], Georgina Ellison-Hughes[SUP] 14 28 [/SUP], Calogero Caruso[SUP] 14 29 [/SUP], Kunlin Jin[SUP] 14 30 [/SUP], Robert Chunhua Zhao[SUP] 31 32 33 [/SUP]
Affiliations
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[SUP]+[/SUP] 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.
. 2021 Oct 26.
doi: 10.1038/s41422-021-00573-y. Online ahead of print.
Mesenchymal stem cell treatment improves outcome of COVID-19 patients via multiple immunomodulatory mechanisms
Rongjia Zhu[SUP] #[/SUP][SUP] 1 [/SUP], Tingdong Yan[SUP] #[/SUP][SUP] 2 [/SUP], Yingmei Feng[SUP] #[/SUP][SUP] 3 [/SUP], Yan Liu[SUP] #[/SUP][SUP] 4 [/SUP], Hongcui Cao[SUP] #[/SUP][SUP] 5 6 [/SUP], Gongxin Peng[SUP] #[/SUP][SUP] 7 [/SUP], Yanlei Yang[SUP] 8 [/SUP], Zhen Xu[SUP] 2 9 [/SUP], Jingqi Liu[SUP] 5 [/SUP], Wei Hou[SUP] 3 [/SUP], Xiaoyue Wang[SUP] 7 [/SUP], Zhe Li[SUP] 2 [/SUP], Luchan Deng[SUP] 1 [/SUP], Shihua Wang[SUP] 1 [/SUP], Jing Li[SUP] 1 [/SUP], Qin Han[SUP] 1 [/SUP], Hongling Li[SUP] 1 [/SUP], Guangliang Shan[SUP] 1 [/SUP], Yinghao Cao[SUP] 7 [/SUP], Xingyan An[SUP] 1 [/SUP], Jianshe Yan[SUP] 2 [/SUP], Zhonghui Zhang[SUP] 2 [/SUP], Huafei Li[SUP] 2 [/SUP], Xuebin Qu[SUP] 2 [/SUP], Jiaqi Zhu[SUP] 5 6 [/SUP], Shumin Zhou[SUP] 2 [/SUP], Jiao Wang[SUP] 2 [/SUP], Fengchun Zhang[SUP] 8 [/SUP], Jinming Gao[SUP] 8 [/SUP], Ronghua Jin[SUP] 10 [/SUP], Dayong Xu[SUP] 4 [/SUP], Yan-Qing Ma[SUP] 11 [/SUP], Tao Huang[SUP] 12 [/SUP], Shuang Peng[SUP] 13 [/SUP], Zhi Zheng[SUP] 1 [/SUP], Ilia Stambler[SUP] 14 15 [/SUP], Eric Gilson[SUP] 14 16 17 [/SUP], Lee Wei Lim[SUP] 14 18 [/SUP], Alexey Moskalev[SUP] 14 19 20 [/SUP], Antonio Cano[SUP] 14 21 [/SUP], Sasanka Chakrabarti[SUP] 14 22 [/SUP], Brun Ulfhake[SUP] 14 23 [/SUP], Huanxing Su[SUP] 14 24 [/SUP], Haoying Xu[SUP] 1 [/SUP], Sihuan Xu[SUP] 4 [/SUP], Feng Wei[SUP] 25 [/SUP], Holly M Brown-Borg[SUP] 14 26 [/SUP], Kyung-Jin Min[SUP] 14 27 [/SUP], Georgina Ellison-Hughes[SUP] 14 28 [/SUP], Calogero Caruso[SUP] 14 29 [/SUP], Kunlin Jin[SUP] 14 30 [/SUP], Robert Chunhua Zhao[SUP] 31 32 33 [/SUP]
Affiliations
- PMID: 34702946
- DOI: 10.1038/s41422-021-00573-y
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[SUP]+[/SUP] 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.