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 An; Jianshe 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

doi:10.1038/s41422-021-00573-y

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 journal › Article › peer-review

86 Citations (Scopus)

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.

Original language	English
Pages (from-to)	1244-1262
Number of pages	19
Journal	Cell Research
Volume	31
Issue number	12
DOIs	https://doi.org/10.1038/s41422-021-00573-y
Publication status	Published - Dec 2021
Externally published	Yes

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Zhu, R., Yan, T., Feng, Y., Liu, Y., Cao, H., Peng, G., Yang, Y., Xu, Z., Liu, J., Hou, W., Wang, X., Li, Z., Deng, L., Wang, S., Li, J., Han, Q., Li, H., Shan, G., Cao, Y., ... Zhao, R. C. (2021). Mesenchymal stem cell treatment improves outcome of COVID-19 patients via multiple immunomodulatory mechanisms. Cell Research, 31(12), 1244-1262. https://doi.org/10.1038/s41422-021-00573-y

@article{c33f1a8dea4248dd92bc754dfb4a531c,

title = "Mesenchymal stem cell treatment improves outcome of COVID-19 patients via multiple immunomodulatory mechanisms",

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.",

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

note = "Publisher Copyright: {\textcopyright} 2021, The Author(s).",

year = "2021",

month = dec,

doi = "10.1038/s41422-021-00573-y",

language = "English",

volume = "31",

pages = "1244--1262",

journal = "Cell Research",

issn = "1001-0602",

number = "12",

}

Zhu, R, Yan, T, Feng, Y, Liu, Y, Cao, H, Peng, G, Yang, Y, Xu, Z, Liu, J, Hou, W, Wang, X, Li, Z, Deng, L, Wang, S, Li, J, Han, Q, Li, H, Shan, G, Cao, Y, An, X, Yan, J, Zhang, Z, Li, H, Qu, X, Zhu, J, Zhou, S, Wang, J, Zhang, F, Gao, J, Jin, R, Xu, D, Ma, YQ, Huang, T, Peng, S, Zheng, Z, Stambler, I, Gilson, E, Lim, LW, Moskalev, A, Cano, A, Chakrabarti, S, Ulfhake, B, Su, H, Xu, H, Xu, S, Wei, F, Brown-Borg, HM, Min, KJ, Ellison-Hughes, G, Caruso, C, Jin, K & Zhao, RC 2021, 'Mesenchymal stem cell treatment improves outcome of COVID-19 patients via multiple immunomodulatory mechanisms', Cell Research, vol. 31, no. 12, pp. 1244-1262. https://doi.org/10.1038/s41422-021-00573-y

TY - JOUR

T1 - Mesenchymal stem cell treatment improves outcome of COVID-19 patients via multiple immunomodulatory mechanisms

AU - Zhu, Rongjia

AU - Yan, Tingdong

AU - Feng, Yingmei

AU - Liu, Yan

AU - Cao, Hongcui

AU - Peng, Gongxin

AU - Yang, Yanlei

AU - Xu, Zhen

AU - Liu, Jingqi

AU - Hou, Wei

AU - Wang, Xiaoyue

AU - Li, Zhe

AU - Deng, Luchan

AU - Wang, Shihua

AU - Li, Jing

AU - Han, Qin

AU - Li, Hongling

AU - Shan, Guangliang

AU - Cao, Yinghao

AU - An, Xingyan

AU - Yan, Jianshe

AU - Zhang, Zhonghui

AU - Li, Huafei

AU - Qu, Xuebin

AU - Zhu, Jiaqi

AU - Zhou, Shumin

AU - Wang, Jiao

AU - Zhang, Fengchun

AU - Gao, Jinming

AU - Jin, Ronghua

AU - Xu, Dayong

AU - Ma, Yan Qing

AU - Huang, Tao

AU - Peng, Shuang

AU - Zheng, Zhi

AU - Stambler, Ilia

AU - Gilson, Eric

AU - Lim, Lee Wei

AU - Moskalev, Alexey

AU - Cano, Antonio

AU - Chakrabarti, Sasanka

AU - Ulfhake, Brun

AU - Su, Huanxing

AU - Xu, Haoying

AU - Xu, Sihuan

AU - Wei, Feng

AU - Brown-Borg, Holly M.

AU - Min, Kyung Jin

AU - Ellison-Hughes, Georgina

AU - Caruso, Calogero

AU - Jin, Kunlin

AU - Zhao, Robert Chunhua

PY - 2021/12

Y1 - 2021/12

N2 - 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.

AB - 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.

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DO - 10.1038/s41422-021-00573-y

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SN - 1001-0602

VL - 31

SP - 1244

EP - 1262

JO - Cell Research

JF - Cell Research

IS - 12

ER -

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

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