Transplantation of ACE2- Mesenchymal stem cells improves the outcome of patients with covid-19 pneumonia

Zikuan Leng; Rongjia Zhu; Wei Hou; Yingmei Feng; Yanlei Yang; Qin Han; Guangliang Shan; Fanyan Meng; Dongshu Du; Shihua Wang; Junfen Fan; Wenjing Wang; Luchan Deng; Hongbo Shi; Hongjun Li; Zhongjie Hu; Fengchun Zhang; Jinming Gao; Hongjian Liu; Xiaoxia Li; Yangyang Zhao; Kan Yin; Xijing He; Zhengchao Gao; Yibin Wang; Bo Yang; Ronghua Jin; Ilia Stambler; Lee Wei Lim; Huanxing Su; Alexey Moskalev; Antonio Cano; Sasanka Chakrabarti; Kyung Jin Min; Georgina Ellison-Hughes; Calogero Caruso; Kunlin Jin; Robert Chunhua Zhao

doi:10.14336/AD.2020.0228

Transplantation of ACE2^- Mesenchymal stem cells improves the outcome of patients with covid-19 pneumonia

Zikuan Leng, Rongjia Zhu, Wei Hou, Yingmei Feng, Yanlei Yang, Qin Han, Guangliang Shan, Fanyan Meng, Dongshu Du, Shihua Wang, Junfen Fan, Wenjing Wang, Luchan Deng, Hongbo Shi, Hongjun Li, Zhongjie Hu, Fengchun Zhang, Jinming Gao, Hongjian Liu, Xiaoxia LiYangyang Zhao, Kan Yin, Xijing He, Zhengchao Gao, Yibin Wang, Bo Yang, Ronghua Jin, Ilia Stambler, Lee Wei Lim, Huanxing Su, Alexey Moskalev, Antonio Cano, Sasanka Chakrabarti, Kyung Jin Min, Georgina Ellison-Hughes, Calogero Caruso, Kunlin Jin, Robert Chunhua Zhao

Research output: Contribution to journal › Article › peer-review

954 Scopus citations

Abstract

A coronavirus (HCoV-19) has caused the novel coronavirus disease (COVID-19) outbreak in Wuhan, China. Preventing and reversing the cytokine storm may be the key to save the patients with severe COVID-19 pneumonia. Mesenchymal stem cells (MSCs) have been shown to possess a comprehensive powerful immunomodulatory function. This study aims to investigate whether MSC transplantation improves the outcome of 7 enrolled patients with COVID-19 pneumonia in Beijing YouAn Hospital, China, from Jan 23, 2020 to Feb 16, 2020. The clinical outcomes, as well as changes of inflammatory and immune function levels and adverse effects of 7 enrolled patients were assessed for 14 days after MSC injection. MSCs could cure or significantly improve the functional outcomes of seven patients without observed adverse effects. The pulmonary function and symptoms of these seven patients were significantly improved in 2 days after MSC transplantation. Among them, two common and one severe patient were recovered and discharged in 10 days after treatment. After treatment, the peripheral lymphocytes were increased, the C-reactive protein decreased, and the overactivated cytokine-secreting immune cells CXCR3+CD4+ T cells, CXCR3+CD8+ T cells, and CXCR3+ NK cells disappeared in 3-6 days. In addition, a group of CD14+CD11c+CD11b^mid regulatory DC cell population dramatically increased. Meanwhile, the level of TNF-α was significantly decreased, while IL-10 increased in MSC treatment group compared to the placebo control group. Furthermore, the gene expression profile showed MSCs were ACE2- and TMPRSS2- which indicated MSCs are free from COVID-19 infection. Thus, the intravenous transplantation of MSCs was safe and effective for treatment in patients with COVID-19 pneumonia, especially for the patients in critically severe condition.

Original language	English
Pages (from-to)	216-228
Number of pages	13
Journal	Aging and Disease
Volume	11
Issue number	2
DOIs	https://doi.org/10.14336/AD.2020.0228
State	Published - Apr 2020
Externally published	Yes

Bibliographical note

Publisher Copyright:
© 2020 Leng Z et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding

This work was supported by the National Key Research and Development Program of China (2016YFA0101000, 2018YFE0114200), CAMS Innovation Fund for Medical Sciences (2017-I2M-3-007) and the 111 Project (B18007), National Natural Science Foundation of China (81971324, 81672313, 81700782, 81972523, 81771349).

Funders	Funder number
CAMS Innovation Fund for Medical Sciences	2017-I2M-3-007
National Natural Science Foundation of China	81672313, 81700782, 81771349, 81971324, 81972523
National Basic Research Program of China (973 Program)	2018YFE0114200, 2016YFA0101000
Higher Education Discipline Innovation Project	B18007

Keywords

ACE2 negative
COVID-19
Cell transplantation
Function recovery
Immunomodulation
Mesenchymal stem cells

Access to Document

10.14336/AD.2020.0228

Cite this

Leng, Z., Zhu, R., Hou, W., Feng, Y., Yang, Y., Han, Q., Shan, G., Meng, F., Du, D., Wang, S., Fan, J., Wang, W., Deng, L., Shi, H., Li, H., Hu, Z., Zhang, F., Gao, J., Liu, H., ... Zhao, R. C. (2020). Transplantation of ACE2^- Mesenchymal stem cells improves the outcome of patients with covid-19 pneumonia. Aging and Disease, 11(2), 216-228. https://doi.org/10.14336/AD.2020.0228

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title = "Transplantation of ACE2- Mesenchymal stem cells improves the outcome of patients with covid-19 pneumonia",

abstract = "A coronavirus (HCoV-19) has caused the novel coronavirus disease (COVID-19) outbreak in Wuhan, China. Preventing and reversing the cytokine storm may be the key to save the patients with severe COVID-19 pneumonia. Mesenchymal stem cells (MSCs) have been shown to possess a comprehensive powerful immunomodulatory function. This study aims to investigate whether MSC transplantation improves the outcome of 7 enrolled patients with COVID-19 pneumonia in Beijing YouAn Hospital, China, from Jan 23, 2020 to Feb 16, 2020. The clinical outcomes, as well as changes of inflammatory and immune function levels and adverse effects of 7 enrolled patients were assessed for 14 days after MSC injection. MSCs could cure or significantly improve the functional outcomes of seven patients without observed adverse effects. The pulmonary function and symptoms of these seven patients were significantly improved in 2 days after MSC transplantation. Among them, two common and one severe patient were recovered and discharged in 10 days after treatment. After treatment, the peripheral lymphocytes were increased, the C-reactive protein decreased, and the overactivated cytokine-secreting immune cells CXCR3+CD4+ T cells, CXCR3+CD8+ T cells, and CXCR3+ NK cells disappeared in 3-6 days. In addition, a group of CD14+CD11c+CD11bmid regulatory DC cell population dramatically increased. Meanwhile, the level of TNF-α was significantly decreased, while IL-10 increased in MSC treatment group compared to the placebo control group. Furthermore, the gene expression profile showed MSCs were ACE2- and TMPRSS2- which indicated MSCs are free from COVID-19 infection. Thus, the intravenous transplantation of MSCs was safe and effective for treatment in patients with COVID-19 pneumonia, especially for the patients in critically severe condition.",

keywords = "ACE2 negative, COVID-19, Cell transplantation, Function recovery, Immunomodulation, Mesenchymal stem cells",

author = "Zikuan Leng and Rongjia Zhu and Wei Hou and Yingmei Feng and Yanlei Yang and Qin Han and Guangliang Shan and Fanyan Meng and Dongshu Du and Shihua Wang and Junfen Fan and Wenjing Wang and Luchan Deng and Hongbo Shi and Hongjun Li and Zhongjie Hu and Fengchun Zhang and Jinming Gao and Hongjian Liu and Xiaoxia Li and Yangyang Zhao and Kan Yin and Xijing He and Zhengchao Gao and Yibin Wang and Bo Yang and Ronghua Jin and Ilia Stambler and Lim, {Lee Wei} and Huanxing Su and Alexey Moskalev and Antonio Cano and Sasanka Chakrabarti and Min, {Kyung Jin} and Georgina Ellison-Hughes and Calogero Caruso and Kunlin Jin and Zhao, {Robert Chunhua}",

note = "Publisher Copyright: {\textcopyright} 2020 Leng Z et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.",

year = "2020",

month = apr,

doi = "10.14336/AD.2020.0228",

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volume = "11",

pages = "216--228",

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Leng, Z, Zhu, R, Hou, W, Feng, Y, Yang, Y, Han, Q, Shan, G, Meng, F, Du, D, Wang, S, Fan, J, Wang, W, Deng, L, Shi, H, Li, H, Hu, Z, Zhang, F, Gao, J, Liu, H, Li, X, Zhao, Y, Yin, K, He, X, Gao, Z, Wang, Y, Yang, B, Jin, R, Stambler, I, Lim, LW, Su, H, Moskalev, A, Cano, A, Chakrabarti, S, Min, KJ, Ellison-Hughes, G, Caruso, C, Jin, K & Zhao, RC 2020, 'Transplantation of ACE2^- Mesenchymal stem cells improves the outcome of patients with covid-19 pneumonia', Aging and Disease, vol. 11, no. 2, pp. 216-228. https://doi.org/10.14336/AD.2020.0228

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T1 - Transplantation of ACE2- Mesenchymal stem cells improves the outcome of patients with covid-19 pneumonia

AU - Leng, Zikuan

AU - Zhu, Rongjia

AU - Hou, Wei

AU - Feng, Yingmei

AU - Yang, Yanlei

AU - Han, Qin

AU - Shan, Guangliang

AU - Meng, Fanyan

AU - Du, Dongshu

AU - Wang, Shihua

AU - Fan, Junfen

AU - Wang, Wenjing

AU - Deng, Luchan

AU - Shi, Hongbo

AU - Li, Hongjun

AU - Hu, Zhongjie

AU - Zhang, Fengchun

AU - Gao, Jinming

AU - Liu, Hongjian

AU - Li, Xiaoxia

AU - Zhao, Yangyang

AU - Yin, Kan

AU - He, Xijing

AU - Gao, Zhengchao

AU - Wang, Yibin

AU - Yang, Bo

AU - Jin, Ronghua

AU - Stambler, Ilia

AU - Lim, Lee Wei

AU - Su, Huanxing

AU - Moskalev, Alexey

AU - Cano, Antonio

AU - Chakrabarti, Sasanka

AU - Min, Kyung Jin

AU - Ellison-Hughes, Georgina

AU - Caruso, Calogero

AU - Jin, Kunlin

AU - Zhao, Robert Chunhua

N1 - Publisher Copyright: © 2020 Leng Z et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

PY - 2020/4

Y1 - 2020/4

N2 - A coronavirus (HCoV-19) has caused the novel coronavirus disease (COVID-19) outbreak in Wuhan, China. Preventing and reversing the cytokine storm may be the key to save the patients with severe COVID-19 pneumonia. Mesenchymal stem cells (MSCs) have been shown to possess a comprehensive powerful immunomodulatory function. This study aims to investigate whether MSC transplantation improves the outcome of 7 enrolled patients with COVID-19 pneumonia in Beijing YouAn Hospital, China, from Jan 23, 2020 to Feb 16, 2020. The clinical outcomes, as well as changes of inflammatory and immune function levels and adverse effects of 7 enrolled patients were assessed for 14 days after MSC injection. MSCs could cure or significantly improve the functional outcomes of seven patients without observed adverse effects. The pulmonary function and symptoms of these seven patients were significantly improved in 2 days after MSC transplantation. Among them, two common and one severe patient were recovered and discharged in 10 days after treatment. After treatment, the peripheral lymphocytes were increased, the C-reactive protein decreased, and the overactivated cytokine-secreting immune cells CXCR3+CD4+ T cells, CXCR3+CD8+ T cells, and CXCR3+ NK cells disappeared in 3-6 days. In addition, a group of CD14+CD11c+CD11bmid regulatory DC cell population dramatically increased. Meanwhile, the level of TNF-α was significantly decreased, while IL-10 increased in MSC treatment group compared to the placebo control group. Furthermore, the gene expression profile showed MSCs were ACE2- and TMPRSS2- which indicated MSCs are free from COVID-19 infection. Thus, the intravenous transplantation of MSCs was safe and effective for treatment in patients with COVID-19 pneumonia, especially for the patients in critically severe condition.

AB - A coronavirus (HCoV-19) has caused the novel coronavirus disease (COVID-19) outbreak in Wuhan, China. Preventing and reversing the cytokine storm may be the key to save the patients with severe COVID-19 pneumonia. Mesenchymal stem cells (MSCs) have been shown to possess a comprehensive powerful immunomodulatory function. This study aims to investigate whether MSC transplantation improves the outcome of 7 enrolled patients with COVID-19 pneumonia in Beijing YouAn Hospital, China, from Jan 23, 2020 to Feb 16, 2020. The clinical outcomes, as well as changes of inflammatory and immune function levels and adverse effects of 7 enrolled patients were assessed for 14 days after MSC injection. MSCs could cure or significantly improve the functional outcomes of seven patients without observed adverse effects. The pulmonary function and symptoms of these seven patients were significantly improved in 2 days after MSC transplantation. Among them, two common and one severe patient were recovered and discharged in 10 days after treatment. After treatment, the peripheral lymphocytes were increased, the C-reactive protein decreased, and the overactivated cytokine-secreting immune cells CXCR3+CD4+ T cells, CXCR3+CD8+ T cells, and CXCR3+ NK cells disappeared in 3-6 days. In addition, a group of CD14+CD11c+CD11bmid regulatory DC cell population dramatically increased. Meanwhile, the level of TNF-α was significantly decreased, while IL-10 increased in MSC treatment group compared to the placebo control group. Furthermore, the gene expression profile showed MSCs were ACE2- and TMPRSS2- which indicated MSCs are free from COVID-19 infection. Thus, the intravenous transplantation of MSCs was safe and effective for treatment in patients with COVID-19 pneumonia, especially for the patients in critically severe condition.

KW - ACE2 negative

KW - COVID-19

KW - Cell transplantation

KW - Function recovery

KW - Immunomodulation

KW - Mesenchymal stem cells

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