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Mesenchymal stem cell treatment improves outcome of COVID-19 patients via multiple immunomodulatory mechanisms.
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.
  • Zhu R; Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China.
  • Yan T; School of Life Sciences, Shanghai University, Shanghai, China.
  • Feng Y; You'an Hospital, Capital Medical University, Beijing, China.
  • Liu Y; Puren Hospital Affiliated to Wuhan University of Science and Technology, Wuhan, Hubei, China.
  • Cao H; State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
  • Peng G; National Clinical Research Center for Infectious Diseases, Hangzhou, Zhejiang, China.
  • Yang Y; Center for Bioinformatics, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & School of Basic Medicine, Peking Union Medical College, Beijing, China.
  • Xu Z; Department of Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
  • Liu J; School of Life Sciences, Shanghai University, Shanghai, China.
  • Hou W; Versiti Blood Research Institute, Milwaukee, WI, USA.
  • Wang X; State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
  • Li Z; You'an Hospital, Capital Medical University, Beijing, China.
  • Deng L; Center for Bioinformatics, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & School of Basic Medicine, Peking Union Medical College, Beijing, China.
  • Wang S; School of Life Sciences, Shanghai University, Shanghai, China.
  • Li J; Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China.
  • Han Q; Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China.
  • Li H; Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China.
  • Shan G; Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China.
  • Cao Y; Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China.
  • An X; Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China.
  • Yan J; Center for Bioinformatics, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & School of Basic Medicine, Peking Union Medical College, Beijing, China.
  • Zhang Z; Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China.
  • Li H; School of Life Sciences, Shanghai University, Shanghai, China.
  • Qu X; School of Life Sciences, Shanghai University, Shanghai, China.
  • Zhu J; School of Life Sciences, Shanghai University, Shanghai, China.
  • Zhou S; School of Life Sciences, Shanghai University, Shanghai, China.
  • Wang J; State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
  • Zhang F; National Clinical Research Center for Infectious Diseases, Hangzhou, Zhejiang, China.
  • Gao J; School of Life Sciences, Shanghai University, Shanghai, China.
  • Jin R; School of Life Sciences, Shanghai University, Shanghai, China.
  • Xu D; Department of Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
  • Ma YQ; Department of Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
  • Huang T; You'an Hospital, Capital Medical University, Beijing, China. jin_eagle@sina.com.
  • Peng S; Puren Hospital Affiliated to Wuhan University of Science and Technology, Wuhan, Hubei, China.
  • Zheng Z; Versiti Blood Research Institute, Milwaukee, WI, USA. yma@versiti.org.
  • Stambler I; Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, China.
  • Gilson E; Qingdao Walson Standard Biopharmaceutical Co, Ltd, Qingdao, Shangdong, China.
  • Lim LW; Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China.
  • Moskalev A; International Society on Aging and Disease, Bryan, TX, USA.
  • Cano A; Department of Science, Technology and Society, Bar Ilan University, Ramat Gan, Israel.
  • Chakrabarti S; International Society on Aging and Disease, Bryan, TX, USA.
  • Ulfhake B; Université Côte d'Azur, CNRS, Inserm, IRCAN, Faculty of Medicine, Nice, France.
  • Su H; Department of Medical Genetics, Centre Hospitalier Universitaire (CHU), Nice, France.
  • Xu H; International Society on Aging and Disease, Bryan, TX, USA.
  • Xu S; School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, China.
  • Wei F; International Society on Aging and Disease, Bryan, TX, USA.
  • Brown-Borg HM; Institute of Biology, Komi Science Center of Russian Academy of Sciences, Syktyvkar, Russia.
  • Min KJ; Russian Gerontological Research Clinical Center, Moscow, Russia.
  • Ellison-Hughes G; International Society on Aging and Disease, Bryan, TX, USA.
  • Caruso C; Department of Pediatrics, Obstetrics and Gynecology, University of Valencia, Valencia, Spain.
Cell Res ; 31(12): 1244-1262, 2021 12.
Article in English | MEDLINE | ID: covidwho-1493090
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.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Mesenchymal Stem Cell Transplantation / Immunomodulation / COVID-19 Type of study: Experimental Studies / Prognostic study / Randomized controlled trials Limits: Aged / Animals / Female / Humans / Male / Middle aged Language: English Journal: Cell Res Year: 2021 Document Type: Article Affiliation country: S41422-021-00573-y

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Mesenchymal Stem Cell Transplantation / Immunomodulation / COVID-19 Type of study: Experimental Studies / Prognostic study / Randomized controlled trials Limits: Aged / Animals / Female / Humans / Male / Middle aged Language: English Journal: Cell Res Year: 2021 Document Type: Article Affiliation country: S41422-021-00573-y