Volume 30, No 9, Sep 2020

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 30 Issue 9, September 2020: 794-809   |  Open Access

ORIGINAL ARTICLES

Immunity-and-matrix-regulatory cells derived from human embryonic stem cells safely and effectively treat mouse lung injury and fibrosis

Jun Wu^1,2,3 , Dingyun Song^4,5 , Zhongwen Li^1,2,3 , Baojie Guo^1,2,3,6 , Yani Xiao⁷ , Wenjing Liu^1,2,3 , Lingmin Liang^1,2,3,6 , Chunjing Feng¹ , Tingting Gao^1,2,3 , Yanxia Chen^1,2,3 , Ying Li⁸ , Zai Wang^9,10 , Jianyan Wen^9,10,11 , Shengnan Yang^4,12 , Peipei Liu^4,5 , Lei Wang^1,2,3 , Yukai Wang^1,2,3 , Liang Peng^9,10 , Glyn Nigel Stacey^3,13 , Zheng Hu^14,15 , Guihai Feng^1,2 , Wei Li^1,2 , Yan Huo⁷ , Ronghua Jin¹⁶ , Ng Shyh-Chang^1,2,6 , Qi Zhou^1,2,3,6 , Liu Wang^1,2,3,6 , Baoyang Hu^1,2,3,6,* , Huaping Dai^4,5,* , Jie Hao^1,2,3,*

¹State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
²Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China
³National Stem Cell Resource Center, Chinese Academy of Sciences, Beijing 100101, China
⁴Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital; National Clinical Research Center for Respiratory Diseases, Institute of Respiratory Medicine, Chinese Academy of Medical Sciences, Beijing 100029, China
⁵Graduate School of Peking Union Medical College, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100730, China
⁶University of Chinese Academy of Sciences, Beijing 100049, China
⁷National Center for Safety Evaluation of Drugs, National Institutes for Food and Drug Control, Beijing 100176, China
⁸Department of Gastroenterology, The First Hospital of Jilin University, Changchun, Jilin 130061, China
⁹Institute of Clinical Medical Sciences, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing, China
¹⁰Institute of Respiratory Medicine, Chinese Academy of Medical Sciences, Beijing 100029, China
¹¹Department of Cardiology, China-Japan Friendship Hospital, Beijing 100029, China
¹²Medical University of Ha Er Bin, Ha’erbin, Heilongjiang 150081, China
¹³International Stem Cell Banking Initiative, 2 High Street, Barley, Hertfordshire SG8 8HZ, UK
¹⁴Key Laboratory of Organ Regeneration & Transplantation of Ministry of Education, The First Hospital of Jilin University, Changchun, Jilin 130061, China
¹⁵National-Local Joint Engineering Laboratory of Animal Models for Human Diseases, Changchun, Jilin 130061, China
¹⁶Beijing Youan Hospital, Capital Medical University, Beijing 100069, China
^†These authors contributed equally: Jun Wu, Dingyun Song, Zhongwen Li, Baojie Guo
Correspondence: Baoyang Hu(byhu@ioz.ac.cn)Huaping Dai(daihuaping@ccmu.edu.cn)Jie Hao(haojie@ioz.ac.cn)

Lung injury and fibrosis represent the most significant outcomes of severe and acute lung disorders, including COVID-19. However, there are still no effective drugs to treat lung injury and fibrosis. In this study, we report the generation of clinical-grade human embryonic stem cells (hESCs)-derived immunity- and matrix-regulatory cells (IMRCs) produced under good manufacturing practice requirements, that can treat lung injury and fibrosis in vivo. We generate IMRCs by sequentially differentiating hESCs with serum-free reagents. IMRCs possess a unique gene expression profile distinct from that of umbilical cord mesenchymal stem cells (UCMSCs), such as higher expression levels of proliferative, immunomodulatory and anti-fibrotic genes. Moreover, intravenous delivery of IMRCs inhibits both pulmonary inflammation and fibrosis in mouse models of lung injury, and significantly improves the survival rate of the recipient mice in a dose-dependent manner, likely through paracrine regulatory mechanisms. IMRCs are superior to both primary UCMSCs and the FDA-approved drug pirfenidone, with an excellent efficacy and safety profile in mice and monkeys. In light of public health crises involving pneumonia, acute lung injury and acute respiratory distress syndrome, our findings suggest that IMRCs are ready for clinical trials on lung disorders.

https://doi.org/10.1038/s41422-020-0354-1

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