Immunity-and-Matrix-Regulatory Cells Derived from Human Embryonic Stem Cells Safely and Effectively Treat Mouse Lung Injury and Fibrosis

Jun Wu; Dingyun Song; Zhongwen Li; Baojie Guo; Yani Xiao; Wenjing Liu; Lingmin Liang; Chunjing Feng; Tingting Gao; Zai Wang; Jianyan Wen; Shengnan Yang; Peipei Liu; Lei Wang; Yukai Wang; Liang Peng; Guihai Feng; Shiqiang Huang; Glyn Nigel Stacey; Wei Li; Yan Huo; Ronghua Jin; Qi Zhou; Liu Wang; Baoyang Hu; Huaping Dai; Jie Hao

The mouse BLM model is similar to human ALI/ARDS during the acute inflammatory phase. Although 604 fibroblastic foci, alveolar epithelial type 2 cells hyperplasia and honeycombing lesions are reduced 605 compared with those in humans, indicating that the reproduction of human ARDS is not complete in the 606 mouse BLM model, injury to alveolar epithelial cells has been shown to be a common contributing factor 607 to the pathogenesis of both human ARDS and BLM-induced mouse pulmonary injury 40,41 . To test the 608 therapeutic efficacy of IMRCs in the BLM mouse model, the delivery route and schedule of 609 administration (e.g. single dose versus repeated doses) was carefully considered. Intravenous infusion is 610 one of the principal delivery routes, considered to be minimally invasive, simple-to-use, and is the most 611 common mode for primary MSCs delivery in diverse lung disorders 42,43 . Furthermore, systemic 612 intravenous transplantation may be a suitable administration route in other future clinical scenarios. In 613 our present study, intravenous IMRCs improved the survival rate of mice with BLM-induced lung injury 614 in a dose-dependent manner, by inhibiting both pulmonary inflammation and fibrosis. As demonstrated 615 in vitro, IMRCs inhibited the production of pro-inflammatory cytokines and pro-fibrosis cytokines, such 616 as TNF-α and TGF-β1, in lung tissue in vivo. Furthermore, lung function indicators such as PV, IC, Rrs, 617