法尼甾体X受体
内生
胆汁酸
癌症研究
间质细胞
间充质干细胞
药理学
核受体
医学
化学
细胞生物学
生物
生物化学
转录因子
基因
作者
Yunlong Xia,Xinyue Xu,Yongzhen Guo,Lin Chen,Xiaoming Xu,Fuyang Zhang,Min Fan,Tingting Qi,Congye Li,Guangyu Hu,Peng Lu,Shan Wang,Ling Zhang,Chen Hai,Rui Li,Yan Wang,Tao Lei
标识
DOI:10.1002/advs.202200431
摘要
Abstract Bile acid metabolites have been increasingly recognized as pleiotropic signaling molecules that regulate cardiovascular functions, but their role in mesenchymal stromal cells (MSC)‐based therapy has never been investigated. It is found that overexpression of farnesoid X receptor (FXR), a main receptor for bile acids, improves the retention and cardioprotection of adipose tissue‐derived MSC (ADSC) administered by intramyocardial injection in mice with myocardial infarction (MI), which shows enhanced antiapoptotic, proangiogenic, and antifibrotic effects. RNA sequencing, LC‐MS/MS, and loss‐of‐function studies reveal that FXR overexpression promotes ADSC paracrine angiogenesis via Angptl4. FXR overexpression improves ADSC survival in vivo but fails in vitro. By performing bile acid‐targeted metabolomics using ischemic heart tissue, 19 bile acids are identified. Among them, cholic acid and deoxycholic acid significantly increase Angptl4 secretion from ADSC overexpressing FXR and further improve their proangiogenic capability. Moreover, ADSC overexpressing FXR shows significantly lower apoptosis by upregulating Nqo‐1 expression only in the presence of FXR ligands. Retinoid X receptor α is identified as a coactivator of FXR. It is first demonstrated that there is a bile acid pool in the myocardial microenvironment. Targeting the bile acid‐FXR axis may be a novel strategy for improving the curative effect of MSC‐based therapy for MI.
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