Human Placental Mesenchymal Stem Cells Relieve Primary Sclerosing Cholangitis via Upregulation of TGR5 in Mdr2 −/− Mice and Human Intrahepatic Cholangiocyte Organoid Models

作者：Qigu Yao, Wenyi Chen, Yingduo Yu, Feiqiong Gao, Jiahang Zhou, Jian Wu, Qiaoling Pan, Jinfeng Yang, Lingling Zhou, Jiong Yu, Hongcui Cao, Lanjuan Li · 发表于：Research · 年份：2023 · DOI：10.34133/research.0207 · 被引用次数：28 · 研究领域：Organ Transplantation Techniques and Outcomes、Liver Diseases and Immunity、Pediatric Hepatobiliary Diseases and Treatments

Primary sclerosing cholangitis (PSC) is a biliary disease accompanied by chronic inflammation of the liver and biliary stricture. Mesenchymal stem cells (MSCs) are used to treat liver diseases because of their immune regulation and regeneration-promoting functions. This study was performed to explore the therapeutic potential of human placental MSCs (hP-MSCs) in PSC through the Takeda G protein-coupled receptor 5 (TGR5) receptor pathway. Liver tissues were collected from patients with PSC and healthy donors ( n = 4) for RNA sequencing and intrahepatic cholangiocyte organoid construction. hP-MSCs were injected via the tail vein into Mdr2 −/− , bile duct ligation (BDL), and 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) mouse models or co-cultured with organoids to confirm their therapeutic effect on biliary cholangitis. Changes in bile acid metabolic profile were analyzed by liquid chromatography/tandem mass spectrometry (LC-MS/MS). Compared with healthy controls, liver tissues and intrahepatic cholangiocyte organoids from PSC patients were characterized by inflammation and cholestasis, and marked downregulation of bile acid receptor TGR5 expression. hP-MSC treatment apparently reduced the inflammation, cholestasis, and fibrosis in Mdr2 −/− , BDL, and DDC model mice. By activating the phosphatidylinositol 3 kinase/extracellular signal-regulated protein kinase pathway, hP-MSC treatment promoted the proliferation of cholangiocytes, and affected the transcription of downstream n...