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

Qigu Yao; Wenyi Chen; Yingduo Yu; Feiqiong Gao; Jiahang Zhou; Jian Wu; Qiaoling Pan; Jinfeng Yang; Lingling Zhou; Jiong Yu; Hongcui Cao; Lanjuan Li

doi:10.34133/research.0207

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

Research (Wash D C). 2023 Aug 17:6:0207. doi: 10.34133/research.0207. eCollection 2023.

Authors

Qigu Yao^{1

2}, Wenyi Chen^{1

2}, Yingduo Yu^{1

2}, Feiqiong Gao^{1

2}, Jiahang Zhou^{1

2}, Jian Wu^{1

2}, Qiaoling Pan^{1

2}, Jinfeng Yang^{1

2}, Lingling Zhou^{1

2}, Jiong Yu^{1

2}, Hongcui Cao^{1

2

3}, Lanjuan Li^{1

2

4}

Affiliations

¹ State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou 310003, China.
² National Clinical Research Center for Infectious Diseases, Hangzhou, China.
³ Key Laboratory of Diagnosis and Treatment of Aging and Physic-chemical Injury Diseases of Zhejiang Province, 79 Qingchun Rd., Hangzhou 310003, China.
⁴ Jinan Microecological Biomedicine Shandong Laboratory, Jinan 250117, China.

Abstract

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 nuclear factor κB through regulation of the binding of TGR5 and Pellino3, thereby affecting the cholangiocyte inflammatory phenotype.