Osr1-mediated mesothelial transition of liver mesenchymal cells exacerbates fibrotic liver damage

Xinxin Nian; Pengyan Lin; Yunfei Bai; Donglin Yu; Xinyan Yang; Bin Zhou; Jie Gao; Yang Zhao

doi:10.1016/j.ymthe.2024.02.024

Osr1-mediated mesothelial transition of liver mesenchymal cells exacerbates fibrotic liver damage

Mol Ther. 2024 Feb 27:S1525-0016(24)00093-5. doi: 10.1016/j.ymthe.2024.02.024. Online ahead of print.

Authors

Xinxin Nian¹, Pengyan Lin², Yunfei Bai², Donglin Yu³, Xinyan Yang⁴, Bin Zhou⁵, Jie Gao⁶, Yang Zhao⁷

Affiliations

¹ State Key Laboratory of Natural and Biomimetic Drugs, Ministry of Education Key Laboratory of Cell Proliferation and Differentiation, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing 100871, China; Peking-Tsinghua Center for Life Science, Peking University, Beijing 100871, China.
² State Key Laboratory of Natural and Biomimetic Drugs, Ministry of Education Key Laboratory of Cell Proliferation and Differentiation, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing 100871, China.
³ Department of Biochemistry and Biophysics, Peking University Health Science Center, Beijing 100191, P.R. China.
⁴ State Key Laboratory of Organ Failure Research, Department of Developmental Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China.
⁵ New Cornerstone Science Laboratory, State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
⁶ Department of Hepatobiliary Surgery, Peking University People's Hospital, Beijing Key Surgical Basic Research Laboratory of Liver Cirrhosis and Liver Cancer, Beijing 100044, China.
⁷ State Key Laboratory of Natural and Biomimetic Drugs, Ministry of Education Key Laboratory of Cell Proliferation and Differentiation, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing 100871, China; Peking-Tsinghua Center for Life Science, Peking University, Beijing 100871, China. Electronic address: yangzhao@pku.edu.cn.

PMID: 38414241
DOI: 10.1016/j.ymthe.2024.02.024

Abstract

In chronic liver diseases, hepatic stellate cells (HSCs) are induced to form the myofibroblasts responsible for scar formation, leading to liver fibrosis and cirrhosis. Here, single-cell RNA sequencing with in vivo lineage tracing in nonalcoholic steatohepatitis (NASH) model mice reveals a subpopulation of HSCs transitioning back to a state resembling their developmental precursors, mesothelial cells (MCs), after liver injury. These damage-associated intermediates between HSCs and MCs (DIHMs) can be traced with a dual recombinase system by labeling Krt19-expressing cells within prelabeled Pdgfrb⁺ HSCs, and DIHMs highly express inflammation- and fibrosis-associated genes. Cre and Dre-inducible depletion of DIHMs by administering diphtheria toxin reduces liver fibrosis and alleviates liver damage in NASH model mice. Importantly, knockdown of Osr1, a zinc finger transcription factor of the OSR gene family, can block DIHM induction in vitro. Conditional knockout Osr1 in Pdgfrb-expressing mesenchymal cells in NASH model mice can reduce liver fibrosis in vivo. Our study collectively uncovers an injury-induced developmental reversion process wherein HSCs undergo what we call a mesenchymal-to-mesothelial transition, which can be targeted to develop interventions to treat chronic liver diseases.

Keywords: DIHMs; HSC; MMesoT; NASH; Osr1.