2. Academic Validation
  3. A spatiotemporal atlas of cholestatic injury and repair in mice

A spatiotemporal atlas of cholestatic injury and repair in mice

  • Nat Genet. 2024 May;56(5):938-952. doi: 10.1038/s41588-024-01687-w.
Baihua Wu # 1,  Xinyi Shentu # 2,  Haitao Nan # 1,  Pengcheng Guo # 3,  Shijie Hao # 3 4 5,  Jiangshan Xu 3 4,  Shuncheng Shangguan 6 7 4,  Lei Cui 1,  Jin Cen 1,  Qiuting Deng 3 4,  Yan Wu 3 4,  Chang Liu 3 4,  Yumo Song 3 4,  Xiumei Lin 3 4,  Zhifeng Wang 4,  Yue Yuan 3 4,  Wen Ma 3 4,  Ronghai Li 3 4,  Yikang Li 8,  Qiwei Qian 8,  Wensi Du 9,  Tingting Lai 9,  Tao Yang 9,  Chuanyu Liu 3 4 10,  Xiong Ma 8,  Ao Chen 4,  Xun Xu 4 10,  Yiwei Lai 11 12 13,  Longqi Liu 14 15 16 17 18,  Miguel A Esteban 19 20 21 22,  Lijian Hui 23 24
Affiliations

Affiliations

  • 1 State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
  • 2 School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
  • 3 BGI Research, Hangzhou, China.
  • 4 BGI Research, Shenzhen, China.
  • 5 College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China.
  • 6 Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health and Guangzhou Medical University, Guangzhou, China.
  • 7 Laboratory of Integrative Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.
  • 8 Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, NHC Key Laboratory of Digestive Diseases, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China.
  • 9 China National GeneBank, BGI Research, Shenzhen, China.
  • 10 Shanxi Medical University-BGI Collaborative Center for Future Medicine, Shanxi Medical University, Taiyuan, China.
  • 11 BGI Research, Hangzhou, China. [email protected].
  • 12 BGI Research, Shenzhen, China. [email protected].
  • 13 Shanxi Medical University-BGI Collaborative Center for Future Medicine, Shanxi Medical University, Taiyuan, China. [email protected].
  • 14 BGI Research, Hangzhou, China. [email protected].
  • 15 BGI Research, Shenzhen, China. [email protected].
  • 16 College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China. [email protected].
  • 17 China National GeneBank, BGI Research, Shenzhen, China. [email protected].
  • 18 Shanxi Medical University-BGI Collaborative Center for Future Medicine, Shanxi Medical University, Taiyuan, China. [email protected].
  • 19 BGI Research, Hangzhou, China. [email protected].
  • 20 BGI Research, Shenzhen, China. [email protected].
  • 21 Laboratory of Integrative Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China. [email protected].
  • 22 The Fifth Affiliated Hospital of Guangzhou Medical University-BGI Research Center for Integrative Biology, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, China. [email protected].
  • 23 State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China. [email protected].
  • 24 School of Life Science and Technology, ShanghaiTech University, Shanghai, China. [email protected].
  • # Contributed equally.
PMID: 38627596 DOI: 10.1038/s41588-024-01687-w
Abstract

Cholestatic liver injuries, characterized by regional damage around the bile ductular region, lack curative therapies and cause considerable mortality. Here we generated a high-definition spatiotemporal atlas of gene expression during cholestatic injury and repair in mice by integrating spatial enhanced resolution omics Sequencing and single-cell transcriptomics. Spatiotemporal analyses revealed a key role of cholangiocyte-driven signaling correlating with the periportal damage-repair response. Cholangiocytes express genes related to recruitment and differentiation of lipid-associated macrophages, which generate feedback signals enhancing ductular reaction. Moreover, cholangiocytes express high TGFβ in association with the conversion of liver progenitor-like cells into cholangiocytes during injury and the dampened proliferation of periportal hepatocytes during recovery. Notably, Atoh8 restricts hepatocyte proliferation during 3,5-diethoxycarbonyl-1,4-dihydro-collidin damage and is quickly downregulated after injury withdrawal, allowing hepatocytes to respond to growth signals. Our findings lay a keystone for in-depth studies of cellular dynamics and molecular mechanisms of cholestatic injuries, which may further develop into therapies for cholangiopathies.

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