title: Notch Signaling Coordinates Progenitor Cell-Mediated Biliary Regeneration Following Partial Hepatectomy.
abstract: Aberrant transcriptional regulation contributes to the pathogenesis of both congenital and adult forms of liver disease. Although the transcription factor RBPJ is essential for liver morphogenesis and biliary development, its specific function in the differentiation of hepatic progenitor cells (HPC) has not been investigated, and little is known about its role in adult liver regeneration. HPCs are bipotent liver stem cells that can self-replicate and differentiate into hepatocytes or cholangiocytes in vitro. HPCs are thought to play an important role in liver regeneration and repair responses. While the coordinated repopulation of both hepatocyte and cholangiocyte compartment is pivotal to the structure and function of the liver after regeneration, the mechanisms coordinating biliary regeneration remain vastly understudied. Here, we utilized complex genetic manipulations to drive liver-specific deletion of the Rbpj gene in conjunction with lineage tracing techniques to delineate the precise functions of RBPJ during biliary development and HPC-associated biliary regeneration after hepatectomy. Furthermore, we demonstrate that RBPJ promotes HPC differentiation toward cholangiocytes in vitro and blocks hepatocyte differentiation through mechanisms involving Hippo-Notch crosstalk. Overall, this study demonstrates that the Notch-RBPJ signaling axis critically regulates biliary regeneration by coordinating the fate decision of HPC and clarifies the molecular mechanisms involved.
authors.affiliation: Department of Gastroenterology, Shanghai 10th People's Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China.
authors.forename: Jie
authors.initials: J
authors.lastname: Lu
authors.affiliation: Department of Gastroenterology, Shanghai 10th People's Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China.
authors.forename: Yingqun
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, People's Republic of China.
authors.forename: Tianyuan
authors.initials: T
authors.lastname: Hu
authors.affiliation: Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, People's Republic of China.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Gastroenterology, Shanghai 10th People's Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China.
authors.forename: Miao
authors.initials: M
authors.lastname: Shen
authors.affiliation: Department of Gastroenterology, Shanghai 10th People's Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China.
authors.forename: Ping
authors.initials: P
authors.lastname: Cheng
authors.affiliation: Department of Gastroenterology, Shanghai 10th People's Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China.
authors.forename: Weiqi
authors.initials: W
authors.lastname: Dai
authors.affiliation: Department of Gastroenterology, Shanghai 10th People's Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China.
authors.forename: Fan
authors.initials: F
authors.lastname: Wang
authors.affiliation: Department of Gastroenterology, Shanghai 10th People's Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China.
authors.forename: Kan
authors.initials: K
authors.lastname: Chen
authors.affiliation: Department of Gastroenterology, Shanghai 10th People's Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Gastroenterology, Shanghai 10th People's Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China.
authors.forename: Chengfeng
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Gastroenterology, Shanghai 10th People's Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Gastroenterology, Shanghai 10th People's Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Department of Gastroenterology, Shanghai 10th People's Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China.
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Gastroenterology, Shanghai 10th People's Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China.
authors.forename: Rong
authors.initials: R
authors.lastname: Zhu
authors.affiliation: Department of Gastroenterology, Shanghai 10th People's Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China.
authors.forename: Jianrong
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Gastroenterology, Shanghai 10th People's Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China.
authors.forename: Wenxia
authors.initials: W
authors.lastname: Lu
authors.affiliation: Department of Gastroenterology, Shanghai 10th People's Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China.
authors.forename: Huawei
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Gastroenterology, Shanghai 10th People's Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China.
authors.forename: Junshan
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Gastroenterology, Shanghai 10th People's Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China.
authors.forename: Yujing
authors.initials: Y
authors.lastname: Xia
authors.affiliation: Division of Gastroenterology and Hepatology; Mayo Clinic and Foundation, Rochester, MN, USA.
authors.forename: Thiago M
authors.initials: TM
authors.lastname: De Assuncao
authors.affiliation: Division of Gastroenterology and Hepatology; Mayo Clinic and Foundation, Rochester, MN, USA.
authors.forename: Nidhi
authors.initials: N
authors.lastname: Jalan-Sakrikar
authors.affiliation: Division of Gastroenterology and Hepatology; Mayo Clinic and Foundation, Rochester, MN, USA.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Huebert
authors.affiliation: Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, People's Republic of China.
authors.lastname: Bin Zhou
authors.affiliation: Department of Gastroenterology, Shanghai 10th People's Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China.
authors.forename: Chuanyong
authors.initials: C
authors.lastname: Guo
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D001659:Biliary Tract / Q000502:physiology*; D002454:Cell Differentiation / Q000502:physiology; D049109:Cell Proliferation; D002478:Cells, Cultured; D006498:Hepatectomy; D022781:Hepatocytes / Q000166:cytology*; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000166:cytology / Q000601:surgery; D008115:Liver Regeneration / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D011401:Promoter Regions, Genetic / Q000235:genetics; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013234:Stem Cells / Q000166:cytology*; D000091102:YAP-Signaling Proteins
chemical_list: D051017:Apoptosis Regulatory Proteins; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; D051880:Receptors, Notch; D000091102:YAP-Signaling Proteins; C509425:Yap1 protein, rat