Notch Signaling Coordinates Progenitor Cell-Mediated Biliary Regeneration Following Partial Hepatectomy

Jie Lu, Yingqun Zhou, Tianyuan Hu, Hui Zhang, Miao Shen, Ping Cheng, Weiqi Dai, Fan Wang, Kan Chen, Yan Zhang, Chengfeng Wang, Jingjing Li, Yuanyuan Zheng, Jing Yang, Rong Zhu, Jianrong Wang, Wenxia Lu, Huawei Zhang, Junshan Wang, Yujing XiaThiago M. De Assuncao, Nidhi Jalan-Sakrikar, Robert C. Huebert, Bin Zhou, Chuanyong Guo

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

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.

Original languageEnglish (US)
Article number22754
JournalScientific reports
Volume6
DOIs
StatePublished - Mar 8 2016

ASJC Scopus subject areas

  • General

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