Farnesoid X Receptor Is Required for the Redifferentiation of Bipotential Progenitor Cells During Biliary‐Mediated Zebrafish Liver Regeneration

作者：Pengcheng Cai, Xiaoyu Mao, Jieqiong Zhao, Li Nie, Yan Jiang, Qifen Yang, Rui Ni, Jianbo He, Lingfei Luo · 发表于：Hepatology · 年份：2021 · DOI：10.1002/hep.32076 · 被引用次数：33 · 研究领域：Liver physiology and pathology、Organ Transplantation Techniques and Outcomes、Developmental Biology and Gene Regulation

BACKGROUND AND AIMS: Liver regeneration after extreme hepatocyte loss occurs through transdifferentiation of biliary epithelial cells (BECs), which includes dedifferentiation of BECs into bipotential progenitor cells (BPPCs) and subsequent redifferentiation into nascent hepatocytes and BECs. Although multiple molecules and signaling pathways have been implicated to play roles in the BEC-mediated liver regeneration, mechanisms underlying the dedifferentiation-redifferentiation transition and the early phase of BPPC redifferentiation that is pivotal for both hepatocyte and BEC directions remain largely unknown. APPROACH AND RESULTS: The zebrafish extreme liver damage model, genetic mutation, pharmacological inhibition, transgenic lines, whole-mount and fluorescent in situ hybridizations and antibody staining, single-cell RNA sequencing, quantitative real-time PCR, and heat shock-inducible overexpression were used to investigate roles and mechanisms of farnesoid X receptor (FXR; encoded by nuclear receptor subfamily 1, group H, member 4 [nr1h4]) in regulating BPPC redifferentiation. The nr1h4 expression was significantly up-regulated in response to extreme liver injury. Genetic mutation or pharmacological inhibition of FXR was ineffective to BEC-to-BPPC dedifferentiation but blocked the redifferentiation of BPPCs to both hepatocytes and BECs, leading to accumulation of undifferentiated or less-differentiated BPPCs. Mechanistically, induced overexpression of extracellular signal-...