Establishment of a Fah-LSL mouse model to study BEC-to-hepatocyte conversion

Abstract

The liver consists predominantly of hepatocytes and biliary epithelial cells (BECs), which serve distinct physiological functions. Although hepatocytes primarily replenish their own population during homeostasis and injury repair, recent findings have suggested that BECs can transdifferentiate into hepatocytes when hepatocyte-mediated liver regeneration is impaired. However, the cellular and molecular mechanisms governing this BEC-to-hepatocyte conversion remain poorly understood largely because of the inefficiency of existing methods for inducing lineage conversion. Therefore, this study introduces a novel mouse model engineered by the Zhou's lab, where hepatocyte senescence is induced by the deletion of the fumarylacetoacetate (Fah) gene. This model facilitates the efficient conversion of BECs to hepatocytes and allows for the simultaneous lineage tracing of BECs; consequently, a transitional liver progenitor cell population can be identified during lineage conversion. This study also outlines the technical procedures for utilizing this model to determine the underlying cellular and molecular mechanisms of BEC-to-hepatocyte conversion and provides new insights into liver regeneration and its underlying molecular mechanism.

Graphical abstract

Keywords

Liver regeneration / BEC-to-hepatocyte transdifferentiation / Fumarylacetoacetate (Fah) gene / Transitional liver progenitor cells (TLPC) / Lineage tracing

Acknowledgements

We thank Shanghai Biomodel Organism Co., Ltd. for the generation of Fah-LSL mice. This study was supported by the National Science Foundation of China (32370783, 32100592, 82088101, 32050087), National Key Research & Development Program of China (2019YFA0110403, 2019YFA0802000), Collaborative Innovation Program of Shanghai Municipal Health Commission (2020CXJQ01), the Pearl River Talent Recruitment Program of Guangdong Province (2017ZT07S347), The National Ten Thousand Talents Program – the Top-Notch Young Talent, and the New Cornerstone Science Foundation through the New Cornerstone Investigator Program and the XPLORER PRIZE.

RIGHTS & PERMISSIONS

2023 The Author(s)