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Roles for Notch‐Sox9 in biliary epithelial cells‐to‐hepatocytes differentiation during liver regeneration

Liver regeneration after most forms of injury is mediated through proliferation of hepatocytes. However, when hepatocyte proliferation is impaired, such as during chronic liver disease, liver progenitor cells (LPCs) from the biliary epithelial cell (BEC) compartment can give rise to hepatocytes to mediate hepatic repair. Promotion of LPC‐to‐hepatocyte differentiation in patients with chronic liver disease could serve as a potential new therapeutic option, but first requires the identification of the molecular mechanisms driving this process. Notch signaling has been identified as an important signaling pathway promoting the BEC fate during development, and has also been implicated in regulating LPC differentiation during regeneration. SRY‐related HMG box transcription factor 9 (Sox9) is a direct target of Notch signaling in the liver, and Sox9 has also been shown to promote the BEC fate during development. We have recently shown that inhibition of Hdac1 activity during liver regeneration in both zebrafish and mouse models enhances sox9 expression in LPCs and impairs LPC‐to‐hepatocyte differentiation. Therefore, we hypothesized that inhibition of Notch signaling would promote LPC‐to‐hepatocyte differentiation by repressing sox9 expression. To this end, we blocked Notch activation during liver regeneration through treatment with γ‐secretase inhibitor LY411575 in a zebrafish LPC‐driven regeneration model and demonstrated enhanced induction of Hnf4a in LPCs. Alternatively, enhancing Notch signaling via Notch3 intracellular domain (N3ICD) overexpression impaired Hnf4a induction. Hepatocyte ablation in sox9b heterozygous mutant embryos enhanced Hnf4a induction, while BEC‐specific Sox9b overexpression impaired LPC‐to‐hepatocyte differentiation. Moreover, LY411575 treatment promoted the differentiation of murine LPCs into hepatocytes in vitro. Lastly, we administrated LY411575 to mice with hepatocyte‐specific deletion of β‐catenin, which induces differentiation of LPCs into hepatocytes following a choline‐deficient, ethionine‐supplemented (CDE) diet. We also examined the effect of liver‐specific Sox9 ablation upon CDE diet liver injury. Our results will elucidate the detailed roles for Notch‐Sox9 signaling in liver regeneration and LPC‐to‐hepatocyte differentiation.