Abstract A13: Yap activity in bile ducts, but not in hepatocytes, is required for normal liver regeneration

The Hippo-pathway effectors Yap/Taz are assumed to be master regulators of organ regeneration. In the mouse liver, loss of Yap indeed affects the regeneration potential of hepatocytes. However, we found that this is not due to a requirement for Yap in hepatocytes to drive proliferation and regeneration, but is rather due to non-cell autonomous effects of the bile duct defects that develop in the absence of Yap. Developmental deletion of Yap and Taz in liver progenitors, which develop into hepatocytes and bile epithelial cells (BECs), impaired liver regeneration after toxin-induced injury. However, hepatocyte-specific deletion of Yap/Taz in adult mice revealed that Yap/Taz are dispensable in hepatocytes for liver regeneration. In contrast, deletion of Yap/Taz in mature BECs recapitulated the liver regeneration defects that were observed after knockout in liver progenitor cells. Notably, loss of Yap/Taz in BECs impaired bile duct integrity over time, induced a cholestatic liver phenotype, and increased apoptosis in wild-type hepatocytes after toxic liver injury. Our data show that Yap and Taz are required to maintain bile duct integrity, which is essential to maintain the regenerative capacity of adult hepatocytes. Citation Format: Elisabeth Verboven, Ivan M. Moya, Georg Halder. Yap activity in bile ducts, but not in hepatocytes, is required for normal liver regeneration [abstract]. In: Proceedings of the AACR Special Conference on the Hippo Pathway: Signaling, Cancer, and Beyond; 2019 May 8-11; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(8_Suppl):Abstract nr A13.