Dr. Paul Monga, PLRC member and Professor of Pathology and Medicine, and his colleagues, published a manuscript in Cell Reports, entitled, “Compensatory hepatic adaptation accompanies permanent absence of intrahepatic biliary network due to YAP1 loss in liver progenitors.” PLRC members, Dr. Andrew Feranchak– Associate Director PLRC, Dr. Kari Nejak-Bowen– Director Enrichment Program, Dr. Takis Benos– Director GSBC, Dr. Aatur Singhi– Director CBRPC, Dr. Bharat Bhushan– 2021 P&F Recipient, Dr. George Michalopoulos, Dr. Xiaochao Ma, Dr. Simon Watkins, Dr. Prithu Sundd, Dr. Sungjin Ko, Dr. Tirthadipa Pradhan-Sundd, and Dr. Aaron Bell all contributed to this article.
Molina LM, Zhu J, Li Q, Pradhan-Sundd T, Krutsenko Y, Sayed K, Jenkins N, Vats R, Bhushan B, Ko S, Hu S, Poddar M, Singh S, Tao J, Sundd P, Singhi A, Watkins S, Ma X, Benos PV, Feranchak A, Michalopoulos G, Nejak-Bowen K, Watson A, Bell A, Monga SP. Compensatory hepatic adaptation accompanies permanent absence of intrahepatic biliary network due to YAP1 loss in liver progenitors. Cell Rep. 2021 Jul 6;36(1):109310. doi: 10.1016/j.celrep.2021.109310. PMID: 34233187.
Yes-associated protein 1 (YAP1) regulates cell plasticity during liver injury, regeneration, and cancer, but its role in liver development is unknown. We detect YAP1 activity in biliary cells and in cells at the hepatobiliary bifurcation in single-cell RNA sequencing analysis of developing livers. Deletion of Yap1 in hepatoblasts does not impair Notch-driven SOX9+ ductal plate formation but does prevent the formation of the abutting second layer of SOX9+ ductal cells, blocking the formation of a patent intrahepatic biliary tree. Intriguingly, these mice survive for 8 months with severe cholestatic injury and without hepatocyte-to-biliary transdifferentiation. Ductular reaction in the perihilar region suggests extrahepatic biliary proliferation, likely seeking the missing intrahepatic biliary network. Long-term survival of these mice occurs through hepatocyte adaptation via reduced metabolic and synthetic function, including altered bile acid metabolism and transport. Overall, we show YAP1 as a key regulator of bile duct development while highlighting a profound adaptive capability of hepatocytes.