Notch2 converts hepatoblasts and adult hepatocytes to the biliary lineage via canonical Notch signalling independent of Hes1 in mice

P Jeliazkova; S Jörs; M Lee; U Zimber-Strobl; J Ferrer; RM Schmid; JT Siveke; F Geisler

doi:10.1055/s-0032-1331900

Zeitschrift für Gastroenterologie, Table of Contents

Notch2 converts hepatoblasts and adult hepatocytes to the biliary lineage via canonical Notch signalling independent of Hes1 in mice

P Jeliazkova ¹, S Jörs ¹, M Lee ¹, U Zimber-Strobl ², J Ferrer ³, RM Schmid ¹, JT Siveke ¹, F Geisler ¹

¹Technical University of Munich, Gastroenterology, II. Medical department, Munich, Germany
²Hemholtz Zentrum, Institute of Clinical Molecular Biology and Tumor Genetics, Munich, Germany
³Institut d'Investigacions Biomediques Pi i Sunyer, Genomic Programming of Beta Cells Laboratory, Barcelona, Spain

Abstract

Notch signaling via the Notch2 receptor is essential for normal biliary tubulogenesis during liver development. However, the signaling events downstream of Notch2 critical for this process are less well defined. Furthermore, whether Notch signaling also underlies adult hepatic cell fate decisions is largely unknown.

By implementing different genetic mouse models, we provide a comprehensive analysis that defines the role of Notch in cell fate control in the developing and adult liver. We show that cell-specific activation of Notch2 signaling by a Notch2IC (N2IC) transgene leads to rapid biliary specification and morphogenesis of embryonic hepatoblasts, but also – when expressed in up to 6 months old adult livers – rapidly reprograms adult hepatocytes to biliary cells with formation of tubular-cystic structures. When directed specifically to the adult biliary and facultative liver progenitor cell compartment, Notch2 is capable to induce a ductular reaction. Furthermore, by using conditional knockout mice for key effectors of canonical Notch signaling, RBP-Jκ and Hes1, we characterize the significance of these proteins during normal development and in N2IC-expressing models. We demonstrate that tubule formation of intrahepatic bile ducts during embryonic development as well as N2IC-induced specification of embryonic hepatoblasts and reprogramming of adult hepatocytes all critically rely on canonical Notch signaling via RBP-Jκ but do not require Hes1.

Conclusion: Notch2 signaling not only drives tubulogenesis of embryonic hepatoblasts but is also capable to determine cell fates of adult liver cell compartments. Notch2-dictated cell fates in both embryonic hepatoblast and adult hepatocytes rely on canonical Notch signaling but do not require Hes1. Our results support the concept that adult liver cells possess a remarkable plasticity to assume new cell fates when embryonic signaling pathways are active.