Macrophage-derived Wnt Opposes Notch Signaling to Specify Hepatic Progenitor Cell Fate in Chronic Liver Disease

Overview

Journal Nat Med

Specialties General Medicine
Molecular Biology

Date 2012 Mar 6

PMID 22388089

Citations 383

Authors

Luke Boulter

Olivier Govaere

Tom G Bird

Sorina Radulescu

Prakash Ramachandran

Antonella Pellicoro

Rachel A Ridgway

Sang Soo Seo

Bart Spee

Nico van Rooijen

Owen J Sansom

John P Iredale

Sally Lowell

Tania Roskams

Stuart J Forbes

Affiliations

Soon will be listed here.

Abstract

During chronic injury a population of bipotent hepatic progenitor cells (HPCs) become activated to regenerate both cholangiocytes and hepatocytes. Here we show in human diseased liver and mouse models of the ductular reaction that Notch and Wnt signaling direct specification of HPCs via their interactions with activated myofibroblasts or macrophages. In particular, we found that during biliary regeneration, expression of Jagged 1 (a Notch ligand) by myofibroblasts promoted Notch signaling in HPCs and thus their biliary specification to cholangiocytes. Alternatively, during hepatocyte regeneration, macrophage engulfment of hepatocyte debris induced Wnt3a expression. This resulted in canonical Wnt signaling in nearby HPCs, thus maintaining expression of Numb (a cell fate determinant) within these cells and the promotion of their specification to hepatocytes. By these two pathways adult parenchymal regeneration during chronic liver injury is promoted.

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