Macrophage-derived Wnt opposes Notch signaling to specify hepatic progenitor cell fate in chronic liver disease

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

Research output: Contribution to journalArticlepeer-review

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.
Original languageEnglish
Pages (from-to)572-579
Number of pages8
JournalNature Medicine
Volume18
Issue number4
DOIs
Publication statusPublished - Apr 2012

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