Macrophage-derived Wnt opposes Notch signaling to specify hepatic progenitor cell fate in chronic liver disease |
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| Authors: | Boulter Luke Govaere Olivier Bird Tom G Radulescu Sorina Ramachandran Prakash Pellicoro Antonella Ridgway Rachel A Seo Sang Soo Spee Bart Van Rooijen Nico Sansom Owen J Iredale John P Lowell Sally Roskams Tania Forbes Stuart J |
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| Affiliation: | Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK. |
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| 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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