Journal
NATURE MEDICINE
Volume 18, Issue 4, Pages 572-579Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nm.2667
Keywords
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Funding
- MRC
- Sir Jules Thorn Trust
- Wellcome Trust
- MRC [MR/J010766/1, G0901697, G0600033, G1000868] Funding Source: UKRI
- Cancer Research UK [12481] Funding Source: researchfish
- Medical Research Council [G1000868, G0901697, G0700711B, G0600033, MR/J010766/1] Funding Source: researchfish
- The Sir Jules Thorn Charitable Trust [07JTA] Funding Source: researchfish
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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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