Macrophage derived Wnt signalling opposes Notch signalling in a Numb mediated manner to specify HPC fate in chronic liver disease in human and mouse
By L. Boulter, O. Govaere, T. Bird, S. Radulescu, P. Ramachandran, A. Pellicoro, Rachel A. Ridgway, S. S. Seo, B. Spee, Nico van Rooijen and 5 more. Nature Medicine, 2012
724 citations recorded by the source corpus.
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.
Subfields: Hepatology, Surgery
View Paper: https://www.semanticscholar.org/paper/bc28f16249e70510a32bf6392df8f619f6747a44
How researchers see this paper
The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.
In Hepatology
In Surgery
Citations in the corpus
- Therapy for Fibrotic Diseases: Nearing the Starting Line (2013, background): “Conversion of resident mesenchymal cells such as stellate cells into myofibroblasts in response to tissue injury, a process termed cellular activation, engages many of the same pathways underlying their embryonic development (143).”
- Origin and Functions of Tissue Macrophages (2014, background): “After injury, liver macrophages engulf hepatocyte debris and activate a program leading to the secretion of WNT ligands, which direct hepatocyte differentiation from progenitors (You et al., 2013; Boulter et al., 2012).”
- Kupffer Cells in the Liver (2013, positive): “Interestingly, Kupffer cells are also critical to the appropriate speciation of hepatic progenitor cells in the liver during hepatocyte regeneration; when Kupffer cells engulf debris in the damaged liver, they increase expression of Wnt3, a ligand in the Wnt/Notch signaling pathways (13).”