β-Catenin Regulates Mesenchymal Progenitor Cell Differentiation During Hepatogenesis

Background Understanding the pathways regulating mesenchymal progenitor cell fate during hepato genesis may provide insight into postnatal liver injury or liver bioengineering While beta Catenin has been implicated in the proliferation of fetal hepatic epithelial progenitor cells, its role in mesenchymal precursors during hepatogenesis has not been established Materials and Methods We used a murine model of conditional deletion of beta Catenin in mesenchyme using the Dermal locus (beta-Catenin(Dermo1)) to characterize the role of beta-Catenin in liver mesenchyme during hepatogenesis Results Lineage tracing using a LacZ reporter indicates that both hepatic stellate cells and pericytes derive from mesenchymal Dermal expressing precursor cells Compared to control littermate livers, beta-Catenin(Dermo1) embryonic livers are smaller and filled with dilated sinusoids While the fraction of mesenchymally-derived cells in beta Catenin(Dermo1) embryos is unchanged compared to littermate controls, there is an increase in the expression of the mesenchymal markers, DESMIN, alpha-SMA, and extra cellular deposition of COLLAGEN type I, particularly concentrated around dilated sinusoids Analysis of the endothelial cell compartment in beta-Catenin(Dermo1)/Flk1(lacZ) embryos revealed a marked reorganization of the intrahepatic vasculature Analysis of various markers for the endodermally-derived hepatoblast population revealed marked alterations in the spatial expression pattern of pan-cytokeratin but not E cadherin, or albumin beta Catenin(Dermo1) phenocopies mesenchymal deletion of Pitx2, a known regulator of hepatic mesenchymal differentiation both during both organogenesis and postnatal injury Conclusions Our data implicate mesenchymal beta-Catenin signaling pathway in the differentiation of liver mesenchymal progenitor cells during organogenesis, possibly via Pitx2 Hepatic mesenchymal beta-Catenin signaling, in turn, modulates the development of both endothelium and endodermally-derived hepatoblasts, presumably via other downstream paracrine pathways (C) 2010 Elsevier Inc All rights reserved