β-catenin regulates mesenchymal progenitor cell differentiation during hepatogenesis.
BACKGROUND
Understanding the pathways regulating mesenchymal progenitor cell fate during hepatogenesis may provide insight into postnatal liver injury or liver bioengineering. While β-Catenin has been implicated in the proliferation of fetal hepatic epithelial progenitor cells, its role in mesenchymal precursors during hepatogenesis has not been established.


METHODS
We used a murine model of conditional deletion of β-Catenin in mesenchyme using the Dermo1 locus (β-Catenin(Dermo1)) to characterize the role of β-Catenin in liver mesenchyme during hepatogenesis.


RESULTS
Lineage tracing using a LacZ reporter indicates that both hepatic stellate cells and pericytes derive from mesenchymal Dermo1 expressing precursor cells. Compared to control littermate livers, β-Catenin(Dermo1) embryonic livers are smaller and filled with dilated sinusoids. While the fraction of mesenchymally-derived cells in β-Catenin(Dermo1) embryos is unchanged compared to littermate controls, there is an increase in the expression of the mesenchymal markers, DESMIN, α-SMA, and extracellular deposition of COLLAGEN type I, particularly concentrated around dilated sinusoids. Analysis of the endothelial cell compartment in β-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. β-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 β-Catenin signaling pathway in the differentiation of liver mesenchymal progenitor cells during organogenesis, possibly via Pitx2. Hepatic mesenchymal β-Catenin signaling, in turn, modulates the development of both endothelium and endodermally-derived hepatoblasts, presumably via other downstream paracrine pathways.
Berg
Tove
T
Saban Research Institute, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, California 90027, USA.
DeLanghe
Stijn
S
Al Alam
Denise
D
Utley
Sarah
S
Estrada
Joaquin
J
Wang
Kasper S
KS
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects*; D004622:Embryo, Mammalian; D047108:Embryonic Development / Q000187:drug effects; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D007150:Immunohistochemistry; D007763:Lac Operon / Q000187:drug effects; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D051176:beta Catenin / Q000172:deficiency / Q000494:pharmacology* / Q000633:toxicity; D001616:beta-Galactosidase / Q000378:metabolism
D051176:beta Catenin; D001616:beta-Galactosidase
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