Fibroblast growth factor 10 is critical for liver growth during embryogenesis and controls hepatoblast survival via β-catenin activation

Fibroblast growth factor (FGF) signaling and ss-catenin activation have been shown to be crucial for early embryonic liver development. This study determined the significance of FGF10-mediated signaling in a murine embryonic liver progenitor cell population as well as its relation to ss-catenin activation. We observed that Fgf10(-/-) and Fgfr2b(-/-) mouse embryonic livers are smaller than wild-type livers; Fgf10(-/-) livers exhibit diminished proliferation of hepatoblasts. A comparison of ss-galactosidase activity as a readout of Fgf10 expression in Fgf10(+/LacZ) mice and of ss-catenin activation in TOPGAL mice, demonstrated peak Fgf10 expression from E9 to E13.5 coinciding with peak ss-catenin activation. Flow cytometric isolation and marker gene expression analysis of LacZ(+) cells from E13.5 Fgf10(+/LacZ) and TOPGAL livers, respectively, revealed that Fgf10 expression and ss-catenin signaling occur distinctly in stellate/myofibroblastic cells and hepatoblasts, respectively. Moreover, hepatoblasts express Fgfr2b, which strongly suggests they can respond to recombinant FGF10 produced by stellate cells. Fgfr2b(-/-)/TOPGAL(+/+) embryonic livers displayed less ss-galactosidase activity than livers of Fgfr2b(+/+)vertical bar TOPGAL(+/+) littermates. In addition, cultures of whole liver explants in Matrigel or cell in suspension from E12.5 TOPGAL(+/+) mice displayed a marked increase in ss-galactosidase activity and cell survival upon treatment with recombinant FGF10, indicating that FGFR (most likely FGFR2B) activation is upstream of ss-catenin signaling and promote hepatoblast survival. Conclusion: Embryonic stellate/myofibroblastic cells promote ss-catenin activation in and survival of hepatoblasts via FGF10-mediated signaling. We suggest a role for stellate/myofibroblastic FGF10 within the liver stem cell niche in supporting the proliferating hepatoblast.