Fibroblast growth factor 10 is critical for liver growth during embryogenesis and controls hepatoblast survival via beta-catenin activation.
Fibroblast growth factor (FGF) signaling and beta-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 beta-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 beta-galactosidase activity as a readout of Fgf10 expression in Fgf10(+/LacZ) mice and of beta-catenin activation in TOPGAL mice, demonstrated peak Fgf10 expression from E9 to E13.5 coinciding with peak beta-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 beta-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 beta-galactosidase activity than livers of Fgfr2b(+/+)/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 beta-galactosidase activity and cell survival upon treatment with recombinant FGF10, indicating that FGFR (most likely FGFR2B) activation is upstream of beta-catenin signaling and promote hepatoblast survival.


CONCLUSIONS
Embryonic stellate/myofibroblastic cells promote beta-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.
Saban Research Institute, Childrens Hospital Los Angeles, CA 90027, USA.
Tove
T
Berg
C Bart
CB
Rountree
Lily
L
Lee
Joaquin
J
Estrada
Fréderic G
FG
Sala
Andrea
A
Choe
Jacqueline M
JM
Veltmaat
Stijn
S
De Langhe
Rene
R
Lee
Hide
H
Tsukamoto
Gay M
GM
Crooks
Saverio
S
Bellusci
Kasper S
KS
Wang
D000818:Animals; D049109:Cell Proliferation; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D047108:Embryonic Development / Q000235:genetics / Q000502:physiology*; D051526:Fibroblast Growth Factor 10 / Q000235:genetics / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism*; D008099:Liver / Q000166:cytology / Q000196:embryology* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*; D001616:beta-Galactosidase / Q000378:metabolism
C496464:Fgf10 protein, mouse; D051526:Fibroblast Growth Factor 10; D051176:beta Catenin; D051497:Receptor, Fibroblast Growth Factor, Type 2; D001616:beta-Galactosidase