Fibroblast growth factor 10 is critical for liver growth... : Hepatology (original) (raw)

Liver Injury/Regeneration

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

Berg, Tove1; Rountree, Bart C.1; Lee, Lily1; Estrada, Joaquin1; Sala, Fréderic G.1; Choe, Andrea1; Veltmaat, Jacqueline M.1,**; De Langhe, Stijn1; Lee, Rene1; Tsukamoto, Hide2; Crooks, Gay M.1; Bellusci, Saverio1; Wang, Kasper S.1,2,*

1_Saban Research Institute, Childrens Hospital Los Angeles_

2_Research Center for Alcoholic Liver and Pancreatic Diseases, Keck School of Medicine, University of Southern California, Los Angeles, CA_

**Institute of Molecular and Cell Biology, 61 Biopolis Drive, Singapore 138673

*Address reprint requests to: Developmental Biology Research Program, The Saban Research Institute, Childrens Hospital Los Angeles, Keck School of Medicine, University of Southern California, 4650 Sunset Blvd., Mailstop 100, Los Angeles, CA 90027

Email: [email protected]

Received 11 December 2006; Accepted 10 May 2007

Published online in Wiley InterScience (www.interscience.wiley.com).

Grant sponsor: Research Center for Alcoholic Liver and Pancreatic Diseases; Grant Number: P50 AA11999; Grant sponsor: National Institutes of Health; Grant Numbers: K08 AA016290 K12 HD 00850; Grant sponsor: Saban Research Institute Career Development; Grant sponsor: American Gastroenterology Association Fellow/Faculty Transition.

Potential conflict of interest: Nothing to report.

These authors contributed equally to this study.

fax: 323-666-3466

Abstract

Fibroblast growth factor (FGF) signaling and β-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 β-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 β-galactosidase activity as a readout of Fgf10 expression in Fgf10 +/LacZ mice and of β-catenin activation in TOPGAL mice, demonstrated peak Fgf10 expression from E9 to E13.5 coinciding with peak β-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 β-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 β-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 β-galactosidase activity and cell survival upon treatment with recombinant FGF10, indicating that FGFR (most likely FGFR2B) activation is upstream of β-catenin signaling and promote hepatoblast survival. Conclusion: Embryonic stellate/myofibroblastic cells promote β-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. (HEPATOLOGY 2007.)

Abbreviations: DMEM, Dulbecco's modified Eagle medium; E, embryonic day; FACS, fluorescence-activated cell sorting; FDG, fluorescein digalactoside; FGF, fibroblast growth factor; FGFR, fibroblast growth factor receptor; PI, propidium iodide; RT-PCR, reverse-transcription polymerase chain reaction.