title: Fibroblast growth factor 10 alters the balance between goblet and Paneth cells in the adult mouse small intestine.
abstract: Intestinal epithelial cell renewal relies on the right balance of epithelial cell migration, proliferation, differentiation, and apoptosis. Intestinal epithelial cells consist of absorptive and secretory lineage. The latter is comprised of goblet, Paneth, and enteroendocrine cells. Fibroblast growth factor 10 (FGF10) plays a central role in epithelial cell proliferation, survival, and differentiation in several organs. The expression pattern of FGF10 and its receptors in both human and mouse intestine and their role in small intestine have yet to be investigated. First, we analyzed the expression of FGF10, FGFR1, and FGFR2, in the human ileum and throughout the adult mouse small intestine. We found that FGF10, FGFR1b, and FGFR2b are expressed in the human ileum as well as in the mouse small intestine. We then used transgenic mouse models to overexpress Fgf10 and a soluble form of Fgfr2b, to study the impact of gain or loss of Fgf signaling in the adult small intestine. We demonstrated that overexpression of Fgf10 in vivo and in vitro induces goblet cell differentiation while decreasing Paneth cells. Moreover, FGF10 decreases stem cell markers such as Lgr5, Lrig1, Hopx, Ascl2, and Sox9. FGF10 inhibited Hes1 expression in vitro, suggesting that FGF10 induces goblet cell differentiation likely through the inhibition of Notch signaling. Interestingly, Fgf10 overexpression for 3 days in vivo and in vitro increased the number of Mmp7/Muc2 double-positive cells, suggesting that goblet cells replace Paneth cells. Further studies are needed to determine the mechanism by which Fgf10 alters cell differentiation in the small intestine.
authors.affiliation: Keck School of Medicine, University of Southern California, Los Angeles, California; Developmental Biology and Regenerative Medicine Program, Saban Research Institute of Children's Hospital Los Angeles, Los Angeles, California; dalalam@chla.usc.edu.
authors.forename: Denise
authors.initials: D
authors.lastname: Al Alam
authors.affiliation: Keck School of Medicine, University of Southern California, Los Angeles, California; Developmental Biology and Regenerative Medicine Program, Saban Research Institute of Children's Hospital Los Angeles, Los Angeles, California;
authors.forename: Soula
authors.initials: S
authors.lastname: Danopoulos
authors.affiliation: Keck School of Medicine, University of Southern California, Los Angeles, California; Developmental Biology and Regenerative Medicine Program, Saban Research Institute of Children's Hospital Los Angeles, Los Angeles, California;
authors.forename: Kathy
authors.initials: K
authors.lastname: Schall
authors.affiliation: Keck School of Medicine, University of Southern California, Los Angeles, California; Developmental Biology and Regenerative Medicine Program, Saban Research Institute of Children's Hospital Los Angeles, Los Angeles, California;
authors.forename: Frederic G
authors.initials: FG
authors.lastname: Sala
authors.affiliation: Keck School of Medicine, University of Southern California, Los Angeles, California; Developmental Biology and Regenerative Medicine Program, Saban Research Institute of Children's Hospital Los Angeles, Los Angeles, California;
authors.forename: Dana
authors.initials: D
authors.lastname: Almohazey
authors.affiliation: Keck School of Medicine, University of Southern California, Los Angeles, California;
authors.forename: G Esteban
authors.initials: GE
authors.lastname: Fernandez
authors.affiliation: Developmental Biology and Regenerative Medicine Program, Saban Research Institute of Children's Hospital Los Angeles, Los Angeles, California;
authors.forename: Senta
authors.initials: S
authors.lastname: Georgia
authors.affiliation: Keck School of Medicine, University of Southern California, Los Angeles, California; Developmental Biology and Regenerative Medicine Program, Saban Research Institute of Children's Hospital Los Angeles, Los Angeles, California;
authors.forename: Mark R
authors.initials: MR
authors.lastname: Frey
authors.affiliation: Keck School of Medicine, University of Southern California, Los Angeles, California; Developmental Biology and Regenerative Medicine Program, Saban Research Institute of Children's Hospital Los Angeles, Los Angeles, California;
authors.forename: Henri R
authors.initials: HR
authors.lastname: Ford
authors.affiliation: Keck School of Medicine, University of Southern California, Los Angeles, California; Developmental Biology and Regenerative Medicine Program, Saban Research Institute of Children's Hospital Los Angeles, Los Angeles, California;
authors.forename: Tracy
authors.initials: T
authors.lastname: Grikscheit
authors.affiliation: Keck School of Medicine, University of Southern California, Los Angeles, California; Developmental Biology and Regenerative Medicine Program, Saban Research Institute of Children's Hospital Los Angeles, Los Angeles, California; Department of Internal Medicine II, University of Giessen Lung Center and Member of the German Lung Center, Giessen, Germany; and Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russia.
authors.forename: Saverio
authors.initials: S
authors.lastname: Bellusci
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D016923:Cell Death; D002454:Cell Differentiation; D049109:Cell Proliferation; D051526:Fibroblast Growth Factor 10 / Q000235:genetics / Q000378:metabolism*; D020397:Goblet Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007421:Intestine, Small / Q000378:metabolism* / Q000473:pathology; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019879:Paneth Cells / Q000378:metabolism* / Q000473:pathology; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000378:metabolism; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D046509:Tissue Culture Techniques
chemical_list: D015415:Biomarkers; C496463:FGF10 protein, human; C496464:Fgf10 protein, mouse; D051526:Fibroblast Growth Factor 10; C496348:FGFR1 protein, human; C496353:FGFR2 protein, human; C496349:Fgfr1 protein, mouse; C496354:Fgfr2 protein, mouse; D051496:Receptor, Fibroblast Growth Factor, Type 1; D051497:Receptor, Fibroblast Growth Factor, Type 2
keywords: Fgf10; Fgfr2b; differentiation; small intestine