title: Fibroblast growth factor signaling in myofibroblasts differs from lipofibroblasts during alveolar septation in mice.
abstract: Pulmonary alveolar fibroblasts produce extracellular matrix in a temporally and spatially regulated pattern to yield a durable yet pliable gas-exchange surface. Proliferation ensures a sufficient complement of cells, but they must differentiate into functionally distinct subtypes: contractile myofibroblasts (MF), which generate elastin and regulate air-flow at the alveolar ducts, and, in mice and rats, lipofibroblasts (LF), which store neutral lipids. PDGF-A is required but acts in conjunction with other differentiation factors arising from adjacent epithelia or within fibroblasts. We hypothesized that FGF receptor (FGFR) expression and function vary for MF and LF and contributes to their divergent differentiation. Whereas approximately half of the FGFR3 was extracellular in MF, FGFR2 and FGFR4 were primarily intracellular. Intracellular FGFR3 localized to the multivesicular body, and its abundance may be modified by Sprouty and interaction with heat shock protein-90. FGF18 mRNA is more abundant in MF, whereas FGF10 mRNA predominated in LF, which also express FGFR1 IIIb, a receptor for FGF10. FGF18 diminished fibroblast proliferation and was chemotactic for cultured fibroblasts. Although PDGF receptor-α (PDGFR-α) primarily signals through phosphoinositide 3-kinase and Akt, p42/p44 MAP kinase (Erk1/2), a major signaling pathway for FGFRs, influenced the abundance of cell-surface PDGFR-α. Observing different FGFR and ligand profiles in MF and LF is consistent with their divergent differentiation although both subpopulations express PDGFR-α. These studies also emphasize the importance of particular cellular locations of FGFR3 and PDGFR-α, which may modify their effects during alveolar development or repair.
authors.affiliation: Department of Veterans Affairs Research Service and Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa stephen-mcgowan@uiowa.edu.
authors.forename: Stephen E
authors.initials: SE
authors.lastname: McGowan
authors.affiliation: Department of Veterans Affairs Research Service and Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa.
authors.forename: Diann M
authors.initials: DM
authors.lastname: McCoy
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D018835:Chaperonin 10 / Q000235:genetics; D018844:Cyclin-Dependent Kinases; D004549:Elastin / Q000096:biosynthesis; D005109:Extracellular Matrix / Q000378:metabolism; D051526:Fibroblast Growth Factor 10 / Q000235:genetics / Q000378:metabolism; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D057146:Multivesicular Bodies / Q000378:metabolism; D058628:Myofibroblasts / Q000166:cytology / Q000378:metabolism*; D010982:Platelet-Derived Growth Factor / Q000378:metabolism*; D011650:Pulmonary Alveoli / Q000166:cytology / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000096:biosynthesis / Q000378:metabolism; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000378:metabolism; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000378:metabolism*; D051499:Receptor, Fibroblast Growth Factor, Type 4 / Q000378:metabolism; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000378:metabolism*; D015398:Signal Transduction; D000095043:Cyclin-Dependent Kinase-Activating Kinase
chemical_list: D018835:Chaperonin 10; C496464:Fgf10 protein, mouse; D051526:Fibroblast Growth Factor 10; D008565:Membrane Proteins; D010982:Platelet-Derived Growth Factor; D012333:RNA, Messenger; C113569:fibroblast growth factor 18; C075278:platelet-derived growth factor A; D005346:Fibroblast Growth Factors; D004549:Elastin; C496349:Fgfr1 protein, mouse; C496354:Fgfr2 protein, mouse; C496366:Fgfr3 protein, mouse; C496372:Fgfr4 protein, mouse; D051496:Receptor, Fibroblast Growth Factor, Type 1; D051497:Receptor, Fibroblast Growth Factor, Type 2; D051498:Receptor, Fibroblast Growth Factor, Type 3; D051499:Receptor, Fibroblast Growth Factor, Type 4; D020796:Receptor, Platelet-Derived Growth Factor alpha; D018844:Cyclin-Dependent Kinases; D000095043:Cyclin-Dependent Kinase-Activating Kinase
keywords: PDGF receptor-α; adipocyte; cell differentiation; endosome; fibroblast