title: TGF-β signaling in stromal cells acts upstream of FGF-10 to regulate epithelial stem cell growth in the adult lung.
abstract: Tissue resident mesenchymal stromal cells (MSCs) contribute to tissue regeneration through various mechanisms, including the secretion of trophic factors that act directly on epithelial stem cells to promote epithelialization. However, MSCs in tissues constitute a heterogeneous population of stromal cells and different subtypes may have different functions. In this study we show that CD166(neg) and CD166(pos) lung stromal cells have different proliferative and differentiative potential. CD166(neg) lung stromal cells exhibit high proliferative potential with the capacity to differentiate along the lipofibroblastic and myofibroblastic lineages, whereas CD166(pos) lung stromal cells have limited proliferative potential and are committed to the myofibroblastic lineage. Moreover, we show that CD166(pos) lung stromal cells do not share the same epithelial-supportive capacity as their CD166(neg) counterparts, which support the growth of lung epithelial stem cell (EpiSPC) colonies in vitro. In addition, ex vivo expansion of lung stromal cells also resulted in the loss of epithelial-supportive capacity, which could be reinstated by inhibition of the TGF-β signaling pathway. We show that epithelial-supportive capacity correlated with the level of FGF-10 expression and the reactivation of several lung development-associated genes. In summary, these studies suggest that TGF-β signaling in stromal cells acts upstream of FGF-10 to regulate epithelial stem cell growth in the adult lung.
authors.affiliation: Lung Health Research Centre, Department of Pharmacology and Therapeutics, University of Melbourne, Victoria 3010, Australia. Electronic address: jlmcq@unimelb.edu.au.
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: McQualter
authors.forename: Rosa C
authors.initials: RC
authors.lastname: McCarty
authors.forename: Joanne
authors.initials: J
authors.lastname: Van der Velden
authors.forename: Robert J J
authors.initials: RJ
authors.lastname: O'Donoghue
authors.forename: Marie-Liesse
authors.initials: ML
authors.lastname: Asselin-Labat
authors.forename: Steven
authors.initials: S
authors.lastname: Bozinovski
authors.forename: Ivan
authors.initials: I
authors.lastname: Bertoncello
mesh_terms: D020410:Activated-Leukocyte Cell Adhesion Molecule / Q000378:metabolism; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D002454:Cell Differentiation; D019070:Cell Lineage; D049109:Cell Proliferation; D002478:Cells, Cultured; D004149:Dioxoles / Q000494:pharmacology; D004847:Epithelial Cells / Q000166:cytology* / Q000378:metabolism; D005260:Female; D051526:Fibroblast Growth Factor 10 / Q000378:metabolism*; D008168:Lung / Q000166:cytology / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D058628:Myofibroblasts / Q000166:cytology / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*; D017154:Stromal Cells / Q000166:cytology* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: C459179:4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide; D020410:Activated-Leukocyte Cell Adhesion Molecule; D001549:Benzamides; D004149:Dioxoles; D051526:Fibroblast Growth Factor 10; D016212:Transforming Growth Factor beta
keywords: CFU-Epi; CFU-F; EpiSPC; MSC; colony-forming unit-epithelial; colony-forming unit-fibroblast; epithelial stem/progenitor cell; mesenchymal stromal cell