title: Platelet-derived growth factor-A and sonic hedgehog signaling direct lung fibroblast precursors during alveolar septal formation.
abstract: Alveolar septal formation is required to support the respiration of growing mammals; in humans effacement of the alveolar surface and impaired gas exchange are critical features of emphysema and pulmonary fibrosis. Platelet-derived growth factor-A (PDGF-A) and its receptor PDGF-receptor-α (PDGFRα) are required for secondary septal elongation in mice during postnatal days 4 through 12 and they regulate the proliferation and septal location of interstitial fibroblasts. We examined lung fibroblasts (LF) to learn whether PDGFRα expression distinguished a population of precursor cells, with enhanced proliferative and migratory capabilities. We identified a subpopulation of LF that expresses sonic hedgehog (Shh) and stem cell antigen-1 (Sca1). PDGF-A and Shh both increased cytokinesis and chemotaxis in vitro, but through different mechanisms. In primary LF cultures, Shh signaled exclusively through a noncanonical pathway involving generation of Rac1-GTP, whereas both the canonical and noncanonical pathways were used by the Mlg neonatal mouse LF cell line. LF preferentially oriented their primary cilia toward their anterior pole during migration. Furthermore, a larger proportion of PDGFRα-expressing LF, which are more abundant at the septal tips, bore primary cilia compared with other alveolar cells. In pulmonary emphysema, destroyed alveolar septa do not regenerate, in part because cells fail to assume a configuration that allows efficient gas exchange. Better understanding how LF are positioned during alveolar development could identify signaling pathways, which promote alveolar septal regeneration.
authors.affiliation: Department of Veterans Affairs Research Service, Iowa City, IA, USA. stephen-mcgowan@uiowa.edu
authors.forename: Stephen E
authors.initials: SE
authors.lastname: McGowan
authors.forename: Diann M
authors.initials: DM
authors.lastname: McCoy
mesh_terms: D000199:Actins / Q000032:analysis; D000818:Animals; D018952:Antigens, CD34 / Q000032:analysis; D000950:Antigens, Ly / Q000032:analysis; D002460:Cell Line; D002465:Cell Movement; D049109:Cell Proliferation; D005347:Fibroblasts / Q000378:metabolism; D053823:Hedgehog Proteins / Q000032:analysis / Q000378:metabolism*; D019394:Ki-67 Antigen / Q000032:analysis; D008168:Lung / Q000196:embryology / Q000378:metabolism; D008565:Membrane Proteins / Q000032:analysis; D051379:Mice; D008822:Mice, Transgenic; D009479:Neuropeptides / Q000096:biosynthesis / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000378:metabolism*; D011650:Pulmonary Alveoli / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000378:metabolism*; D015398:Signal Transduction; D020830:rac1 GTP-Binding Protein / Q000096:biosynthesis / Q000378:metabolism
chemical_list: D000199:Actins; D018952:Antigens, CD34; D000950:Antigens, Ly; D053823:Hedgehog Proteins; D019394:Ki-67 Antigen; C074650:Ly6a protein, mouse; D008565:Membrane Proteins; C498355:Mki67 protein, mouse; D009479:Neuropeptides; D010982:Platelet-Derived Growth Factor; C484602:Rac1 protein, mouse; C465570:Shh protein, mouse; C544013:alpha-smooth muscle actin, mouse; C075278:platelet-derived growth factor A; D020796:Receptor, Platelet-Derived Growth Factor alpha; D020830:rac1 GTP-Binding Protein
keywords: emphysema; lung development; primary cilia; stem cell antigen-1