Sonic Hedgehog Signaling Regulates Myofibroblast Function during Alveolar Septum Formation in Murine Postnatal Lung

• Published in: American journal of respiratory cell and molecular biology Vol. 57; no. 3; pp. 280 - 293
• Main Authors: Kugler, Matthias C, Loomis, Cynthia A, Zhao, Zhicheng, Cushman, Jennifer C, Liu, Li, Munger, John S
• Format: Journal Article
• Language: English
• Published: United States American Thoracic Society 01-09-2017
• Subjects: Actin; Alveoli; Animals; Animals, Newborn; Apoptosis; Cell Differentiation; Cell proliferation; Chronic obstructive pulmonary disease; Compliance; Disease; Embryogenesis; Extracellular Matrix - metabolism; Fibroblasts; Fibrosis; Gene Expression Regulation, Developmental; Growth factors; Hedgehog protein; Hedgehog Proteins - metabolism; Lung diseases; Mesenchyme; Mice; Mice, Inbred C57BL; Myofibroblasts - metabolism; Obstructive lung disease; Organogenesis; Original Research; Proteins; Pulmonary Alveoli - growth & development; Pulmonary Alveoli - metabolism; Pulmonary fibrosis; Rodents; Septum; Signal Transduction; Smooth muscle; Stem cells; Versicans - metabolism; Zinc Finger Protein GLI1 - metabolism; Sonic hedgehog signaling; α-smooth muscle actin; fibroblast; myofibroblast; postnatal lung development
• ISSN: 1044-1549; 1535-4989
• DOI: 10.1165/rcmb.2016-0268OC

Sonic Hedgehog (Shh) signaling regulates mesenchymal proliferation and differentiation during embryonic lung development. In the adult lung, Shh signaling maintains mesenchymal quiescence and is dysregulated in diseases such as idiopathic pulmonary fibrosis and chronic obstructive pulmonary disease. Our previous data implicated a role for Shh in postnatal lung development. Here, we report a detailed analysis of Shh signaling during murine postnatal lung development. We show that Shh pathway expression and activity during alveolarization (postnatal day [P] 0-P14) are distinct from those during maturation (P14-P24). This biphasic pattern is paralleled by the transient presence of Gli1
;α-smooth muscle actin (α-SMA)
myofibroblasts in the growing alveolar septal tips. Carefully timed inhibition of Hedgehog (Hh) signaling during alveolarization defined mechanisms by which Shh influences the mesenchymal compartment. First, interruption of Hh signaling at earlier time points results in increased lung compliance and wall structure defects of increasing severity, ranging from moderately enlarged alveolar airspaces to markedly enlarged airspaces and fewer secondary septa. Second, Shh signaling is required for myofibroblast differentiation: Hh inhibition during early alveolarization almost completely eliminates Gli1
;α-SMA
cells at the septal tips, and Gli1-lineage tracing revealed that Gli1
cells do not undergo apoptosis after Hh inhibition but remain in the alveolar septa and are unable to express α-SMA. Third, Shh signaling is vital to mesenchymal proliferation during alveolarization, as Hh inhibition decreased proliferation of Gli1
cells and their progeny. Our study establishes Shh as a new alveolarization-promoting factor that might be affected in perinatal lung diseases that are associated with impaired alveolarization.