Epithelial β1 integrin is required for lung branching morphogenesis and alveolarization

Abstract

Integrin-dependent interactions between cells and extracellular matrix regulate lung development; however, specific roles for β1-containing integrins in individual cell types, including epithelial cells, remain incompletely understood. In this study, the functional importance of β1 integrin in lung epithelium during mouse lung development was investigated by deleting the integrin from E10.5 onwards using surfactant protein C promoter-driven Cre. These mutant mice appeared normal at birth but failed to gain weight appropriately and died by 4 months of age with severe hypoxemia. Defects in airway branching morphogenesis in association with impaired epithelial cell adhesion and migration, as well as alveolarization defects and persistent macrophagemediated inflammation were identified. Using an inducible system to delete β1 integrin after completion of airway branching, we showed that alveolarization defects, characterized by disrupted secondary septation, abnormal alveolar epithelial cell differentiation, excessive collagen I and elastin deposition, and hypercellularity of the mesenchyme occurred independently of airway branching defects. By depleting macrophages using liposomal clodronate, we found that alveolarization defects were secondary to persistent alveolar inflammation. β1 integrin-deficient alveolar epithelial cells produced excessive monocyte chemoattractant protein 1 and reactive oxygen species, suggesting a direct role for β1 integrin in regulating alveolar homeostasis. Taken together, these studies define distinct functions of epithelial β1 integrin during both early and late lung development that affect airway branching morphogenesis, epithelial cell differentiation, alveolar septation and regulation of alveolar homeostasis.

Epithelial cell integrin β1 is required for developmental angiogenesis in the pituitary gland

“…Our findings provide unambiguous evidence of critical non-cellautonomous roles for integrin β1 in vascular development that contrast with numerous reports of other tissue-specific integrin β1 knockouts (31)(32)(33)(34), and complement established vascular cellautonomous functions of integrin β1 (9-13). Our data support the idea that there are distinct tissue and temporal context-dependent requirements for specific integrin heterodimers in vascular development (11).…”

Analysis of TMEFF2 allografts and transgenic mouse models reveals roles in prostate regeneration and cancer

“…Therefore, the role of TMEFF2 in prostate regeneration could be facilitated by its effect on integrin expression via its role in metabolism. It has been described that changes in integrin expression, specifically b1, not only affect cell migration but also glandular morphogenesis in different tissues [47][48][49]. Alternative mechanisms related to the TMEFF2 signaling potential can also explain its role in prostate morphogenesis after castration.…”

α5β1 integrin mediates pulmonary epithelial cyst formation

“…Previous studies determined that loss of the ECM and b1 integrin negatively impacts lung branching during development. Plosa et al established that epithelial b1 integrin was required throughout the different stages of lung development for airway branching morphogenesis, alveolarization, and maintenance of homeostasis (Plosa et al, 2014). However, the mechanisms of how epithelial branching and factors contributing to alveolar lumen structural formation have not been determined.…”

“…In contrast, genetic manipulation of aVb3 and aVb5 integrins indicate that the aV integrin / FN interactions are not necessary for vascular formation (Hynes, 2002). During pulmonary morphogenesis, a5b1 integrin and its ECM ligand FN are expressed during lung development (Chen et al, 1986;Snyder et al, 1987;Roman and McDonald, 1992) and have been shown to be essential for lung branching morphogenesis (Sakai et al, 2003;Plosa et al, 2014).…”