Integrin α3β1 is required for alveolar-capillary barrier formation through regulation of epithelial differentiation

Abstract

Laminin-binding integrins regulate critical morphogenic processes, but their specific roles in lung development are unknown. In this study, we combined an in vivo model of epithelial 3 subunit deletion in the murine lung with a multiomics approach to investigate the role of the epithelial 3{beta}1 integrin during murine lung development. We demonstrate that 3{beta}1 integrin is dispensable for airway branching morphogenesis due to delayed epithelial expression. Instead, in vivo deletion of 3{beta}1 integrin impaired alveolar epithelial cell differentiation and disrupted alveolar-capillary barrier formation, functionally limiting gas exchange. A discontinuous alveolar BM contained abnormal collagen IV and laminin networks and widened the gap between epithelial and endothelial cells in the alveolar-capillary barrier niche. Mechanistically, mice deficient in epithelial 3{beta}1 integrin possessed an intracellular trafficking and secretion defect for BM components. Thus, integrin 3{beta}1 orchestrates the temporal maturation of alveolar epithelial cells required for organization of the alveolar-capillary barrier.