Integrin α3β1 is required for alveolar-capillary barrier formation through regulation of epithelial differentiation
Year: 2026
Type: preprint
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 α3 subunit deletion in the murine lung with a multiomics approach to investigate the role of the epithelial α3β1 integrin during murine lung development. We demonstrate that α3β1 integrin is dispensable for airway branching morphogenesis due to delayed epithelial expression. Instead, in vivo deletion of α3β1 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 α3β1 integrin possessed an intracellular trafficking and secretion defect for BM components. Thus, integrin α3β1 orchestrates the temporal maturation of alveolar epithelial cells required for organization of the alveolar-capillary barrier. Summary statement: Integrin α3β1 is required for alveolar-capillary barrier formation through regulation of alveolar epithelial differentiation and alveolar BM composition.
Authors: Allison D. Henry, Annica L. Alwine, Matthew J. Niederhuber, Anika K. Yarlagadda, Nikita R. Muthakana, Angie L. Mordant, Jason J. Gokey, Jennifer M.S. Sucre, Austin J. Hepperla, Jean-Philippe Cartailler, Elle N. Franciscus, Peter M. Gulleman, Alexandria L. Sharkey, Naoko Boatwright, Seunghyi Kook, Jessica C. Lee, Christopher S. Jetter, Shawyon P. Shirazi, Dawn C. Newcomb, Rachel C. Hart, J. Jeffrey Reese, Arnoud Sonnenberg, Rachel Lennon, Timothy S. Blackwell, Roy Zent, Erin J. Plosa
Institutions: Vanderbilt University Medical Center, University of North Carolina at Chapel Hill, Vanderbilt University, The Netherlands Cancer Institute, Manchester Academic Health Science Centre, University of Manchester, Royal Manchester Children's Hospital, University of Michigan, Michigan Medicine, Nashville VA Medical Center
Language: English
Subfield: Immunology and Allergy
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: Vanderbilt University, National Institutes of Health, National Heart, Lung, and Blood Institute, National Eye Institute, National Cancer Institute, National Institute of Diabetes and Digestive and Kidney Diseases, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill
Awards: G1149166549, G3865556588, G4320917349, G5853943267, G7220527126, G7366156696, G9000002043, G9000106052, Molecular and Cellular Basis for Digestive Diseases, Cancer Center Support Grant, Pharmacologic Contributors to Patent Ductus Arteriosus, Core Grant in Vision Research, Cancer Center Support Grant, G958207224
OpenAlex ID: W7220729941