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

Henry, A. D.; Alwine, A. L.; Niederhuber, M. J.; Yarlagadda, A. K.; Muthakana, N. R.; Mordant, A. L.; Gokey, J. J.; Sucre, J. M. S.; Hepperla, A. J.; Cartailler, J.-P.; Gulleman, P. M.; Sharkey, A. L.; Boatwright, N.; Kook, S.; Lee, J. C.; Jetter, C. S.; Shirazi, S. P.; Newcomb, D. C.; Hart, R. C.; Reese, J. J.; Sonnenberg, A.; Lennon, R.; Blackwell, T. S.; Zent, R.; Plosa, E.

doi:10.64898/2026.10.05.755686

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bioRxiv · 10.64898/2026.10.05.755686

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

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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.

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Henry, A. D., Alwine, A. L., Niederhuber, M. J., Yarlagadda, A. K., Muthakana, N. R., Mordant, A. L., Gokey, J. J., Sucre, J. M. S., Hepperla, A. J., Cartailler, J.-P., Gulleman, P. M., Sharkey, A. L., Boatwright, N., Kook, S., Lee, J. C., Jetter, C. S., Shirazi, S. P., Newcomb, D. C., Hart, R. C., Reese, J. J., Sonnenberg, A., Lennon, R., Blackwell, T. S., Zent, R., Plosa, E.. 2026-10-06. Integrin α3β1 is required for alveolar-capillary barrier formation through regulation of epithelial differentiation. https://doi.org/10.64898/2026.10.05.755686

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