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bioRxiv · 10.1101/2025.01.30.635624

A human organoid model of alveolar regeneration reveals distinct epithelial responses to interferon-gamma

Dost, A. F. M.·Balazova, K.·Pou Casellas, C.·van Rooijen, L. M.·Epskamp, W.·van Son, G. J. F.·Wetering, W. J.·Lopez-Iglesias, C.·Begthel, H.·Peters, P. J.·Smakman, N.·van Es, J. H.·Clevers, H.
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Abstract

Chronic obstructive pulmonary disease is characterized by inflammation and emphysema, leading to progressive alveolar destruction. Currently, no therapies effectively regenerate the alveolar epithelium. Here, we describe a feeder- and serum-free primary adult human organoid model to investigate how inflammation influences alveolar regeneration. We achieve long-term expansion of multipotent progenitor-like cells, while an alveolar type 2 (AT2) maturation protocol enhances surfactant production and supports tubular myelin formation. Introducing a LATS inhibitor to the expansion condition induces alveolar type 1 (AT1) differentiation while maintaining AT2 cells. Using this platform, we find that interferon-gamma exerts cytotoxic effects on AT1 cells while promoting the growth of regenerating AT2 cells, illustrating how a single inflammatory stimulus can have divergent effects on alveolar epithelial cell types. These findings underscore the nuanced influence of pro-inflammatory cytokines on alveolar regeneration. Our organoid model provides a reductionist platform for mechanistic studies, aimed to identify strategies to enhance alveolar regeneration.

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Dost, A. F. M., Balazova, K., Pou Casellas, C., van Rooijen, L. M., Epskamp, W., van Son, G. J. F., Wetering, W. J., Lopez-Iglesias, C., Begthel, H., Peters, P. J., Smakman, N., van Es, J. H., Clevers, H.. 2025-01-31. A human organoid model of alveolar regeneration reveals distinct epithelial responses to interferon-gamma. https://doi.org/10.1101/2025.01.30.635624

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