Abstract
Alveolar microcysts, a hallmark of Idiopathic Pulmonary Fibrosis (IPF), are basal cell (BC)-lined structures that develop near terminal airways and correlate with poor clinical outcomes. Using primary-cell organoids and spatial transcriptomics, we identified striking epithelial similarities between respiratory bronchioles (RBs) and IPF alveolar microcysts, both containing AT0 (ABCA3+/SCGB3A2+), SCGB3A2+, and basaloid/BC populations, although basaloid/BCs were markedly expanded in IPF microcysts. A CEACAM6+ subset of normal RB epithelial cells, termed respiratory airway secretory cells (RASCs), consisted predominantly of SCGB3A2+ cells with only rare BCs (1–5%) that by RNA trajectory analysis suggested BCs arise from SCGB3A2+ progenitors. Accordingly, in organoid cultures nearly all RASC-derived colonies converted to BCs within 9 days, resembling colonies generated by purified BCs. BCs derived from either RASCs or normal alveolar type II (AT2) cells strongly expressed the collagenase matrix metalloproteinase-1 (MMP1), recapitulating the phenotype of BCs lining IPF microcysts. MMP1high BCs degraded type I collagen ex vivo and generated microcyst-like structures in vivo following xenotransplantation, both abolished by MMP activity inhibition or specific MMP1 deletion by sh-RNAi. Finally, a Frizzled-5 WNT agonist antibody reversed the MMP1high phenotype, identifying AT2- and RB-derived basal cell transdifferentiation as a previously unrecognized driver of alveolar destruction and microcyst formation in IPF and a potential therapeutic target.
Authors
Marylene Toigo, Kiana Garakani, Alexis N. Brumwell, Ying Wei, Tsung Che Ho, Paul J. Wolters, Michael A. Matthay, Stefano A. Iantorno, Vincent C. Auyeung, Harold A. Chapman, Claude Jourdan Le Saux
