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ResearchIn-Press PreviewCell biologyPulmonology Open Access | 10.1172/jci.insight.202597

Alveolar Type II Cell-derived MMP1high basal cells promote destructive microcysts in idiopathic pulmonary fibrosis

Marylene Toigo,1 Kiana Garakani,1 Alexis N. Brumwell,1 Ying Wei,1 Tsung Che Ho,1 Paul J. Wolters,1 Michael A. Matthay,1 Stefano A. Iantorno,1 Vincent C. Auyeung,1 Harold A. Chapman,1 and Claude Jourdan Le Saux1

1Department of Medicine, Division of Pulmonary, Critical Care, Allergy, and , University of California San Francisco, San Francisco, United States of America

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1Department of Medicine, Division of Pulmonary, Critical Care, Allergy, and , University of California San Francisco, San Francisco, United States of America

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1Department of Medicine, Division of Pulmonary, Critical Care, Allergy, and , University of California San Francisco, San Francisco, United States of America

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1Department of Medicine, Division of Pulmonary, Critical Care, Allergy, and , University of California San Francisco, San Francisco, United States of America

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1Department of Medicine, Division of Pulmonary, Critical Care, Allergy, and , University of California San Francisco, San Francisco, United States of America

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1Department of Medicine, Division of Pulmonary, Critical Care, Allergy, and , University of California San Francisco, San Francisco, United States of America

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1Department of Medicine, Division of Pulmonary, Critical Care, Allergy, and , University of California San Francisco, San Francisco, United States of America

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1Department of Medicine, Division of Pulmonary, Critical Care, Allergy, and , University of California San Francisco, San Francisco, United States of America

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1Department of Medicine, Division of Pulmonary, Critical Care, Allergy, and , University of California San Francisco, San Francisco, United States of America

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1Department of Medicine, Division of Pulmonary, Critical Care, Allergy, and , University of California San Francisco, San Francisco, United States of America

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1Department of Medicine, Division of Pulmonary, Critical Care, Allergy, and , University of California San Francisco, San Francisco, United States of America

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Published November 5, 2026 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.202597.
Copyright © 2026, Toigo et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published November 5, 2026 - Version history
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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.

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  • Version 1 (November 5, 2026): In-Press Preview
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