Human alveolar type 2 epithelium transdifferentiates into metaplastic KRT5+ basal cells

Jaymin J. Kathiriya, Chaoqun Wang, Minqi Zhou, Alexis Brumwell, Monica Cassandras, Claude Jourdan Le Saux, Max Cohen, Kostantinos Dionysios Alysandratos, Bruce Wang, Paul Wolters, Michael Matthay, Darrell N. Kotton, Harold A. Chapman, Tien Peng

Research output: Contribution to journalArticlepeer-review

Abstract

Loss of alveolar type 2 cells (AEC2s) and the ectopic appearance of basal cells in the alveoli characterize severe lung injuries such as idiopathic pulmonary fibrosis (IPF). Here we demonstrate that human alveolar type 2 cells (hAEC2s), unlike murine AEC2s, transdifferentiate into basal cells in response to fibrotic signalling in the lung mesenchyme, in vitro and in vivo. Single-cell analysis of normal hAEC2s and mesenchymal cells in organoid co-cultures revealed the emergence of pathologic fibroblasts and basaloid cells previously described in IPF. Transforming growth factor-β1 and anti-bone morphogenic protein signalling in the organoids promoted transdifferentiation. Trajectory and histologic analyses of both hAEC2-derived organoids and IPF epithelium indicated that hAEC2s transdifferentiate into basal cells through alveolar-basal intermediates that accumulate in proximity to pathologic CTHRC1hi/TGFB1hi fibroblasts. Our study indicates that hAEC2 loss and expansion of alveolar metaplastic basal cells in severe human lung injuries are causally connected through an hAEC2-basal cell lineage trajectory driven by aberrant mesenchyme.

Original languageEnglish (US)
Pages (from-to)10-23
Number of pages14
JournalNature Cell Biology
Volume24
Issue number1
DOIs
StatePublished - Jan 2022
Externally publishedYes

ASJC Scopus subject areas

  • Cell Biology

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