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

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

Nature cell biology (2022-01-01)
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
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Anti-Acetylated Tubulin antibody, Mouse monoclonal, clone 6-11B-1, purified from hybridoma cell culture
Sigma-Aldrich
Deoxyribonuclease I from bovine pancreas, lyophilized powder, Protein ≥85 %, ≥400 Kunitz units/mg protein