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.
【초록키워드】 pulmonary fibrosis, lung, in vitro, Protein, human lung, Lineage, trajectory, in vivo, single-cell analysis, IPF, Analysis, fibroblasts, Injury, Organoid, growth, Basal cell, alveolar, murine, fibroblast, co-culture, Loss, Cell, severe lung injury, described, pathologic, indicated, indicate, driven by, accumulate, promoted, histologic, ectopic, metaplastic, morphogenic, Transforming, 【제목키워드】 Human, Basal cell, alveolar, metaplastic,