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

Loss of alveolar type 2 cells (AEC2s) and 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 signaling 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 basloid cells previously described in IPF. TGFβ1 and anti-BMP signaling in the organoids promoted transdifferentiation. Trajectory and histologic analyses of both hAEC2-derived organoids and IPF epithelium indicated hAEC2s transdifferentiate into basal cells through alveolar-basal intermediates (ABIs) that accumulate in proximity to pathologic CTHRC1(high)/TGFB1(high) fibroblasts. Our study indicates that hAEC2-loss and expansion of alveolar metaplastic basal cells in severe human lung injuries are causally connected through a hAEC2-basal cell lineage trajectory driven by aberrant mesenchyme.