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

Nat Cell Biol. 2022 Jan;24(1):10-23. doi: 10.1038/s41556-021-00809-4. Epub 2021 Dec 30.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alveolar Epithelial Cells / metabolism
  • Animals
  • Bone Morphogenetic Proteins / metabolism
  • Cell Differentiation
  • Cell Transdifferentiation / physiology*
  • Cells, Cultured
  • Epidermal Cells / cytology
  • Epithelial Cells / cytology*
  • Fibroblasts / cytology
  • Humans
  • Idiopathic Pulmonary Fibrosis / pathology*
  • Keratin-5 / metabolism*
  • Mesoderm / cytology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred NOD
  • Mice, SCID
  • Mice, Transgenic
  • Pulmonary Alveoli / cytology*
  • Respiratory Mucosa / cytology*
  • Signal Transduction / physiology
  • Single-Cell Analysis
  • Transforming Growth Factor beta1 / metabolism


  • Bone Morphogenetic Proteins
  • KRT5 protein, human
  • Keratin-5
  • TGFB1 protein, human
  • Transforming Growth Factor beta1