| First Author | Kathiriya JJ | Year | 2022 |
| Journal | Nat Cell Biol | Volume | 24 |
| Issue | 1 | Pages | 10-23 |
| PubMed ID | 34969962 | Mgi Jnum | J:380555 |
| Mgi Id | MGI:6860500 | Doi | 10.1038/s41556-021-00809-4 |
| Citation | Kathiriya JJ, et al. (2022) Human alveolar type 2 epithelium transdifferentiates into metaplastic KRT5(+) basal cells. Nat Cell Biol 24(1):10-23 |
| abstractText | 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-beta1 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 CTHRC1(hi)/TGFB1(hi) 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. |
