Figure 2.

Distal airway/alveolar progenitors contributing to lung regeneration. A myriad of cells serve as alveolar progenitors upon damage. AT2 cells can proliferate and differentiate into AT1 cells after going through an intermediate cell state named pre-alveolar type-1 transitional cell state (PATS), keratin 8-positive alveolar differentiation intermediate (Krt8+ADI) or damage associated transient progenitors (DATPs). IL-1β produced by interstitial macrophages promotes AT2 differentiation into this intermediate cell type that displays a transcriptional signature of p53 signaling, cellular senescence and TGFβ signaling. Alveolar epithelial progenitors (AEPs) represent a subset of AT2 cells characterized by the expression of Axin2 that act as the principal progenitor cell population during injury-induced alveolar regeneration. CD44^hi-expressing AT2 cells show an increased proliferative capacity also contributing to the regeneration of the alveolar epithelium. Interestingly although rarely, AT1 cells are able to dedifferentiate and give rise to AT2 cells. Bronchoalveolar stem cells (BASCs) are cells contributing to both alveolar and airway regeneration because of their ability to self-renew and to give rise to AT2, AT1, club and ciliated cells. Furthermore, subsets of club cells such as Upk3a+ subset, H2-K1^hi subset and MHC-II+ subset can differentiate into AT2 cells; the latter go through a transitional state similar to KRT8+ ADI cells to give rise to AT1 cells. Of note, H2-K1^hi and MHC-II+ club cells show an identical transcriptional signature suggesting that they are the same subpopulation. A rare population of p63+ cells in terminal bronchioles have shown the ability to activate Krt5 expression and expand and migrate to sites of injury. There, these cells give rise to AT2 cells or form pod-like metaplastic structures in a process regulated by hypoxic conditions, Notch signaling and Wnt signaling. Studies in human and non-human primate models have identified two interesting cell populations: AT0 cells, a novel bi-potential transient state that arises in the differentiation from AT2 cells into either terminal respiratory bronchiole secretory cells (TRB-SCs) or AT1 cells; and RAS cells, an airway secretory cell population that can differentiate into AT2 cells in a process regulated by Notch and Wnt signaling (Image created with BioRender).