Co-optation of the regenerative role of type 2 alveolar cells in distal lung repair in mice by terminal airway epithelial cells in humans

The lung is endowed with extensive regenerative capacity. The principal cell of the lung is the type 1 alveolar epithelial (AT1) cell, which mediates gas exchange. Mouse models implicated surfactant-producing type 2 alveolar epithelial (AT2) cells as facultative stem cells that regenerate AT1 cells after injury through a transitional KRT8+ intermediate. Larger mammals, however, possess terminal and respiratory bronchioles that are lined by alveoli and by epithelial cells that are absent in mice. Here we show, using human pluripotent stem cell-derived lung organoids and comparative computational analysis, a prime role for terminal and respiratory bronchiole cells in AT1 regeneration without AT2 intermediate. Furthermore, cells similar to aberrant basaloid cells, profibrotic elements that accumulate in pulmonary fibrosis, are physiological intermediates in a more rapidly committing trajectory from terminal and respiratory bronchioles to AT1 cells marked by expression of KRT17, are regulated by Hippo and TGF{beta} signaling, and are transcriptionally distinct from mouse AT2-derived KRT8+ transitional cells. Our findings indicate that terminal and respiratory bronchioles in humans have to a large extent co-opted the regenerative and pathogenic functions of AT2 cells in mice. Efforts to enhance or correct human lung regeneration should therefore focus on facultative airway-derived alveolar progenitors using human models.