AT1 and AT2 cells arise from bipotent progenitors during development but renew from rare AT2 cells.

  • Major finding: AT1 and AT2 cells arise from bipotent progenitors during development but renew from rare AT2 cells.

  • Concept: AT2 stem cell function and self-renewal are activated by AT1 injury and EGFR–KRAS signaling, respectively.

  • Impact: Deregulated AT2 cell proliferation and self-renewal may underlie lung adenocarcinoma formation.

Pulmonary alveoli, lined by squamous alveolar type (AT) 1 cells and cuboidal AT2 cells, are often sites of lung cancer occurrence. Previous studies have suggested that AT1 cells are derived from AT2 cells, yet the identity of alveolar stem and progenitor cells responsible for AT1 and AT2 establishment and renewal is unclear. By analyzing the expression of known AT1 and AT2 markers in embryonic mouse lungs, Desai and colleagues identified progressive stages of alveolar cell maturation, originating with a bipotent progenitor expressing a subset of both AT1 and AT2 markers that gave rise to either AT1 or AT2 cells. Once lung development was complete, few if any bipotent progenitors were detected, suggesting other sources of AT1 and AT2 cells must exist after birth. In vivo lineage tracing of mature AT2 cells postnatally identified progressively enlarging clonal foci of AT1 cells labeled with the AT2 lineage tag, as well as clonal foci containing only AT2 cells, indicating that AT2 cells are capable of self-renewal and can produce AT1 and/or AT2 cells. Although AT1 renewal was rare, it significantly increased following acute hyperoxia, suggesting that AT1 injury activates AT2 stem cell function for alveolar repair. Interestingly, specific expression of oncogenic Kras in mature AT2 cells produced rapidly growing clonal adenomas throughout the lung, and either in vivo expression of oncogenic Kras or stimulation with EGF ligands in vitro selectively induced the proliferation of AT2 cells without deprogramming to a bipotent progenitor or inducing an AT1 fate. Collectively, these findings support a model in which AT1 and AT2 cells derive independently from a bipotent progenitor during development but are renewed postnatally by mature AT2 cells, whose self-renewal is mediated by EGFR–KRAS signaling, and whose specific susceptibility to oncogenic transformation implicate them as lung cancer–initiating cells.

Desai TJ, Brownfield DG, Krasnow MA. Alveolar progenitor and stem cells in lung development, renewal and cancer. Nature 2014;507:190–4.

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