Laminins and their integrin receptors are implicated in epithelial cell differentiation and progenitor cell maintenance. We report here that a previously unrecognized subpopulation of mouse alveolar epithelial cells (AECs) expressing the laminin receptor α6β4, but little or no pro-surfactant C (pro-SPC), is endowed with regenerative potential. Ex vivo, this subpopulation expanded clonally as progenitors but also differentiated toward mature cell types. Integrin β4 itself was not required for AEC proliferation or differentiation. An in vivo embryonic lung organoid assay, which we believe to be novel, was used to show that purified β4 + adult AECs admixed with E14.5 lung single-cell suspensions and implanted under kidney capsules self-organized into distinct Clara cell 10-kDa secretory protein (CC10 + ) airway-like and SPC + saccular structures within 6 days. Using a bleomycin model of lung injury and an SPC-driven inducible cre to fate-map AECs, we found the majority of type II AECs in fibrotic areas were not derived from preexisting type II AECs, demonstrating that SPC -progenitor cells replenished type II AECs during repair. Our findings support the idea that there is a stable AEC progenitor population in the adult lung, provide in vivo evidence of AEC progenitor cell differentiation after parenchymal injury, and identify a strong candidate progenitor cell for maintenance of type II AECs during lung repair.

The dosage for GW9662 was incorrectly noted in Results, Methods, and the legend for Figure 6. The correct sentences appear below.Results: We treated a cohort of younger animals for 2 weeks at a dose of 4 mg/kg body weight and found that there was a 31% reduction in the expression of Cd36 ( Figure 6F) and a 48% reduction in liver TG content in JAK2L animals treated with GW9662 versus those treated with vehicle ( Figure 6G). Methods: Each day, an aliquot of stock drug was thawed and then resuspended in DMSO/saline at a final concentration of 4 mg/kg body weight in a final volume of 100 μl. The authors regret the error.