Characterization of perivascular alveolar epithelial stem cells and their niche in lung homeostasis and cancer.

Lung alveolar structure and function are maintained by subsets of alveolar type II stem cells (AT2s), but there is a need for characterization of these subsets and their associated niches. Here, we report a CD44^high subpopulation of AT2s characterized by increased expression of genes that regulate immune signaling even during steady-state homeostasis. Disruption of one of these immune regulatory transcription factor STAT1 impaired the stem cell function of AT2s. CD44^high cells were preferentially located near macro- blood vessels and a supportive niche constituted by LYVE1⁺ endothelial cells, adventitial fibroblasts, and accumulated hyaluronan. In this microenvironment, CD44^high AT2 cells were more responsive to transformation by KRAS than general AT2 cells. Moreover, after bacterial lung injury, there was a significant increase of CD44^high AT2s and niche components distributed throughout the lung parenchyma. Taken together, CD44^high AT2 cells and their perivascular niche regulate tissue homeostasis and tumor formation.