Differentiation of lung tissue-resident c-Kit+ cells into microvascular endothelial cells alleviates pulmonary vascular remodeling

Pulmonary vascular remodeling (PVR), encompassing microvascular loss and muscularization, contributes to multiple respiratory diseases. c-Kit+ cells exhibit differentiation potential into both endothelial cells (ECs) and smooth muscle cells. The potential role of lung c-Kit+ cell differentiation in PVR, however, remains unclear. Lung c-Kit+ cells increase in pulmonary hypertension patients and in the SU5416/hypoxia (SuHx)-induced PVR mouse model. Employing genetic lineage tracing and single-cell RNA sequencing (scRNA-seq), we elucidate that lung-resident c-Kit+ cells display an aerocyte and venular endothelial differentiation in the SuHx model. Ablation of tissue-resident c-Kit+ cells exacerbates PVR. We identify an Nr2f2-expressing c-Kit+ cell subgroup, which exhibitsvenous EC differentiation and increases during PVR. Notably, the elevation of Nr2f2 in c-Kit+ cells via AAV enhances differentiation and mitigates PVR. These findings underscore the protective role of lung tissue-resident c-Kit+ cells in PVR, achieved by differentiating into mature ECs. Targeting NR2F2 expression in c-Kit+ cells emerges as a promising strategy for reversing PVR.