CD133 + progenitor cells promote pulmonary hypertension through CXCR4 signaling.

BACKGROUND: Pulmonary hypertension (PH) is characterized by pulmonary vascular remodeling and smooth muscle cell accumulation, but the progenitor-like cells that contribute to this process remain incompletely defined. METHODS: We combined analyses of human pulmonary arterial hypertension lungs and experimental PH models with bulk and single-cell RNA sequencing, lineage tracing, inducible ablation of CD133 + cells, and conditional deletion of Cxcr4 in CD133 + cells. RESULTS: CD133 expression was markedly increased in human and experimental PH lungs. Transcriptomic analyses identified inflammatory, metabolic, chemokine-associated, and smooth muscle cell-like programs in CD133 + cells from PH lungs. Lineage tracing showed that CD133 + cells contributed to endothelial and smooth muscle cell compartments during experimental PH. Genetic ablation of CD133 + cells attenuated hypoxia-induced PH and pulmonary vascular remodeling, whereas Cxcr4 deletion in CD133 + cells reduced PH severity. CONCLUSIONS: CD133 + progenitor cells are functional contributors to pulmonary vascular remodeling, and CXCR4 signaling mediates their pathogenic activity. Targeting pathogenic CD133 + cell states or CXCL12/CXCR4 signaling may provide a strategy to limit vascular remodeling in PH.