CD133 ⁺ progenitor cells promote pulmonary hypertension through CXCR4 signaling

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.

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.

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.

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.