Induced pluripotent stem cells from sporadic pulmonary veno-occlusive disease exhibit altered endothelial commitment and stress-related transcriptional programs.

INTRODUCTION: Pulmonary veno-occlusive disease (PVOD) is a rare form of pulmonary hypertension characterized by progressive vascular remodeling, with limited understanding of its cellular and molecular mechanisms, particularly in sporadic cases lacking identifiable genetic mutations. We investigated whether patient-derived induced pluripotent stem cells (iPSCs) recapitulate disease-associated cellular phenotypes and transcriptional alterations in sporadic PVOD.

METHODS: Integration-free iPSCs were generated from a patient with sporadic PVOD and differentiated toward endothelial and hematopoietic lineages. Endothelial differentiation capacity was assessed by flow cytometry, and transcriptomic profiling was performed using RNA sequencing followed by differential gene expression and gene set enrichment analyses.

RESULTS: PVOD-derived iPSCs demonstrated preserved hemangioblast generation but reduced endothelial commitment compared with control cells. Transcriptomic profiling revealed clear segregation between PVOD-derived and control samples by principal component analysis, indicating distinct global gene expression patterns. Differential expression analysis identified genes associated with cellular stress and metabolic regulation, while gene set enrichment analysis demonstrated enrichment of reactive oxygen species and transforming growth factor-β (TGF-β) signaling pathways, consistent with altered stress-related transcriptional programs.

DISCUSSION: These findings indicate that iPSCs derived from a patient with sporadic PVOD exhibit altered endothelial differentiation and distinct stress-related transcriptional signatures. This patient-specific iPSC model provides a platform for investigating disease-associated cellular alterations in sporadic PVOD.