Endothelial cells differentiated from disease fibroblast-derived iPSCs resemble phenotypic vascular malformations of Port Wine Birthmark

What is already known about this topic?Port Wine Birthmark (PWB) is a congenital vascular malformation with an incidence rate of 1 - 3 per 1,000 live births. PWB results from developmental defects in the dermal vasculature; PWB endothelial cells (ECs) have differentiational impairments. Pulse dye laser (PDL) is currently the preferred treatment for PWB; unfortunately, the efficacy of PDL treatment of PWB has not improved over the past three decades.What does this study add?PWB induced pluripotent stem cells (iPSCs) were generated and differentiated into ECs. PWB ECs recapitulated their pathological phenotypes such as forming enlarged blood vessels in vitro and in vivo. Hippo and Wnt pathways were impaired in both PWB iPSCs and ECs. Zinc-finger family genes were overrepresented among the differentailly expressed genes in PWB iPSCs. Dysregulated NF-kappa B, TNF, MAPK, and cholesterol metabolism pathways were enriched in PWB ECs.What is the translational message?Targeting Hippo and Wnt pathways and ZNFs could restore the physiological differentiation of ECs. Targeting NF-kappa B, TNF, MAPK, and cholesterol metabolism pathways could mitigate the pathological progression of PWB. These mechanisms may lead to the development of paradigm-shifting therapeutic interventions for PWB.