Exploring Endothelial Dysfunction in Hutchinson-Gilford Progeria Syndrome

Introduction: Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare, fatal vascular disease characterized by accelerated aging and early cardiovascular complications, including atherosclerosis and vascular calcification. Endothelial dysfunction is a key early driver of vascular disease and arterial occlusion in HGPS, making endothelial cells (ECs) essential for understanding disease progression. Gaps remain in understanding how endothelial cell dysfunction contributes to the accelerated aging phenotype seen in HGPS. 

Methods: We differentiated HGPS patient-derived iPSCs from The Progeria Research Foundation and differentiated them into ECs (iPSC-ECs). We then assessed capacity for angiogenesis, LDL uptake, and NO release in control and HGPS iPSC-ECs. Additionally, RNA sequencing (RNA-seq) and assay for transposase-accessible chromatin sequencing (ATAC-seq) are underway to determine gene expression and chromatin accessibility differences between the groups.

Results: Our lab developed a robust, defined monolayer differentiation protocol for iPSC-ECs that consistently yields about 80-95% CD31 positive cells. We found HGPS iPSC-ECs showed decreased endothelial markers PECAM1, NOS3, VWF expression compared to control iPSC-ECs by qPCR. HGPS iPSC-ECs also demonstrated impaired endothelial function, evidenced by decreased capacity of LDL uptake, angiogenesis, and NO release compared to control iPSC-ECs. Upcoming RNA-seq and ATAC-seq analyses are expected to provide more insights into molecular and epigenetic differences underlying these functional impairments.

Conclusion: Our findings demonstrate HGPS iPSC-ECs exhibit significant dysfunction, underscoring the role of endothelial health in disease progression. Our patient-derived iPSC platform offers a robust model for advancing the study of HGPS vascular pathology, evaluating therapeutic strategies, and exploring mechanisms of vascular dysfunction and accelerated aging more broadly.