iPSC-Derived Endothelial Cells Affect Vascular Function in a Tissue-Engineered Blood Vessel Model of Hutchinson-Gilford Progeria Syndrome

Hutchinson-Gilford progeria syndrome (HGPS) is a rare disorder caused by a point mutation in the Lamin A gene that produces the protein progerin. Progerin toxicity leads to accelerated aging and death from cardiovascular disease. To elucidate the effects of progerin on endothelial cells, we prepared tissue-engineered blood vessels (viTEBVs) using induced pluripotent stem cell-derived smooth muscle cells (viSMCs) and endothelial cells (viECs) from HGPS patients. HGPS viECs aligned with flow but exhibited reduced flow-responsive gene expression and altered NOS3 levels. Relative to viTEBVs with healthy cells, HGPS viTEBVs showed reduced function and exhibited markers of cardiovascular disease associated with endothelium. HGPS viTEBVs exhibited a reduction in both vasoconstriction and vasodilation. Preparing viTEBVs with HGPS viECs and healthy viSMCs only reduced vasodilation. Furthermore, HGPS viECs produced VCAM1 and E-selectin protein in TEBVs with healthy or HGPS viSMCs. In summary, the viTEBV model has identified a role of the endothelium in HGPS. •Smooth muscle and endothelial cells were derived from progeria and healthy donors•Progeria endothelial cells exhibit altered response to fluid shear stress•Functional engineered blood vessels were fabricated from iPSC-derived SMCs and ECs•Progeria donor-derived engineered blood vessels recapitulated the disease phenotype Atchison and colleagues produced hiPSC-derived vascular smooth muscle cells and vascular endothelial cells from healthy and progeria patients. These cells were used to fabricate functional tissue-engineered blood vessels that express key features of the progeria cardiovascular phenotype. This work provides a novel platform to study progeria and other cardiovascular diseases using iPSC-derived cells in an in vitro platform.