Vascular organoid model of Hutchinson-Gilford progeria syndrome uncovers repression of the SRF pathway in premature aging

Vascular aging is a key driver of cardiovascular disease, yet models capturing its complexity in humans are lacking. Hutchinson-Gilford progeria syndrome (HGPS), a premature aging disorder caused by the LMNA mutation, provides a model to study accelerated vascular decline. Here, we developed a blood vessel organoid (BVO) model from HGPS-mutant human embryonic stem cells (hESCs). These BVOs model HGPS vascular defects and reveal significant downregulation of serum response factor (SRF), a trend also observed in the vasculature of naturally aged primates. We show that SRF regulates angiogenesis-related genes, and that its overexpression rescues endothelial function in HGPS organoids. In summary, we establish a 3D human organoid model of vascular aging, identify SRF as a pivotal regulator and provide a powerful platform for discovering geroprotective therapies.