Patient-derived vascularized skin organoids unravel the role of systemic sclerosis fibroblasts in microvascular dysfunction.

Abstract

Systemic sclerosis (SSc) is a complex connective tissue disease characterized by excessive extracellular matrix deposition and endothelial dysfunction leading to skin fibrosis and vascular complications. To investigate the contribution of fibroblasts to SSc-associated vasculopathy, we generated 3D vascularized skin organoids incorporating patient-derived fibroblasts and healthy endothelial cells. Comparative analyses revealed that SSc fibroblasts alone induce microvascular alterations, including giant capillaries and early fibrotic responses at the secretome level. These findings demonstrate that fibroblasts are a central driver of vascular remodeling in SSc and highlight their key crosstalk with endothelial cells. This SSc-specific organoid model offers a valuable platform for studying disease mechanisms and therapeutic interventions without relying on animal models.