Dysfunctional angiogenesis in Fabry disease-derived iPSCs during differentiation into vascular endothelial cells

Abstract

Fabry disease (FD) is a recessive X-linked lysosomal storage disorder caused by an $\alpha$-galactosidase A (GLA) deficiency. Excessive globotriaosylceramide (Gb3) accumulated by a deficient GLA activity is responsible for the vasculopathy of FD patients. However, the factors related to Gb3 accumulation leading to vasculopathy are poorly understood. To explore the relationship between Gb3 accumulation and vasculopathy, FD-iPSCs were generated from four patients each with different mutations of the GLA gene. The FD-iPSCs differentiated into vascular cells such as endothelial cells (ECs) with the functionality of a tubule-like structure formation

however, FD-ECs represented Gb3 accumulation. FD-ECs showed remarkable down-regulation in the expression of KDR with a morphological anomaly during maturation to endothelial cells compared to wild type (WT)-ECs. Although a prolonged culture down-regulated KDR, interestingly, the endothelial cells had a low activity of angiogenesis, a reduction in endothelial nitric oxide synthase (eNOS), and an enhanced expression of TSP-1 during culture in vitro. Lyso-Gb3 treatment in WT-endothelial cells recapitulated the aberrant phenotypes seen in the FD-endothelial cells, and thrombospondin-1 inhibitor treatment in the FD-endothelial cells successfully rescued the impaired angiogenesis. My finding suggest that dysfunction of alpha-galactosidase contributes to the impairment of angiogenesis, and the down-regulation of TSP-1 expression may be a key therapeutic adjuvant in FD vasculopathy.