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Enhanced thrombospondin-1 causes dysfunction of vascular endothelial cells derived from Fabry disease-induced pluripotent stem cells

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Title
Enhanced thrombospondin-1 causes dysfunction of vascular endothelial cells derived from Fabry disease-induced pluripotent stem cells
Author(s)
Do, Hyo-Sang; Park, Sang-Wook; Im, Ilkyun; Seo, Donghyuk; Yoo, Han-Wook; Go, Heounjeong; Yoo Hyung Kim; Gou Young Koh; Lee, Beom-Hee; Han, Yong-Mahn
Publication Date
2020-02
Journal
EBIOMEDICINE, v.52
Publisher
ELSEVIER
Abstract
Background: Fabry disease (FD) is a recessive X-linked lysosomal storage disorder caused by alpha-galactosidase A (GLA) deficiency. Although the mechanism is unclear, GLA deficiency causes an accumulation of globotriaosylceramide (Gb3), leading to vasculopathy. Methods: To explore the relationship between the accumulation of Gb3 and vasculopathy, induced pluripotent stem cells generated from four Fabry patients (FD-iPSCs) were differentiated into vascular endothelial cells (VECs). Genome editing using CRISPR-Cas9 system was carried out to correct the GLA mutation or to delete Thrombospondin-1 (TSP-1). Global transcriptomes were compared between wild-type (WT)- and FD-VECs by RNA-sequencing analysis. Findings: Here, we report that overexpression of TSP-1 contributes to the dysfunction of VECs in FD. VECs originating from FD-iPSCs (FD-VECs) showed aberrant angiogenic functionality even upon treatment with recombinant alpha-galactosidase. Intriguingly, FD-VECs produced more p-SMAD2 and TSP-1 than WT-VECs. We also found elevated TSP-1 in the peritubular capillaries of renal tissues biopsied from FD patients. Inhibition of SMAD2 signaling or knock out of TSP-1 (TSP-1(-/-)) rescues normal vascular functionality in FD-VECs, like in gene-corrected FD-VECs. In addition, the enhanced oxygen consumption rate is reduced in TSP-1(-/-) FD-VECs. Interpretation: The overexpression of TSP-1 secondary to Gb3 accumulation is primarily responsible for the observed FD-VEC dysfunction. Our findings implicate dysfunctional VEC angiogenesis in the peritubular capillaries in some of the complications of Fabry disease. (C) 2020 The Author(s). Published by Elsevier B.V.
URI
https://pr.ibs.re.kr/handle/8788114/10403
DOI
10.1016/j.ebiom.2020.102633
ISSN
2352-3964
Appears in Collections:
Center for Vascular Research(혈관 연구단) > 1. Journal Papers (저널논문)
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