Download Cellular modeling of Fabry disease using human induced

Cellular modeling of Fabry disease
using human induced pluripotent stem cells
Hyo-Sang Do1, Sang-Wook Park1, Beom-Hee Lee2, Han-Wook Yoo2, and Yong-Man
Han1
Department of Biological Sciences and Center for Stem Cell Differentiation, KAIST,
Daejeon, KOREA1; Department of Pediatrics, Asan Medical Center, University of
Ulsan College of Medicine, Seoul, Korea2
Fabry disease (FD) is a recessive X-linked lysosomal storage disorder which is
caused by α-galactosidase (GLA) deficiency. Dissipation of GLA activity results in
excessive globotriaosylceramide (Gb3) accumulation in the most cell types, thereby
leading to progressive complications. In particular, accumulation of Gb3 in vascular
cells causes life-threatening complications such as ischemic stroke, hypertrophic
cardiomyopathy, and renal failure at the terminal stage of Fabry . Here, induced
pluripotent stem cells were generated from dermal fibroblasts derived from a Fabry
patient (FD-iPSCs) by ectopic expression of Yamanaka's factors. The FD-hiPSCs
exhibited
low
galactosidase
activity
and
excessive
Gb3
accumulation
in
undifferentiated state. Also, FD-iPSCs could differentiate vascular cells such as
endothelial cells (ECs) and smooth muscle cells (SMCs) with functionality of tubulelike structure formation, although FD-ECs and SMCs represented Gb3 accumulation.
Accumulated Gb3 was cleared by treatment with alpha-galactosidase recombinant
protein (Fabrazyme®) during vascular differentiation of FD-iPSCs. FD-ECs showed
endothelial dysfunction and decreased eNOS expression. The results demonstrate
that endothelial dysfunction may be caused by low activity of eNOS in Fabry disease.