Abstract 396: Uncontrolled Endothelial Migration In Hereditary Hemorrhagic Telangiectasia: Disease Modeling With Ips Cell
Introduction: Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant heritable disease caused by mutation of Activin like receptor-1 (ALK1), an endothelial specific TGF-β family receptor. The histological hallmark in HHT is abnormal atriovenous communication, caused by abnormal migration of endothelial cells (ECs). These findings suggest that the enhanced migration of ECs would have a role in the development of HHT. However, how EC migration is regulated in HHT remains unclear. Hence, the aim of this study is to develop an in vitro HHT model with ECs derived from patient-specific induced pluripotent (iPS) cells.
Methods: We generated iPS cells from a HHT patient with ALK1 mutation (ALK1mt) and two control subjects (WT). ECs were derived from these iPS cells with prespecified differentiation method. We compared the effects of BMP-9, a selective agonist of ALK1, between ALK1mt- and WT-ECs. Also, microarray analysis comparing transcriptome of ALK1mt- and WT ECs with or without BMP-9 stimulation was conducted.
Results: Migration capacity was significantly reduced with BMP-9 in WT-ECs, but not in ALK1mt-ECs. With BMP-9 stimulation, elevation of genes associated with vascular stabilization and maturation was observed in WT-ECs but not in ALK1mt-ECs.
Conclusion: With ECs derived from iPS cells, modeling of HHT phenotype, uncontrolled endothelial migration, was achieved.
Clinical implications: By elucidating the biological process with which BMP-9 controls the migration of endothelial cells, new drug targets for HHT may be found. Also, these result may lead to the development of a new experimental drug screening system for HHT.
Author Disclosures: M. Takei: None. S. Yuasa: None. D. Kusumoto: None. A. Kunitomi: None. S. Kashiumura: None. G. Yodu: None. M. Shimojima: None. C. Motoda: None. A. Tanaka: None. Y. Kuroda: None. S. Tohyama: None. T. Seki: None. K. Fukuda: None.
- © 2015 by American Heart Association, Inc.