Modeling supravalvular aortic stenosis syndrome with human induced pluripotent stem cells.
BACKGROUND
Supravalvular aortic stenosis (SVAS) is caused by mutations in the elastin (ELN) gene and is characterized by abnormal proliferation of vascular smooth muscle cells (SMCs) that can lead to narrowing or blockage of the ascending aorta and other arterial vessels. Having patient-specific SMCs available may facilitate the study of disease mechanisms and development of novel therapeutic interventions.


RESULTS
Here, we report the development of a human induced pluripotent stem cell (iPSC) line from a patient with SVAS caused by the premature termination in exon 10 of the ELN gene resulting from an exon 9 four-nucleotide insertion. We showed that SVAS iPSC-derived SMCs (iPSC-SMCs) had significantly fewer organized networks of smooth muscle α-actin filament bundles, a hallmark of mature contractile SMCs, compared with control iPSC-SMCs. The addition of elastin recombinant protein or enhancement of small GTPase RhoA signaling was able to rescue the formation of smooth muscle α-actin filament bundles in SVAS iPSC-SMCs. Cell counts and BrdU analysis revealed a significantly higher proliferation rate in SVAS iPSC-SMCs than control iPSC-SMCs. Furthermore, SVAS iPSC-SMCs migrated at a markedly higher rate to the chemotactic agent platelet-derived growth factor compared with the control iPSC-SMCs. We also provided evidence that elevated activity of extracellular signal-regulated kinase 1/2 is required for hyperproliferation of SVAS iPSC-SMCs. The phenotype was confirmed in iPSC-SMCs generated from a patient with deletion of elastin owing to Williams-Beuren syndrome.


CONCLUSIONS
SVAS iPSC-SMCs recapitulate key pathological features of patients with SVAS and may provide a promising strategy to study disease mechanisms and to develop novel therapies.
YCVRC Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, Yale Stem Cell Center, Ste 773A, 300 George St, New Haven, CT 06510, USA.
Xin
X
Ge
Yongming
Y
Ren
Oscar
O
Bartulos
Min Young
MY
Lee
Zhichao
Z
Yue
Kun-Yong
KY
Kim
Wei
W
Li
Peter J
PJ
Amos
Esra Cagavi
EC
Bozkulak
Amulya
A
Iyer
Wei
W
Zheng
Hongyu
H
Zhao
Kathleen A
KA
Martin
Darrell N
DN
Kotton
George
G
Tellides
In-Hyun
IH
Park
Lixia
L
Yue
Yibing
Y
Qyang
D000328:Adult; D000818:Animals; D021921:Aortic Stenosis, Supravalvular / Q000473:pathology*; D002478:Cells, Cultured; D002648:Child; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000473:pathology*; D008297:Male; D051379:Mice; D018980:Williams Syndrome / Q000473:pathology*