Stem Cells International

Review Article

The Application of Induced Pluripotent Stem Cells in Pathogenesis Study and Gene Therapy for Vascular Disorders: Current Progress and Future Challenges

Table 1

List of studies using human IPSCs derived from patients for pathogenesis investigation.


Vascular disorders	Gene	Chr, exon, mutation	Pathogenesis-related SMC/EC phenotype and signal changes	iPSC resource	Pluripotency markers (+)	Gene therapy, effect	Author, year	Reference

Marfan syndrome (MFS)	FBN1	15, 30, C1242Y	MFS^C1242Y-iPSC-NC-SMC: proliferative capacity↓, cell death↑, contractility↓, propagating calcium↓, MMP9 expression in stretching↑; MFS^C1242Y-ECM: fibrillin-1 deposition↓, TGF-β signaling↑, collagen I deposition and stiffness↑	Patient dermal fibroblasts	OCT3/4, SOX2, SSEA4, TRA-1-60	CRISPR/Cas9 gene editing, rescues fibrillin-1 phenotype	Granata et al., 2016	[15]
Loeys-Dietz syndrome (LDS)	TGFBR2	3, 4, R193W	Not detected	Patient peripheral blood mononuclear cells	OCT4, SOX2, NANOG, TRA-1-60	Not referred	Hu et al., 2017	[18]
Williams-Beuren syndrome (WBS)	ELN	7, not referred, 7q11.23 heterozygous deletion	WBS^{7q11.23deletion}-iPSC-SMC: immature phenotype↑, proliferation↑, expression of differentiated SMC markers↓, response to vasoactive agonists↓, vascular tuber formation↓, calcium flux↓	Patient skin fibroblasts	NANOG, OCT4, SSEA4	EBPL2 peptide injection, partially rescues WBS cell phenotype	Kinnear et al., 2013	[19]
Hutchinson-Gilford progeria syndrome (HGPS)	LMNA	1, 11, G608R	HGPS^G608R-iPSC-SMC: senescence under hypoxia↑, nuclear dysmorphology↑, DNA damage↑, cell viability↓	Patient skin fibroblasts	OCT4, NANOG, SOX2, SSEA4, TRA-1-80	Reprogramming, low expression of LMNA	Zhang et al., 2011	[20]
Pulmonary artery hypertension (PAH)	BMPR2	2, 3, C118W	PAH^C118W-iPSC-EC: capability of adhesion, survival, migration, and angiogenesis↓, BMPR2 signaling↓	Patient skin fibroblasts	OCT4, KLF4, NANOG, SOX2, TRA-1-81, SSEA4	CRISPR/Cas9 gene editing, rescues PAH cell phenotype	Gu et al., 2017	[21]
Bicuspid aortic valve- (BAV-) related thoracic aortic aneurysm (TAA)	No mutation of NOTCH1 was found.	Not referred	BAV/TAA-iPSC-SMC: differentiation↓, contraction↓, TGF-β signaling↓, mTOR signaling↑	Patient peripheral blood mononuclear cells	OCT4, SOX2, NANOG, SSEA4, TRA-1-60, TRA-1-81	mTOR inhibitor rapamycin, rescues cell phenotype	Jiao et al., 2016	[22]
Supravalvular aortic stenosis (SVAS) syndrome	ELN	7, 9, 4 bp insert mutation	SVAS^insert-iPSC-SMC: property of contractile SMC↓, proliferation↑, migration↑, ERK1/2 activation↑	Patient epicardial coronary artery VSMCs	TRA-1-60, SSEA4, NANOG, OCT4	Elastin, rescues SVAS-SMC phenotype	Ge et al., 2012	[23]
Huntington’s disease (HD)	HTT	4, not referred, 66 CAG repeats	HD^repeats-iPSC-BMECs: angiogenic potential↑, migration↑, permeability↑, barrier property↓, endothelial transcytosis↓	Patient skin fibroblasts	OCT4, SOX2, KLF4, L-MYC	Wnt inhibitor rescues angiogenesis defects	Lim et al., 2017	[24]