Dataset Information

Differentiation defect in neural crest-derived smooth muscle cells in patients with aortopathy associated with bicuspid aortic valves.

ABSTRACT: Individuals with bicuspid aortic valves (BAV) are at a higher risk of developing thoracic aortic aneurysms (TAA) than patients with trileaflet aortic valves (TAV). The aneurysms associated with BAV most commonly involve the ascending aorta and spare the descending aorta. Smooth muscle cells (SMCs) in the ascending and descending aorta arise from neural crest (NC) and paraxial mesoderm (PM), respectively. We hypothesized defective differentiation of the neural crest stem cells (NCSCs)-derived SMCs but not paraxial mesoderm cells (PMCs)-derived SMCs contributes to the aortopathy associated with BAV. When induced pluripotent stem cells (iPSCs) from BAV/TAA patients were differentiated into NCSC-derived SMCs, these cells demonstrated significantly decreased expression of marker of SMC differentiation (MYH11) and impaired contraction compared to normal control. In contrast, the PMC-derived SMCs were similar to control cells in these aspects. The NCSC-SMCs from the BAV/TAA also showed decreased TGF-? signaling based on phosphorylation of SMAD2, and increased mTOR signaling. Inhibition of mTOR pathway using rapamycin rescued the aberrant differentiation. Our data demonstrates that decreased differentiation and contraction of patient's NCSC-derived SMCs may contribute to that aortopathy associated with BAV.

SUBMITTER: Jiao J

PROVIDER: S-EPMC5006642 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Differentiation defect in neural crest-derived smooth muscle cells in patients with aortopathy associated with bicuspid aortic valves.

Jiao Jiao J Xiong Wei W Wang Lunchang L Yang Jiong J Qiu Ping P Hirai Hiroyuki H Shao Lina L Milewicz Dianna D Chen Y Eugene YE Yang Bo B

EBioMedicine 20160701

Individuals with bicuspid aortic valves (BAV) are at a higher risk of developing thoracic aortic aneurysms (TAA) than patients with trileaflet aortic valves (TAV). The aneurysms associated with BAV most commonly involve the ascending aorta and spare the descending aorta. Smooth muscle cells (SMCs) in the ascending and descending aorta arise from neural crest (NC) and paraxial mesoderm (PM), respectively. We hypothesized defective differentiation of the neural crest stem cells (NCSCs)-derived SMC ...[more]

PMID: 27394642

Similar Datasets

Project description:Cellular and molecular mechanisms of thoracic aortic aneurysm are not clear and therapeutic approaches are mostly absent. Thoracic aortic aneurysm is associated with defective differentiation of smooth muscle cells (SMC) of aortic wall. Bicuspid aortic valve (BAV) comparing to tricuspid aortic valve (TAV) significantly predisposes to a risk of thoracic aortic aneurysms. It has been suggested recently that BAV-associated aortopathies represent a separate pathology comparing to TAV-associated dilations. The only proven candidate gene that has been associated with BAV remains NOTCH1. In this study we tested the hypothesis that Notch-dependent and related TGF-β and BMP differentiation pathways are differently altered in aortic SMC of BAV- vs. TAV-associated aortic aneurysms. SMC were isolated from aortic tissues of the patients with BAV- or TAV-associated aortic aneurysms and from healthy donors used as controls. Gene expression was verified by qPCR and Western blotting. For TGF-β induced differentiation SMC were treated with the medium containing TGF-β1. To induce proosteogenic signaling we cultured SMC in the presence of specific osteogenic factors. Notch-dependent differentiation was induced via lentiviral transduction of SMC with activated Notch1 domain. MYOCD expression, a master gene of SMC differentiation, was down regulated in SMC of both BAV and TAV patients. Discriminant analysis of gene expression patterns included a set of contractile genes specific for SMC, Notch-related genes and proosteogenic genes and revealed that control cells form a separate cluster from both BAV and TAV group, while BAV- and TAV-derived SMC are partially distinct with some overlapping. In differentiation experiments TGF-β caused similar patterns of target gene expression for BAV- and TAV derived cells while the induction was higher in the diseased cells than in control ones. Osteogenic induction caused significant change in RUNX2 expression exclusively in BAV group. Notch activation induced significant ACTA2 expression also exclusively in BAV group. We show that Notch acts synergistically with proosteogenic factors to induce ACTA2 transcription and osteogenic differentiation. In conclusion we have found differences in responsiveness of SMC to Notch and to proosteogenic induction between BAV- and TAV-associated aortic aneurysms.

Project description:ObjectiveWe have previously reported that human calcified aortic cusps have abundant expression of smooth muscle (SM) markers and co-activators. We hypothesised that cells in bicuspid aortic valve (BAV) cusps and those affected by rheumatic heart valve (RHV) disease may follow a similar phenotypic transition into smooth muscle cells, a process that could be regulated by transforming growth factors (TGFs).AimsCusps from eight patients with BAV and seven patients with RHV were analysed for early and late SM markers and regulators of SM gene expression by immunocytochemistry and compared to healthy aortic valves from 12 unused heart valve donors. The ability of TGFs to induce these markers in valve endothelial cells (VECs) on two substrates was assessed.ResultsIn total, 7 out of 8 BAVs and all the RHVs showed an increased and atypical expression of early and late SM markers α-SMA, calponin, SM22 and SM-myosin. The SM marker co-activators were aberrantly expressed in six of the BAV and six of the RHV, in a similar regional pattern to the expression of SM markers. Additionally, regions of VECs, and endothelial cells lining the vessels within the cusps were found to be positive for SM markers and co-activators in three BAV and six RHV. Both BAVs and RHVs were significantly thickened and HIF1α expression was prominent in four BAVs and one RHV. The ability of TGFβs to induce the expression of SM markers and myocardin was greater in VECs cultured on fibronectin than on gelatin. Fibronectin was shown to be upregulated in BAVs and RHVs, within the cusps as well as in the basement membrane.ConclusionBicuspid aortic valves and RHVs expressed increased numbers of SM marker-positive VICs and VECs. Concomittantly, these cells expressed MRTF-A and myocardin, key regulators of SM gene expression. TGFβ1 was able to preferentially upregulate SM markers and myocardin in VECs on fibronectin, and fibronectin was found to be upregulated in BAVs and RHVs. These findings suggest a role of VEC as a source of cells that express SM cell markers in BAVs and RHVs. The similarity between SM marker expression in BAVs and RHVs with our previous study with cusps from patients with aortic stenosis suggests the existance of a common pathological pathway between these different pathologies.

Dataset Information

Differentiation defect in neural crest-derived smooth muscle cells in patients with aortopathy associated with bicuspid aortic valves.

Publications

Differentiation defect in neural crest-derived smooth muscle cells in patients with aortopathy associated with bicuspid aortic valves.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets