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-β 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.

Bicuspid Aortic Valve

“…Mesenchymal cells originating from the migrating cardiac neural crest cells reach the outflow tract cushions and contribute to the formation of the aortic and pulmonary valves together with the endocardially derived mesenchymal cells. Abnormal migration of neural crest cells has been postulated as a common pathway that results in BAV and aortopathy [21][22][23][24].…”

“…Conical Wnt, non-conical Wnt, TGF-β, fibroblast growth factor, bone morphogenetic protein, and Notch are some important proteins in the development of aortic valve and aorta. Errors of this pathway may result in various outflow tract structural abnormalities including BAV disease [11,16,19,23].…”

Differentiation and Application of Induced Pluripotent Stem Cell–Derived Vascular Smooth Muscle Cells

“…90 The authors of this study found that only immature VSMCs with impaired contractile ability could be generated from neural crest cell precursors, responsible for populating VSMCs in the ascending aorta, where biscupid aortic valve aneurysms commonly arise. In contrast, paraxial mesoderm-derived VSMCs, which populate the descending aorta, 95 generated from the same patients did not display altered phenotype or behavior.…”

“…In contrast, paraxial mesoderm-derived VSMCs, which populate the descending aorta, 95 generated from the same patients did not display altered phenotype or behavior. 90 The authors concluded that the use of patient-derived iPSCs offers a unique approach to understanding disease pathology and provided them with conclusive evidence that a combination of altered hemodynamics because of biscupid aortic valves as well as the immature neural crest-derived VSMCs predisposes biscupid aortic valves patients to aneurysm formation in the ascending aorta.…”

Brain cytoplasmic RNA 1 suppresses smooth muscle differentiation and vascular development in mice

“…SMC progenitors are recruited and then differentiated to SMCs to ensheath the endothelial vasculature (2). Disruption of this process during embryonic development causes vascular abnormalities such as thoracic aortic aneurysms and vascular anomalies or leads to embryo lethality (3)(4)(5). SMC differentiation is regulated elaborately in embryos at the transcriptional and translational levels (6).…”