Key result
Neural crest stem cell-derived smooth muscle cells from patients with bicuspid aortic valves and thoracic aortic aneurysms demonstrated significantly decreased MYH11 expression and impaired contraction compared to controls, which was rescued by mTOR inhibition with rapamycin.
Defective differentiation and contraction of neural crest-derived smooth muscle cells may contribute to BAV-associated aortopathy, a defect that can be rescued in vitro by mTOR inhibition with rapamycin.
Should not yet change BAV aortopathy management; leaves open mTOR inhibition as a hypothesis-generating therapeutic target.
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.
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Jiao et al. (2016) studied Bicuspid aortic valve associated with thoracic aortic aneurysm (n=3). BAV/TAA patient-derived induced pluripotent stem cells vs. Healthy control patient-derived induced pluripotent stem cells was evaluated on Expression of smooth muscle cell differentiation marker (MYH11) and contractile function in neural crest stem cell-derived smooth muscle cells. Neural crest stem cell-derived smooth muscle cells from patients with bicuspid aortic valves and thoracic aortic aneurysms demonstrated significantly decreased MYH11 expression and impaired contraction compared to controls, which was rescued by mTOR inhibition with rapamycin.
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