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

• Model of the BAV/TAA is established using iPSCs differentiated into SMCs through distinct embryonic progenitors.
• BAV/TAA iPSCs differentiated SMCs from NCSCs were impaired in contractile function, whereas, iPSCs PMCs-SMCs were normal.
• NCSC-SMCs from BAV/TAA decreased in TGF-β signaling but increased in mTOR signaling. Rapamycin normalized contractile function.Aneurysms associated with bicuspid aortic valves (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. When induced pluripotent stem cells (iPSCs) from BAV patients were differentiated into NC stem cells (NCSCs)-derived SMCs, these cells demonstrated impaired contraction compared to normal control. In contrast, the PM cells-derived SMCs were similar to control cells. The NCSC-SMCs from the BAV/TAA also showed increased mTOR signaling. Inhibition of mTOR pathway using rapamycin rescued the aberrant differentiation.

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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