title: 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.
authors.affiliation: Department of Cardiac Surgery, Frankel Cardiovascular Center, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Jiao
authors.initials: J
authors.lastname: Jiao
authors.affiliation: Department of Cardiac Surgery, Frankel Cardiovascular Center, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Xiong
authors.affiliation: Department of Cardiac Surgery, Frankel Cardiovascular Center, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Lunchang
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Jiong
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Cardiac Surgery, Frankel Cardiovascular Center, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: Qiu
authors.affiliation: Department of Cardiac Surgery, Frankel Cardiovascular Center, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Hirai
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Lina
authors.initials: L
authors.lastname: Shao
authors.affiliation: Department of Internal Medicine, University of Texas, Houston, TX 77030, USA.
authors.forename: Dianna
authors.initials: D
authors.lastname: Milewicz
authors.affiliation: Department of Cardiac Surgery, Frankel Cardiovascular Center, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Y Eugene
authors.initials: YE
authors.lastname: Chen
authors.affiliation: Department of Cardiac Surgery, Frankel Cardiovascular Center, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: boya@med.umich.edu.
authors.forename: Bo
authors.initials: B
authors.lastname: Yang
mesh_terms: D001018:Aortic Diseases / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D001021:Aortic Valve / Q000002:abnormalities* / Q000378:metabolism / Q000473:pathology; D000082882:Bicuspid Aortic Valve Disease; D015415:Biomarkers; D018929:Cell Culture Techniques; D002454:Cell Differentiation; D006349:Heart Valve Diseases / Q000150:complications / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D016130:Immunophenotyping; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism; D009119:Muscle Contraction; D032389:Myocytes, Smooth Muscle / Q000166:cytology* / Q000378:metabolism; D018995:Myosin Heavy Chains / Q000378:metabolism; D009432:Neural Crest / Q000166:cytology*; D010641:Phenotype; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D015415:Biomarkers; C509903:MYH11 protein, human; D016212:Transforming Growth Factor beta; D058570:TOR Serine-Threonine Kinases; D018995:Myosin Heavy Chains