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    • The following are the supplementary data related

    2018-10-23

    The following are the supplementary data related to this article.
    Author Contribution
    Acknowledgments This study is supported in part by the Bureau of Health Promotion, Department of Health, R.O.C. (Taiwan) (DOH99-HP-1205), Taiwan Ministry of Health and Welfare Clinical Trial and Research Center of Excellence (MOHW105-TDU-B-212-133019), China Medical University Hospital, Academia Sinica Taiwan Biobank Stroke Biosignature Project (BM10501010037), NRPB Stroke Clinical Trial Consortium (MOST 104-2325-B-039 -005), Tseng-Lien Lin Foundation, Taichung, Taiwan, Taiwan Brain Disease Foundation, Taipei, Taiwan, and Katsuzo and Kiyo Aoshima Memorial Funds, Japan, Ministry of Science and Technology, Taiwan, R.O.C. (MOST103-2314-B-039-035-MY3 and MOST102-2632-B-039-001-MY3), China Medical University Hospital, Taichung, Taiwan (DMR-105-066, DMR-105-087 and DMR-105-164), China Medical University, Taichung, Taiwan (CMU102-ASIA-09), and the Bureau of Health Promotion, Department of Health, Taiwan (DOH99-HP-1205). All the funders provided budget for reagents in this study and played no part in study design, data collection, data analysis, interpretation, and writing of the manuscript.
    Introduction Bicuspid aortic valves (BAV) are the most common congenital cardiovascular malformation affecting 0.9–2% of the general hedgehog inhibitor (Michelena et al., 2014; Prakash et al., 2014). BAV account for more morbidity and mortality than all other cardiovascular congenital malformations combined. Thoracic aortic aneurysm (TAA) occurs in approximately 50–70% of patients with BAV which is significantly higher than the rate of TAA formation in patients with tricuspid aortic valves (TAV) (Fedak et al., 2005). Furthermore, patients with BAV have an eight-fold higher risk of aortic dissection, which carries very high mortality (Michelena et al., 2011). There are no therapeutic agents to prevent TAA in BAV. Whether the aneurysms in BAV patients arise due to altered hemodynamic forces from the abnormal valve or from an underlying genetic defect leading to both BAV and TAA is currently unknown (Prakash et al., 2014). The assessment of hemodynamic flow in BAV patients shows distinct differences of the flow patterns compared to TAV patients (Keane et al., 2000). However, even after aortic valve replacement to correct the hemodynamics, some BAV patients still develop an ascending aortic aneurysm (Itagaki et al., 2015). Studies using aortic tissue from BAV patients have shown potential evidence of aortopathy of the aortic wall, including immature smooth muscle cells (SMCs) (Grewal et al., 2014b; Nkomo et al., 2003). However, these results failed to delineate between the two possible causes of TAA mentioned above. Accumulating evidence suggests an inherited component to the etiology of BAV complicated by TAA (BAV/TAA), but the responsible locus or loci are still largely unknown (Cripe et al., 2004; Horne et al., 2004). Rare variants of NOTCH1, GATA5 and FBN1 were correlated with 4–10%, 2.6% and one in eight BAV patients, respectively (Bonachea et al., 2014; Garg et al., 2005; Padang et al., 2013; Pepe et al., 2014). Common variants in FBN1 were also found to be associated with BAV/TAA (LeMaire et al., 2011). Lack of knowledge of gene alterations predisposing to majority of BAV/TAA patients has prevented the development of mouse models. Due to the inaccessibility of appropriate cellular or mouse model, so far, the mechanism of TAA in BAV patients remains largely unknown. Interestingly, the aortic root, ascending aorta, and aortic arch are commonly involved in aneurysms, whereas the descending aorta is rarely impacted in BAV/TAA (Fazel et al., 2008). Embryonic fate-mapping studies have demonstrated that the aortic root, ascending aorta and aortic arch are populated by SMCs arising from neural crest (NC), while the descending aorta is populated by SMCs from the paraxial mesoderm (PM) (Cheung et al., 2012; Majesky, 2007). Based on these facts, we hypothesize that the aortopathy in BAV patients is due to a defective differentiation of neural crest stem cells (NCSCs) to SMCs that spares the paraxial mesoderm cells (PMCs)-derived SMCs. Advancement of induced pluripotent stem cells (iPSCs) and lineage-specific SMCs differentiation technology now provides unique methods to test this hypothesis (Cheung et al., 2014).