A novel source of arterial valve cells linked to bicuspid aortic valve without raphe in mice

• DOI: 10.7554/elife.34110
• Publication Date: 2018-06-29T10:00:55Z
• Authors: Lorriane Eley; Ahlam MS Alqahtani; Donal MacGrogan; Rachel V Richardson; Lindsay Murphy; Alejandro Salguer...; Marcos Sintes Rod...; Shindi Tiurma; Lauren McCutcheon; Adam Gilmore; José Luis de La P...; Bill Chaudhry; Deborah J Henderson
• Keywords: 0301 basic medicine; bicuspid aortic valve; QH301-705.5; Science; LIM-Homeodomain Proteins; Myocytes, Smooth Muscle; Heart Valve Diseases; Gene Expression; Mice, Transgenic; Mice; 03 medical and health sciences; arterial valve; Bicuspid Aortic Valve Disease; Animals; Humans; Cell Lineage; Biology (General); Receptor, Notch1; Integrases; Stem Cells; Q; R; progenitor; Cell Differentiation; Epithelial Cells; second heart field; Embryo, Mammalian; Cell Tracking; Aortic Valve; Medicine; Biomarkers; Jagged-1 Protein; Developmental Biology

Abnormalities of the arterial valve leaflets, predominantly bicuspid aortic valve, are the commonest congenital malformations. Although many studies have investigated the development of the arterial valves, it has been assumed that, as with the atrioventricular valves, endocardial to mesenchymal transition (EndMT) is the predominant mechanism. We show that arterial is distinctly different from atrioventricular valve formation. Whilst the four septal valve leaflets are dominated by NCC and EndMT-derived cells, the intercalated leaflets differentiate directly from Tnnt2-Cre+/Isl1+ progenitors in the outflow wall, via a Notch-Jag dependent mechanism. Further, when this novel group of progenitors are disrupted, development of the intercalated leaflets is disrupted, resulting in leaflet dysplasia and bicuspid valves without raphe, most commonly affecting the aortic valve. This study thus overturns the dogma that heart valves are formed principally by EndMT, identifies a new source of valve interstitial cells, and provides a novel mechanism for causation of bicuspid aortic valves without raphe.