A novel source of arterial valve cells linked to bicuspid aortic valve without raphe in mice
Lorriane Eley,
Ahlam MS Alqahtani,
Donal MacGrogan,
Rachel V Richardson,
Lindsay Murphy,
Alejandro Salguero-Jimenez,
Marcos Sintes Rodriguez San Pedro,
Shindi Tiurma,
Lauren McCutcheon,
Adam Gilmore,
José Luis de La Pompa,
Bill Chaudhry,
Deborah J Henderson
Affiliations
Lorriane Eley
Institute of Genetic Medicine, Cardiovascular Research Centre, Newcastle University, Newcastle upon Tyne, United Kingdom
Ahlam MS Alqahtani
Institute of Genetic Medicine, Cardiovascular Research Centre, Newcastle University, Newcastle upon Tyne, United Kingdom
Donal MacGrogan
Intercellular Signalling in Cardiovascular Development and Disease Laboratory, Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares, Instituto de Salud Carlos III, Madrid, Spain
Rachel V Richardson
Institute of Genetic Medicine, Cardiovascular Research Centre, Newcastle University, Newcastle upon Tyne, United Kingdom
Lindsay Murphy
Institute of Genetic Medicine, Cardiovascular Research Centre, Newcastle University, Newcastle upon Tyne, United Kingdom
Alejandro Salguero-Jimenez
Intercellular Signalling in Cardiovascular Development and Disease Laboratory, Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares, Instituto de Salud Carlos III, Madrid, Spain
Marcos Sintes Rodriguez San Pedro
Institute of Genetic Medicine, Cardiovascular Research Centre, Newcastle University, Newcastle upon Tyne, United Kingdom
Shindi Tiurma
Institute of Genetic Medicine, Cardiovascular Research Centre, Newcastle University, Newcastle upon Tyne, United Kingdom
Lauren McCutcheon
Institute of Genetic Medicine, Cardiovascular Research Centre, Newcastle University, Newcastle upon Tyne, United Kingdom
Adam Gilmore
Institute of Genetic Medicine, Cardiovascular Research Centre, Newcastle University, Newcastle upon Tyne, United Kingdom
Intercellular Signalling in Cardiovascular Development and Disease Laboratory, Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares, Instituto de Salud Carlos III, Madrid, Spain
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.