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

TLDR

Bicuspid aortic valve is the most common congenital arterial valve malformation, and it has been assumed that endocardial‑to‑mesenchymal transition drives arterial valve development. Intercalated arterial valve leaflets arise directly from Tnnt2‑Cre⁺/Isl1⁺ progenitors in the outflow wall through a Notch‑Jag pathway, unlike the NCC/EndMT‑derived septal leaflets. Loss of these progenitors leads to leaflet dysplasia and bicuspid aortic valves without raphe, overturning the EndMT dogma and identifying a novel source of valve interstitial cells.

Abstract

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.