A developmental model of human early cardiac valvulogenesis (I). Homo sapiens

One third of cardiac congenital diseases affect cardiac valves. Genetically modified mice have advanced our understanding of valve development and related pathologies. However, little is known with regard to human valve development.We aimed to derive a novel human pluripotent stem cell model in order to decode the early steps of human valvulogenesis. Human MesP1+mesodermal cells were differentiated toward the fate of second heart field progenitors and then to a selected population of pre-valvular endocardial cells. Gene arrays revealed that these human prevalvular cells (HPVC) express patterns of genes similar to those expressed in the atrioventricular canal (AVC) endocardium of E9.0 mouse embryos. In mice this developmental time precedes endocardial mesenchymal transition (EndoMT),which is required for mature valve formation. HPVC treated with BMP2, cultured onto chick or mouse AVC cushions, or transplanted into the outflow tract or AVC of embryonic chick and mouse hearts, underwent EndoMTin both a Notch-dependent and independent-manner and expressed markers of valve mesenchymal cells and fibroblasts. Similar to the previously described valve interstitial cells (VICs), HPVC also differentiate into tendinous/chondrogenic cells. Our study indicates tha thuman pluripotent stem cells canrecapitulate early valvulogenesis and thus provide a powerful model to further decipher the origin and lineage contribution of different valvular cell types in humans. Overall design: experiments were performed in triplicates; references are the HUES24 pluripotent stem cells.