| Popis: |
During sprouting angiogenesis, endothelial cells take on a spatial pattern of unique cell fates, becoming either the tip cell or the stalk cell. This process of fate selection is guided by lateral inhibition via the Delta-Notch signalling pathway. Classical Delta-Notch lateral inhibition models generate the salt-and-pepper pattern where tip cells are separated exactly by one stalk cell. However, it has been observed during angiogenesis that other forms of tip-stalk patterning are present, such as two or three stalk cells spaced between consecutive tip cells. To reproduce the diverse forms of angiogenic patterns, we develop a mathematical model that incorporates both intracellular Notch heterogeneity and tension-dependent rate of Delta-Notch binding into the classical lateral inhibition model. We first provide experimental evidence to justify the inclusion of these additional mechanisms. Next, we present our computational analysis where we demonstrate that unlike classical lateral inhibition models, our enhanced Delta-Notch lateral inhibition model is capable of explaining a larger range of cellular patterning during sprouting angiogenesis. A pivotal prediction in our enhanced Delta-Notch lateral inhibition model is the existence of intermediate cell states, i.e., cells that exhibit moderate Delta or Notch levels thus manifesting both tip cell and stalk cell traits. We provide experimental evidence that such intermediate cell states do exist by staining of endothelial cell cultures with CD34, a known tip cell marker, thus substantiating our enhanced model. |
