Cell-based simulations of Notch-dependent cell differentiation on growing domains

Abstract

Notch signalling controls cell differentiation and proliferation in many tissues. The Notch signal is generated by the interaction between the Notch receptor of one cell with the Notch ligand (Delta or Jagged) of a neighbouring cell. Therefore, the pathway requires cell-cell contact in order to be active. During organ development, cell differentiation occurs concurrently with tissue growth and changes in cell morphology. How growth impacts on Notch signalling and cell differentiation remains poorly understood. Here, we developed a modelling environment to simulate Notch signalling in a growing tissue. We use our model to simulate the differentiation process of pancreatic progenitor cells. Our results suggest that Notch-mediated differentiation in the developing pancreas is first mediated by geometric effects that result in loss of Notch signalling on the tissue boundary, leading to the differentiation of tip versus trunk cells. A second wave of differentiation further happens in the trunk cells due to a reduction in the expression of the ligand Jagged, which has been shown to be controlled by signalling factors secreted from the surrounding mesenchyme. Our results bring new insights into how cells coordinate tissue growth with cell fate specification during organ development.