Cells as state machines: Cell behavior patterns arise during capillary formation as a function of BDNF and VEGF

Cell behavior patterns that lead to distinct tissue or capillary phenotypes are difficult to identify using existing approaches. We present a strategy to characterize the form, frequency, magnitude and sequence of human endothelial cell activity when stimulated by vascular endothelial growth factor (VEGF) and brain-derived neurotrophic factor (BDNF). We introduce a “Rules-as-Agents” method for rapid comparison of cell behavior hypotheses to in vitro angiogenesis experiments. Endothelial cells are represented as machines that transition between finite behavior states, and their properties are explored by a search algorithm. We rank and quantify differences between competing hypotheses about cell behavior during the formation of unique capillary phenotypes. Results show the interaction of tip and stalk endothelial cells, and predict how migration, proliferation, branching, and elongation integrate to form capillary structures within a 3D matrix in the presence of varying VEGF and BDNF concentrations. This work offers the ability to understand – and ultimately control – human cell behavior at the microvasculature level.

► Endothelial cells have key behavior states regulated by BDNF and VEGF.
► The frequency and sequence of transitions in cell behaviors determine angiogenic sprouting.
► A Rules-as-Agents framework allows automated, rapid hypothesis testing.
► A genetic algorithm correlates cell decision-making to in vitro tissue level response.