A hybrid agent-based model of the developing mammary terminal end bud.

Mammary gland ductal elongation is spearheaded by terminal end buds (TEBs), where populations of highly proliferative cells are maintained throughout post-pubertal organogenesis in virgin mice until the mammary fat pad is filled by a mature ductal tree. We have developed a hybrid multiscale agent-based model to study how cellular differentiation pathways, cellular proliferation capacity, and endocrine and paracrine signaling play a role during development of the mammary gland. A simplified cellular phenotypic hierarchy that includes stem, progenitor, and fully differentiated cells within the TEB was implemented. Model analysis finds that mammary gland development was highly sensitive to proliferation events within the TEB, with progenitors likely undergoing 2-3 proliferation cycles before transitioning to a non-proliferative phenotype, and this result is in agreement with our previous experimental work. Endocrine and paracrine signaling were found to provide reliable ductal elongation rate regulation, while variations in the probability a new daughter cell will be of a proliferative phenotype were seen to have minimal effects on ductal elongation rates. Moreover, the distribution of cellular phenotypes within the TEB was highly heterogeneous, demonstrating significant allowable plasticity in possible phenotypic distributions while maintaining biologically relevant growth behavior. Finally, simulation results indicate ductal elongation rates due to cellular proliferation within the TEB may have a greater sensitivity to upstream endocrine signaling than endothelial to stromal paracrine signaling within the TEB. This model provides a useful tool to gain quantitative insights into cellular population dynamics and the effects of endocrine and paracrine signaling within the pubertal terminal end bud.