Abstract
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.