Agent-based model of angiogenesis simulates capillary sprout initiation in multicellular networks

Abstract

Many biological processes are controlled by both deterministic and stochastic influences. However, efforts to model these systems often rely on either purely stochastic or purely rule-based methods. To better understand the balance between stochasticity and determinism in biological processes a computational approach that incorporates both influences may afford additional insight into underlying biological mechanisms that give rise to emergent system properties. We apply a combined approach to the simulation and study of angiogenesis, the growth of new blood vessels from existing networks. This complex multicellular process begins with selection of an initiating endothelial cell, or tip cell, which sprouts from the parent vessels in response to stimulation by exogenous cues. We have constructed an agent-based model of sprouting angiogenesis to evaluate endothelial cell sprout initiation frequency and location, and we have experimentally validated it using high-resolution time-lapse confocal microscopy. ABM simulations were then compared to a Monte Carlo model, revealing that purely stochastic simulations could not generate sprout locations as accurately as the rule-informed agent-based model. These findings support the use of rule-based approaches for modeling the complex mechanisms underlying sprouting angiogenesis over purely stochastic methods.

Dynamic, heterogeneous endothelial Tie2 expression and capillary blood flow during microvascular remodeling

“…However, this relationship has never before been corroborated by in vivo studies, despite the ongoing clinical evaluation of a drug, VE-PTP, intended to constitutively block this pathway’s inhibitor. Additionally, multiple groups have leveraged complicated computational modeling techniques to investigate endothelial heterogeneity, without the detailed spatial and temporal data on Tie2 gene modulation in tandem with hemodynamic readouts 18 , 22 – 26 . Given that blood flow is dynamic and highly variable from vessel to vessel 27 , we hypothesized that heterogeneity in endothelial cell Tie2-driven green fluorescent protein (GFP) expression during growth and remodeling of the microvascular network may, in part, result from changes in blood flow-induced wall shear stress (WSS) during angiogenesis 28 – 30 .…”

Agent-Based Models Predict Emergent Behavior of Heterogeneous Cell Populations in Dynamic Microenvironments

“…Specifically, ABMs can readily incorporate agent heterogeneity and environmental dynamics with high precision and resolution. Classically used in the social sciences, ABMs have become increasingly popular for studying emergent behavior in biological systems, including bacterial biofilms and infection (Segovia-Juarez et al, 2004;Gorochowski et al, 2012), tumor growth (Enderling et al, 2009;Mehdizadeh et al, 2013;Walpole et al, 2015;Norton et al, 2017), and immune interactions (Folcik et al, 2007;Pienaar et al, 2015).…”

Examination of Microvascular Remodeling to Enhance Autologous Fat Grafting

“…VEGF-A is a potent angiogenic protein that signals through the Notch1-DLL4 signaling axis to activate endothelial cell sprouting and eventually form patent, mature vascular networks [80][81][82] .…”