An integrative methodology for the multi-scale study of collective behavior emerging in a heterogeneous cell population
Abstract
The major goal of this project is to develop an integrative methodology to couple experimental approaches with multi-scale modeling, simulation, and image analysis in a synergetic manner and to provide a deeper, systems-level understanding of the collective cell behavior during endothelial morphogenesis. Specifically, the project aims to establish a comprehensive biomechanical representation of multicellular behavior ranging from molecular to cellular to tissue levels by: 1. developing a predictive model of vascular endothelial cells, which will be parametrized based on experimental observations at the molecular level. This model will be used in simulations of collective cell behavior during vascular tube formation. 2. developing an image-analytics tool for the quantification and direct comparison of numerically simulated and experimentally observed multicellular patterns. This tool will provide a computational platform for the systematic study of the relationships between mechanical properties of individual cells, physical properties of the extracellular matrix (ECM), spatiotemporal regulation of adhesion complexes, and the development of various patterns of multicellular organization. These integrative approaches will allow testing the project s central hypothesis that the interaction-induced segregation of endothelial cells into functionally distinct subpopulations (ÒlinkersÓ and ÒanchorsÓ) is achieved through the dynamic regulation of cell-cell and cell-ECM junctions and plays the key role in maintaining the integrity and function of the vascular system. The specific aims are stated as: Aim 1. Develop a comprehensive multi-scale model of collective cell behavior in three-dimensional microenvironments. We develop a comprehensive cell model that includes: 1) stochastic dynamics of protrusions, by means of which cells interact with each other and the extracellular matrix; 2) an elastic cell body that moves and changes its shape in response to the mechanical forces resulting from interactions with its environment; 3) a stress- dependent spatiotemporal distribution of cadherin- and integrin-based junctions at the cell membrane. This hybrid model will allow us to simulate the emergence of collective cell behavior with sufficient level of detail to capture the complex interplay of molecular regulation of the cytoskeleton and cell adhesion, the mechanics of cell interactions and shape changes, and the self-organization of cells into multicellular structures. Aim 2. Investigate the role of mechanosensitive regulation of cell-cell and cell-matrix interactions in self- organization and stability of heterogeneous cell formations. Using our multiscale model for numerical simulations of vascular morphogenesis, we aim to determine the role of functional heterogeneity in the stability of resulting cellular patterns. We collect live and fixed cell fluorescence images of proteins associated with adherens junctions and focal adhesions and compare their spatial distributions among different patterns of tube formation under various genetic and environmental perturbations. Through the iterative cycling between the model and experiments, we explore alternative hypotheses about the regulation of cell-cell and cell-ECM junctions, such as titration of signaling proteins that are shared between cell-cell and cell-ECM adhesions...
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 11, 2018
- Source ID
- W911NF1710395
Entities
People
- Denis Tsygankov
Organizations
- Army Contracting Command
- Georgia Tech Research Corporation
- United States Army