Modelling the Dynamics of cell-matrix Mechanical interactions to explain Anastomosis in a context of angiogenesis – MoDyMecA

Angiogenesis is the process by which new blood vessels form from pre-existing vessels. The vascular germination which takes place simultaneously at several points of one or more vessels makes it possible to grow a set of neovessels. These come into contact two by two at their ends to form a bridge or vascular loop allowing blood to flow, this is the process of anastomosis. This process is fundamental since it allows blood flow to gradually establish itself through the vascular network in a dynamic way: that is, by redistributing itself as new connections are made. This helps make the network functional and efficient in delivering oxygen (and nutrients) to cells in hypoxic distress when the tissue is damaged. Despite its importance, the process of anastomosis in angiogenesis is still not fully explained due to its complexity which involves understanding how cells perceive and respond to their mechanical environment and how they remodel it dynamically. This reciprocity between the adaptation of the cell to its environment and the remodelling of the environment by cells is a numerical challenge since all the structures to be considered, cells and matrix, constantly evolve in time. As part of this project, our ambition is to explore this bi-directional interaction through a computational model that makes it possible to assess the relative importance of the different mechano-chemical mechanisms and environmental parameters in deciphering the anastomosis. The model will be based on the vast body of knowledge available in the literature on the ability of cells to adapt to the properties of their environment. It will then be calibrated and validated quantitatively by a series of dedicated experiments that we will carry out specifically in this project. We will develop a hybrid and multiscale computational model to study how endothelial cells – i.e. the cells forming the blood vessels – can communicate at a distance via the extracellular matrix to finally meet one another and form the contact required for successful anastomosis. To that end the model will be tightly combined with in vitro experiments. The project is organized into three workpackages. The first workpackage aims at applying well mastered methods for cell characterization on 2D polyacrylamide biogels coated with collagen. This will bring new knowledge on the endothelial cell type that will be used to calibrate the computational model. The endothelial cell morphodynamics and ability to generate forces will be specifically quantified, as well as its matrix remodelling potential (proteolytic activity). The second workpackage aims to validate the model in the more realistic 3D matrix environment made of a network of collagen fibres. Here we make the assumption that the data collected in 2D and characterizing the cell biomechanical properties remain mostly valid in 3D. Generalization of the model in 3D will allow to predict the cell behaviour in the 3D environment. Additionally, imposed matrix deformations will be tested to numerically predict the cell-matrix reactions that will be verified with a posteriori experiments. Finally in the third workpackage, the model developed will be used to identify the optimal conditions that lead to successful anastomosis, i.e. to higher occurrence of cell-cell encounters. From a societal point of view, a better understanding of the mechano-chemical conditions leading to anastomosis is fundamental for tissue engineering and the optimization of tissue reconstruction. The model that we will develop through this project will be the perfect tool to achieve such an optimization.