MACS · The contribution of cellular adhesions to matrix remodeling in health and disease

Tissues in the human body are exposed to cyclic loading and have the capacity to adapt, to meet new loading demands. Cells facilitate such adaptation by responding to mechanical triggers, which depends on the balance between endogenous tension (cellular forces) and exogenous tension (matrix stiffness and resistance to stretch). This is regulated by matrix adhesions: the cellular force sensors. In healthy tissue, cells can positively contribute to tissue functioning by synthesizing additional matrix components, a process initiated at matrix adhesions, the connection between cells and matrix. However, in various fibrous tissue pathologies (e.g. atherosclerosis, cardiomyopathy, tendon overload), a progressive increase in matrix disorganization is observed. In search of the underlying cause of this matrix disorganization, this proposal aims to determine how mechanoresponsive matrix adhesion proteins react to mechanical perturbations and impact matrix remodeling in healthy and diseased tissue. In a multidisciplinary approach, novel 3D model systems will be used to engineer micro-tissues subjected to mechanical perturbations. Real-time imaging will expose matrix adhesion functioning upon imbalance between endogenous and exogenous tension. The response of mechanosensitive matrix adhesion proteins in healthy and diseased tissues will be quantified upon cyclic stretching, and its impact on matrix remodeling. These results will unravel the underlying cause for tissue remodeling associated with fibrous tissue pathology, to ultimately provide a treatment strategy. The proposal aims at bridging the classical 2D cell research and in vivo studies. Both lack the possibility to study cellular processes at the molecular, cell and tissue level in a native-like environment, whereby tissues are exposed to physiologically relevant mechanical and biochemical loading. Bridging this gap by adopting this genuinely new approach will therefore boost European excellence and competitiveness.