The striated muscle of the heart (myocardium) is organized into anisotropic layers, consisting of beating cardiomyocytes (CMs) and structure supporting cardiac fibroblasts (cFBs). Upon injury, a lack of oxygen results not only in a massive loss of beating CMs but also in disruption of the highly organized architecture, impairing coordinated contraction, differentiation, matrix remodeling and mechanotransduction of resident and newly injected or recruited cardiac cells. Although many attempts have been made to restore the number of CMs after injury, there is little evidence of substantial long-term survival or engraftment of transplanted cells, suggesting the hostile fibrotic environment is opposing any attempt of cardiac regeneration. Therefore, it is proposed that regenerative strategies should aim at regaining the structural tissue organization to create a suitable environment for cell engraftment, survival and functionality.
In this project, we aim to gain fundamental knowledge on how beating CMs and cFBs are organized by the anisotropic cues present in the myocardium in order to investigate if and how we can use these cues to restore the organization of cells and extracellular matrix (ECM). To do so, we use 2D and 3D in vitro models of the myocardial wall, consisting of cultures of human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) and human epicardial derived cardiac fibroblasts (hEPDCs) that are subjected to uniaxial cyclic strain and protein patterns or fibers to simulate cardiac beating and fibrous ECM structures, respectively.