STRESSFATE · To Notch up a broken heart

Heart failure is a major health issue and a cause of death and disability. The endogenous regenerative capacity of the heart is too weak to recover from damage and instead the heart repairs damage by synthesis of a scar tissue leading to functional deterioration. To improve cardiac regeneration, stem cell therapies and material-based approaches have been developed but up till now with limited success as we still lack detailed knowledge of and the functional technology to guide the regenerative process. Cardiac tissue is composed of muscle cells, non-muscle cells and extracellular matrix organized into a complex 3-dimensional architecture. The regeneration process requires specialization of cardiac stem cells in combination with remodelling of the extracellular matrix to form a functional contractile tissue. The Notch signalling pathway is a unique therapeutic target for regeneration of the heart, but we no nothing about the crosstalk between Notch and the biomechanical microenvironment. We aim to develop an in vitro model system using in situ differentiation of cardiac stem cells on 3-dimensional microtissue. The tissue can be engineered to mimic healthy or diseased myocardium tissue and be mechanically stimulated to mimic the beating heart. Using the model we aim to gain in-depth understanding on how the extracellular matrix and changes therein and the Notch signalling pathway, are interlinked. To use Notch modulation as a handle in cardiac regeneration we will develop technology for temporally and spatially controlled modulation of Notch signalling and build a prototype of functional scaffold for cardiac stem cell differentiation comprised of controlled delivery of Notch modulators from a synthetic matrix.