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To Notch up a broken heart

Final Report Summary - STRESSFATE (To Notch up a broken heart)

Heart failure is a major health issue and the leading cause of death and disability world wide. The endogenous regenerative capacity of the heart is weak 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 cardiac progenitor cells (CPCs), their interaction with their niche as well as functional technology to guide the regenerative process. Regeneration requires specialization of CPCs in combination with remodeling of the extracellular matrix to form a functional contractile tissue. The Notch signaling pathway is crucial for cardiac repair and is a unique therapeutic target for regeneration of the heart, but we have limited understanding of the crosstalk between Notch and the biomechanical microenvironment and lack tools to modulate Notch signaling in a temporally and spatially controlled manner.

The project aimed to develop in vitro cardiac model systems to study the interplay between CPCs and their microenvironment with a special focus on the crosstalk between the mechanical environment and Notch signaling. The model tissue should mimic healthy or diseased cardiac tissue and be mechanically stimulated to mimic the beating heart. Using the model systems the aim was to gain in-depth understanding on how CPCs interact with their microenvironment and more specifically how the mechanical environment and the Notch signaling pathway are interlinked. The project also aimed to develop technology for controlled modulation of Notch signaling to enable the use of Notch modulatione in cardiac regeneration and repair.

During the course of the project we have developed beating cardiac microtissue, hypoxic and mechanically strained 3D spheroid cultures as well as microfluidic technologies to study the impact of the microenvironment and especially the mechanical microenvironment on cardiac stem cells and Notch signaling. We demonstrated that the CPCs are insensitive to the mechanical environment and the mechanosensitive structures of the cells developed upon differentiation. We demonstrated a clear interdependency of Notch signaling with the mechanical and chemical microenvironment as well as showed the impact of 3D culture conditions on Notch signaling and CPC differentiation in in cardiovascular tissues. We also demonstrated a clear difference in the response of CPCs to mechanical stimuli in 2D and in 3D. In addition, a significant focus was placed on in collaboration with material scientist developing drug delivery vehicles and biofunctionalized scaffolds/surfaces for targeted and precise modulation of Notch activity. These Notch controlling materials were evaluated in different tissue contexts such as activation of Notch for controlled differentiation of cardiovascular cells, spatial patterning of angiogenesis and targeted inhibition of Notch in cancer stem cells.

Our data has clear implications for cardiovascular medicine and regeneration. Traditional cell based therapies to treat myocardial infarction (MI) has shown limited improvement on the long term, mainly due to low cell survival and engraftment in the host tissue. In fact, a MI creates a hostile environment for the injected progenitor cells, due to the inflammatory response and tissue alterations triggered by the cardiac injury. An alternative approach is to generate new, or engineered, microenvironments for the cells to enhance their regenerative potential. However, the interplay between CPCs and the environment, and especially the interplay between the environment and signaling pathways curcial for tissue repair such as Notch is largely unknown. Improved knowledge on the CPC niches and the CPC-niche interactions will enhance our insight into CPC behavior and the influence of the niche on CPC regenerative capacity, which can ultimately help modulate the microenvironment and re-create optimal conditions to enhance the regenerative potential to promote the regenerative potential of CPCs. Given the important role of Notch signaling in cardiovascular development and disease, the mechanistic insight into the relationship between the microenvironment and Notch signalling and the development of smart matrials for Notch modulation we will be able design novel materials for cardiovascular regeneration and repair.