CSC PHYSTRESS · Bidirectional interactions between cardiomyocytes and cardiac stem cells in the adaptive response to physiological stress

Periodic Report Summary - CSC PHYSTRESS (Bidirectional interactions between cardiomyocytes and cardiac stem cells in the adaptive response to physiological stress)

Overall the project aims to ascertain the effects of the exercise-training induced myocyte-dependent growth-factor release on the cellular adaptation of the heart, with particular reference to the role of resident cardiac stem cells (CSCs) in this process. We are specifically assessing which growth factors are up-regulated in the 'physiologically stressed' cardiomyocytes and how these growth factors govern CSC fate both in vitro and in vivo. We will then investigate whether reversible myocardial growth, following a substantial period of de-training, involves CSC de-activation and/or number reduction, resulting in cardiomyocyte atrophy, entailing discontinuation of growth factors' synthesis, which leads to CSC quiescence, decreased number and consequent arrest of significant new cardiomyocyte formation. Finally, we are using the exercise training animal model to evaluate whether CSCs are the direct source of new cardiomyocyte formation in the adult mouse heart. Since the beginning of the project, we have generated novel data which re-defines the adaptation of the heart to physiological stress. Indeed, we have shown that intensity-controlled (relative to VO2 max) treadmill exercise training in adult rats and mice results in myocardial mass remodelling through myocyte hypertrophy, and new myocyte and capillary formation. The latter is due to exercise training intensity-dependent activation and ensuing differentiation of CSCs into newly-formed myocytes and capillaries. Together, these results highlight the role of resident stem cells in the physiological adaptation to different conditions and workloads in the adult myocardium. In order to ascertain the mechanistic underpinnings of the cellular adaptation of the heart with exercise training, we have identified that the adult heart undergoes a myocyte-dependent growth-factor release which drives the activation of CSCs and consequent new cardiomyocyte formation. Specifically, we found that the growth factor IGF-1 is significantly up-regulated in the 'stressed' cardiomyocytes and this growth factor drives CSC proliferation, but not their differentiation Furthermore, we have also identified that TGF-beta1 and Wnt3a/canonical pathway play differential roles in controlling CSC differentiation and self-renewal. The findings expected to emanate from this work are both scientifically and clinically relevant towards the planning and design of protocols and interventions for the treatment of heart disease and failure with regenerative medicine therapies. Indeed, we have shown for the first time that exercise training activates the endogenous regenerative capacity of the adult heart, and as exercise is already part of the integrated programme for the treatment of cardiovascular disease, it should now receive further boost for its application in the daily clinical practice. On the other hand, by disclosing the factors that govern CSC self-renewal and differentiation it should become possible to design a cocktail of growth factors which could be administered for the activation of these regenerative cells in situ. Therefore, these findings will enable us to design better protocols and interventions, which involve endogenous CSCs, for the regeneration of functional contractile mass following myocardial injury.

Data: CORDIS, © European Union