Heart failure (HF) and ischaemic heart disease (IHD) are leading causes of death in Western countries. Consequent cardiac remodelling affects the viability and function of all cardiac cells, and leads to significant changes in the composition and features of the extracellular matrix (ECM) which conversely impacts upon all myocardial cells. Moreover, cardiac microenvironment during HF progression is significantly affected by altered metabolism (e.g. type 2 diabetes mellitus, metabolic syndrome) and biomechanical alterations bringing to fibrosis and stiffening. Indeed mechanical-dependent molecular pathways have strong implications in myocardial fibrosis and HF progression.
Despite continuous medical advancements, novel approaches for regenerative and anti-fibrotic therapies are needed. Among resident stromal cells, a population of primitive cardiac progenitor cells (CPCs) is traceable in the adult human heart, contributing to cardiac homeostasis and repair, and can be exploited for regenerative medicine strategies. Multiple pathways and conditions have been reported to affect the biological features of primitive stromal cells, but an integrated knowledge on how ECM remodeling, metabolic conditions, and altered mechanosensing may impair the balance between pro-fibrotic and pro-regenerative signaling by resident/transplanted CPCs is still lacking.
The present project proposal aims at investigating in an integrated perspective: 1) how ECM remodeling, metabolic co-morbidities, and altered mechanosensing hamper the balance between cardiogenic and fibrotic phenotype of human CPCs from IHD and HF patients; 2) whether modulation of mechanosensing pathways may reverse, at least in part, a pro-fibrotic phenotype. These results will enhance the knowledge on endogenous cardiac remodelling mechanisms, and strongly support the clinical translation of novel regenerative and anti-fibrotic therapies towards the treatment of HF.