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.
SCIENTIFIC/TECHNOLOGICAL IMPACT.
Cardiac regenerative medicine and cardiac cell therapy (CCT) aim at achieving cardiac regeneration to compensate parenchymal loss and recover heart function by stimulating endogenous repair or transplanting cardiogenic cells. Nonetheless several limitations concerning engraftment and therapeutic efficacy still persist. The interplay between cells and the microenvironment involves a complex network. The extracellular matrix (ECM) and its biomechanics guide organ development and physiologic repair, potentially affecting the phenotype and regenerative potential of both endogenous resident, and/or injected/transplanted stromal primitive cells (CPCs) for CCT approaches.
The present project will rely on the complementary skills and expertise of the project leader with that of the participants, all involved in cardiac biomedical research at both translational and clinical levels. The project will provide novel insights on the phenotypic shift from cardiogenic to fibrotic of resident stromal cells, in particular of primitive CPCs, in order to understand the regulatory mechanisms of endogenous heart repair processes, and how they are affected by myocardial remodeling and metabolic conditions. These results will also potentially overcome the current major limitations of CCT, as emerged in recent clinical trials, and propose novel promising targets and strategies for enhancing regenerative therapy in HF patients by conditional mechanosensing.
The integrated research approach will complete the proposed aims of understanding how multiple biomechanical and metabolic cues can affect the biological features of endogenous stromal CPCs, also discovering novel pathways (for example linked to mechanosensing) affecting their cardiogenic potential, thus identifying possible novel targets for the scale-up of regenerative and anti-fibrotic protocols. These results will also support translational advancements to optimize candidate enrollment for autologous CCT, or donor selection criteria for allogenic protocols.
Our integrated approach, in which biotechnological and medical competences will be synergistically integrated, will promote research excellence, and provide results that in the near future could be translated into effective and innovative strategies, with successful transfer from scientific knowledge to clinical practice.
SOCIAL AND ECONOMICAL IMPACT.
In the European Union, cardiovascular pathologies are responsible to more than 2 million deaths every year, costing more than 192 billion euros, and representing a critical health issue with considerable social and economic costs. More than 30% of all HF patients die within two years since diagnosis [1]. Current treatments can improve quality of life and increase life expectancy, but cannot cure the cause of the disease. Furthermore, heart transplantation - the gold-standard treatment for end-stage HF - is limited by severe shortage of organs, and by the possible occurrence of rejection phenomena and side effects related to immunosuppressive therapy. Moreover, considering that HF patients experience several episodes of hospitalization before cardiac transplantation or death, the significant socio-economical impact appears evident. Cardiac regenerative medicine clinical translation responds to Horizon 2020 priorities for the development of personalized treatments for chronic medical conditions in the aging population. Efficient regenerative and CCT protocols would reduce the cost of surgical-clinical interventions and of standard life-long medication, together with the incidence and average time of hospitalization. The expected potential impact of the present project proposal for the National Health Service will be the pre-clinical identification and evaluation of key regulatory pathways affecting the balance between fibrotic and regenerative responses of both endogenous and transplanted CPCs for regenerative and CCT protocols.
EXPECTED RESULTS.
AIM 1.
Stromal CPCs cultured on pathological dECM will display: 1) pro-fibrotic phenotype and paracrine profile; 2) reduced cardiogenic and angiogenic features; 3) markers of activated detrimental mechanosensing due to ECM remodeling and stiffening.
AIM 2.
Stromal CPCs from MS, and possibly DM, patients will display: 1) altered oxidative state; 2) pro-fibrotic phenotype compared to controls, correlating to echocardiographic parameters of altered contractility in situ.
AIM 3.
Culture of pro-fibrotic CPCs on substrates with low stiffness, or treatment with molecules interfering with mechanosensing, will partially reverse their phenotype from pro-fibrotic towards cardiogenic and angiogenic.