Epicardial adipose tissue (EAT), the fat depot that directly surrounds the heart and is contained beneath the pericardium, has recently acquired increasing scientific interest. The discovery of its endocrine role, exerted through cytokines and adipokines secretion, opened the way to the investigation of its potential paracrine crosstalk with the underlying myocardium. Indeed, EAT features have been extensively correlated to onset and progression of cardiovascular pathologies, such as coronary heart disease (CHD). EAT also represents a source of adipose stem cells (ASCs), characterized by multipotent differentiation capacity. Remarkably, epicardial ASCs (e-ASCs) have been reported to have a higher cardiomyogenic potential as compared to pericardial and omental ASCs subtypes, and to exert paracrine proangiogenic and immunomodulatory effects. However, little is known about e-ASCs contribution to the milieu affecting cardiac function or to the endogenous repair process in CHD. Notably, studies aimed to investigate the molecular regulation of e-ASCs differentiative and paracrine effects are still lacking. The present project aims to extend current knowledge on e-ASC gene expression profiles by performing an extensive characterization of their differentiation potential and paracrine effects. We also intend to analyze the modulation of selected genes involved in these cellular mechanisms in the context of CHD pathogenesis, with the aim of identifying novel molecules for targeted experimental validation. Our approach will deepen our knowledge about e-ASC functional characteristics and paracrine role in the context of myocardial dysfunction, contributing to ameliorate the clinical treatment of cardiovascular pathologies, through both the identification of novel markers for CHD stratification and prognosis and the design of improved protocols for e-ASC-based cell therapies in CHD patients.
Cardiovascular diseases are the leading cause of death worldwide, with coronary heart disease (CHD) representing the greatest proportion of those deaths, due to an irreversible loss of proper cardiac function. Implantation of adult stem cells into the ischemic damaged myocardium has been investigated for its potential to repair/regenerate the injured tissue within the infarct zone.
Adipose tissue, besides its known role as energy storage and endocrine organ, has also been considered a rich source of mesenchymal multipotent cells (ASCs) and is currently the focus of interest in the field of inducible spontaneous regeneration and cell therapy. ASCs are easily obtained, show a strong capacity for ex vivo expansion and differentiation to other cell types (adipocytes, cardiomyocytes, endothelial cells), release a large variety of angiogenic factors and show immunomodulatory properties. However, the presence of cardiovascular risk factors, such as type 2 diabetes mellitus and obesity, negatively affects their pluripotency, self-renewal capacities and angiogenic potential. Moreover, the spontaneous regenerative capacity for ASC self-renewal seems to be regulated by the anatomical fat depot (subcutaneous, visceral and epicardial).
Epicardial adipose tissue (EAT) has been reported to exert an endocrine role through secretion of bioactive molecules. The endocrine activity of EAT as an inflammatory tissue secreting cytokines, chemokines and adipokines could also have direct effects on local inflammation and coronary atherosclerosis. Such findings can explain the clinical evidence that higher EAT volume is associated with coronary calcification, coronary stenosis, coronary plaque morphology, and the development of new non-calcified coronary plaque. Thus, EAT effect requires elucidation of its specific features, such as its cellular origin and biologic characteristics, in order to improve the whole understanding of the paracrine mechanisms contributing to CHD pathogenesis.
ASCs derived from EAT (e-ASCs) have been reported to have a higher cardiomyogenic potential as compared to other ASCs subtypes. However, little is known about e-ASC biology and their specific contribution to cardiac cell function or to cardiac endogenous repair processes. EAT seems to represent a perfect environment for the local interaction between ASCs that reside in this fat depot and the surrounding coronary vessels. In particular, it is important to clarify the role of e-ASCs in mediating the EAT-dependent angiogenic and immunomodulatory effects on myocardium, by analyzing the key molecules in e-ASC secretome.
The general goal of this research project is to improve basic knowledge on EAT-derived ASC contribution to CHD, in order to identify key factors regulating e-ASC biology in CHD that could have a role both as a prognostic biomarker and as a potential therapeutic target for cardiovascular diseases.
The characterization of gene regulation in mesenchymal stem cells derived from EAT of CHD patients by means of coding/non-coding gene expression analyses, the overview on the composition of angiogenic/inflammatory milieu supplied by e-ASC and acting on heart function, as well as the in vitro studies of the role of selected pathways in e-ASC biology, will allow to gain a deep insight on EAT contribution in CHD pathogenesis. In particular, the comprehension of the biology network from EAT-derived ASCs will allow the identification of key actors of EAT dysfunction in CHD and will foster the subsequent development of new prognostic/therapeutic markers for patient stratification/therapy.
Indeed, the correlation of expression data with the patients' profile might create a spectrum of molecular/paracrine alterations that can be linked to cardiac conditions after adjustment for baseline risk factors. We think that the correlation between transcription/secretome data and clinical profile of patients, besides deepening our knowledge about CHD, will also improve its tailored clinical treatment. In particular, our network-based approach, followed by validation of specific molecules on patient samples, will reveal potential novel markers that could be used to set up an individual profile of CHD patients. This will allow a stratification of risk that would be useful to better frame each patient with respect to the need for more aggressive/early treatments or for specific primary prevention.
Furthermore, the deep analysis of the pathobiological properties and the mechanisms of action of e-ASC in the context of CHD will contribute to identify key regulators of their function, allowing to select specific molecules and pathways that can be modulated in order to improve e-ASC clinical efficacy in terms of pro-angiogenic and immunomodulatory effects on myocardium. This will foster the design of improved clinical protocols for future e-ASC-based cell therapies in CHD patients.