Although initially considered only as an architectural support element, stromal compartments appear now to orchestrate many pathways influencing viability and functionality of cardiac cells. Cardiac stroma includes different components such as stromal progenitor cells, immunoinflammatory cells and extracellular matrix. These different components interact with each other to maintain the normal cardiac function or repair cardiac injury. On the other hand, inappropriate microenvironment remodeling may contribute to the development of cardiac dysfunction and failure.
Our project focuses on the role of stromal microenvironment in cardiac hypertrophy, failure and ageing. Two different aspects are investigated: the first one concerns the contribution of resident stromal cells and infiltrating immune cells in adverse ventricular remodeling; the second one focuses on the use of engineered bone marrow mesenchymal stem cells (BMMSC) for regulation of stromal microenvironment and cardiomyocytes function in heart failure.
Concerning our first research axis, we showed that subpopulations of cardiac “Mesenchymal-like” Sca-1+ cells are modified during ageing in term of phenotype and proinflammatory properties. In addition, we demonstrated for the first time the major role of CD4+ T cells in transition from ventricular hypertrophy to heart failure in a mouse model of left-ventricular pressure overload (Circulation, 2014). At present, we are using different wild type and genetically modified mouse models to determine i) the molecular mechanisms responsible for senescence of stromal cells, ii) mechanisms that rule immune cells trafficking in and out the pathological heart, iii) the cross talk between senescent stromal and inflammatory cells and iv) their involvement in heart failure with preserved and reduced ejection fraction.
The second research axis of our team is based on our experience in cell therapy of heart failure. Our group demonstrated the efficacy of the administration of bone marrow progenitor cells (mononuclear and mesenchymal) in animal models of heart failure and in humans (BONAMI and MESAMI clinical trials).
To take advantage of the paracrine properties of BMMSC and avoid their intracardiac injection, we then developed a bioengineering strategy based on the administration of BMMSCs included in alginate and alginate/chitosan biomatrices.
Our results showed that i) BMMSCs maintain their paracrine properties after inclusion in biomatrices and ii) administration of encapsulated BMMSCs improves cardiac function. Based on these results, we are optimizing the alginate/chitosan (available as Clinical Grade Preparations) scaffolds to enhance the retention, survival and paracrine activity of BMMSC.