Designing biomaterials for controlled cardiac stem cell differentiation and enhanced cell therapy in the treatment of congestive heart failure

Abstract : Cell therapy is a promising strategy to help regenerate the damaged heart. Recent studies have placed a lot of hopes in embryonic stem cells and our lab had previously found a way to differentiate them into cardiac progenitors, cells that can only differentiate into cardiomyocyte, endothelial cells or smooth muscle cells. This early commitment decreases their proliferative capabilities, yet maintains their plasticity for better integration inside the host tissue. However, clinical and pre-clinical injection studies did not really meet the expectations. Even though slight improvements in cardiac function were demonstrated, very low cell viability has been observed, as well as a very low retention of the cells inside the myocardium. To address this problem, my PhD projects not only focus on the design of new biomaterials to act as a vehicle for cell delivery and retention in the infarcted area, but also on the design of biomaterials that control the cellular environment during the differentiation of pluripotent stem cells into cardiomyocytes. Going back and forth between the labs and the clinics, we first developed new techniques for the fabrication and the characterization of a cell-laden fibrin patch that is now undergoing phase I clinical trial. From the approved clinical formulation, we then propose new blends of clinical materials that will eventually improve the maturation of the cardiac progenitors once grafted onto the failing heart. In this perspective, we developed an in vitro model to investigate the combined influence of matrix elasticity and topographical confinement on stem cell differentiation into cardiomyocytes. By using microfabrication techniques to pattern pluripotent stem cells on substrates of controlled stiffness, we demonstrate that even using a widely recognized chemical-based protocol to modulate signaling cascades during differentiation, much heterogeneity emerges depending on the cellular physical environment. We thus extracted the main features that led to controlled and reproducible cardiac differentiation and applied it to the fabrication of next generation of multi-layered anisotropic cardiac patches in compliances with clinical requirements. This work opens new routes to high-scale production of cardiomyocytes and the fabrication of cell-laden or cell-free clinical patches.
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Yohan Farouz. Designing biomaterials for controlled cardiac stem cell differentiation and enhanced cell therapy in the treatment of congestive heart failure. Biomechanics [physics.med-ph]. Université Sorbonne Paris Cité, 2015. English. ⟨NNT : 2015USPCB114⟩. ⟨tel-01541523⟩

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