0413 : Cardiac differentiation of human pluripotent stem cells: the first step toward cardiac tissue engineering and cell therapy

Human pluripotent stem cells derived cardiomyoctyes are one the most promising cells for cardiac research, i.e. disease modeling, drug screening and cell therapy applications. Obtaining these cells is a critical step and has been the subject of many studies and publications. Recent advances in this field have shown that a sequential activation and inhibition of the Wnt pathway induces the differentiation of human pluripotent stem cells toward the cardiac lineage. This procedure can be achieved in a chemically-defined environment, and beating cells are obtained after 8 days.Several parameters of this protocol could still be improved. For example, the small molecules used (Wnt activators and inhibitors) are not approved by the health authorities, preventing their use in clinical studies. Moreover, there are no standard procedures to recover the cardiomyocytes after the differentiation protocol. Finally, late-stage differentiation to a totally matured ventricular cardiomyocyte population has not been achieved for the moment. The immature cardiac cells obtained have several differences compared to adult cardiomyocytes. There are, for example, mismatches in cell size and shape, gap junction, alignment and calcium handling ability. Raise these technological barriers could lead to new perspectives in the use of these cells.Our studies in this area have led us to develop innovative strategies to obtain, recover and to mature these cells. We have tested several FDAapproved drugs known to modulate the Wnt pathway in order to obtain a clinical- grade population cardiomyocytes. We also determined, using a combination of protease, the condition of recovery allowing the best survival rate and function of these cells. Finally, we improve the maturity of cardiomyocytes derived from pluripotent stem cells by tuning their micro-environment. Our results demonstrate the importance of the extracellular matrix composition and mechanical properties