Poster session 1Cell growth, differentiation and stem cells - Heart72Understanding the metabolism of cardiac progenitor cells: a first step towards controlling their proliferation and differentiation?73Expression of pw1/peg3 identifies a new cardiac adult stem cell population involved in post-myocardial infarction remodeling74Long-term stimulation of iPS-derived cardiomyocytes using optogenetic techniques to promote phenotypic changes in E-C coupling75Benefits of electrical stimulation on differentiation and maturation of cardiomyocytes from human induced pluripotent stem cells76Constitutive beta-adrenoceptor-mediated cAMP production controls spontaneous automaticity of human induced pluripotent stem cell-derived cardiomyocytes77Formation and stability of T-tubules in cardiomyocytes78Identification of miRNAs promoting human cardiomyocyte proliferation by regulating Hippo pathway79A direct comparison of foetal to adult epicardial cell activation reveals distinct differences relevant for

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Emerging evidence supports a mandatory metabolic shift from glycolysis to oxidative phosphorylation during stem cells differentiation. In this study, we investigate cardiac progenitor cells (CPC) metabolic adaptations to a hypoxic environment and the bioenergetic transition underlying cardiomyocyte differentiation process. We intend to identify key metabolic regulators which could be modulated to promote survival/proliferation/differentiation of CPC during the early steps of therapeutic interventions. Under normoxia (21%O2), glucose consumption and lactate release were significantly higher in Sca1+ CPC (isolated from adult mouse hearts by MACS separation) than in neonatal rat cardiac myocytes (NRCM) with a ratio of 2 moles of lactate released per mole of glucose supporting a high glycolytic metabolism. Glucose consumption and lactate release were increased in hypoxia (1%O2), together with increased abundance of the monocarboxylic transporter MCT4 (lactate efflux mediator), of Glut-1 and of PFKFB3 (key regulator of glycolytic rate). BrdU incorporation in CPC was critically dependent on pyruvate, glucose and glutamine availability under normoxia and hypoxia. Oxygen consumption analysis indicated that CPC and NRCM display active mitochondrial ATP production. Notably, basal and maximal respiration were higher in NRCM compared to CPC. Consistently, mitochondrial populations were differentially active in both cell types, as reflected by a 40% decrease in tetramethylrhodamine methyl ester staining intensity (flow cytometry) in CPC compared to NRCM. Moreover, the expression of TOM20 (translocase of outer mitochondrial membrane) was also 50% lower in CPC compared to NRCM. This CPC phenotype dramatically changed upon differentiation (azacytidine/TGFβ/ascorbic acid), with a reduction by third of glucose consumption and lactate release compared to proliferative CPC, in parallel with increased expression of sarcomeric proteins (cardiac TnI, alpha-sr-actinin). In conclusion, despite active mitochondrial ATP production, undifferentiated CPC exhibit lower respiratory reserve than cardiac myocytes, which correlates with a less abundant mitochondrial network. However, they exhibit aerobic glycolysis and lactate production, which further increased under hypoxia together with (HIF-1α dependent) PFKFB3, Glut-1 and MCT4 to eliminate the excess of intracellular lactate. Such glycolytic activity, together with glutamine metabolism supports their proliferation but is dramatically downregulated upon differentiation. This may open the way for pharmacological modulation of the survival/differentiation of CPC for cell therapeutic repair through their mitochondrial fusion and biogenesis.

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