Co-culture with supporting cells of the developing heart promotes maturation of induced pluripotent stem cell-derived cardiomyocytes

Authors

• IH Garcia-Pak
• W Li
• H Uosaki
• E Tampakakis
• J Zou
• Y Lin
• Y Mukouyama

Abstract

The successful derivation of cardiomyocytes from human induced pluripotent stem cells (iPSC) has opened up exciting possibilities for clinical applications such as tissue engineering, disease modeling, and drug toxicity testing. The limitation for such applications is that these cardiomyocytes are immature; they appear and behave like fetal cardiomyocytes. In this study we aim to harness the potential for personalized medicine with these cells and achieve a more accurate, mature model of the heart. Studies in heart development clearly demonstrate that multiple cell types including endothelial cells, sympathetic neurons, and epicardium-derived fibroblasts and vascular smooth muscle cells associate with and provide signals to the developing cardiomyocytes. Here, we use a co-culture system with iPSC-derived cardiomyocytes (iPSC-CMs) to mimic the complex cell-cell interactions in the heart development. We cultured iPSC-CMs, directly associated with epicardial cells and sympathetic ganglia from mouse embryos and human umbilical vein endothelial cells for 30 days. We found that the iPSC-CMs co-cultured with supporting cells exhibit significant maturation in cardiomyocyte structure as indicated in mitochondria shape, z-band organization, and gap junction distribution. In addition, these cells were found to up-regulate cardiac genes highly expressed in human adult cardiomyocytes in comparison to standard culture and growth factor controls. Among all cellular components in this co-culture system, we focus on the role of sympathetic neurons in the cardiomyocyte maturation and are examining whether sympathetic activity influences cardiomyocyte structure and cardiac gene expression. These studies may benefit the field by providing a step forward toward mature cardiomyocyte application and therapies.

Scientific Focus Area: Cell Biology

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