The study of neuro-vascular interactions in the developing heart

National Heart, Lung, And Blood Institute

Investigators

Linked publications, trials & patents

Abstract

Sympathetic control of cardiomyocyte differentiation and maturation. We have developed a 3D co-culture system of GFP- and GCaMP6-expressing iPS-derived cardiomyocytes with sympathetic neurons, endothelial cells, and epicardial cells, and have discovered that the co-cultured cardiomyocytes improve functional, structural and gene expression properties (Kowalski et al. Front Cell Dev Biol 2022). The co-culture with sympathetic neurons up-regulated multiple cardiac structure and ion channel genes related to cardiomyocyte maturation, increased sarcomere organization and connexin 43 (Cx43)-gap junctions, and showed greater Ca2+ transient amplitudes. Interestingly, incorporation of additional non-cardiac cells such as ECs and epicardium-derived VSMCs and fibroblasts into our co-culture model did not produce further cardiomyocyte maturation. Moreover, activation of -adrenergic signaling was not sufficient to up-regulate the genes for cardiomyocyte maturation. These data suggest that sympathetic neurons have a significant impact on developing cardiomyocytes and play an important role in cardiomyocyte maturation by direct association with cardiomyocytes. Examining the role(s) of autonomic innervation on cardiomyocyte maturation is highly interesting and timely, given the paramount importance of the topic of cardiomyocyte maturation and the study led by our collaborators at Johns Hopkins on the impact of sympathetic neurons on cardiomyocyte proliferation during postnatal stages (Tampakakis et al. Sci Adv 2021). We are currently attempting to set up the photo-activated regulation of intracellular cAMP for the adrenergic signaling pathway in sympathetic neurons, and to examine whether sympathetic activation affects cardiomyocyte maturation. These studies will provide a mechanistic framework for the functional consequence of sympathetic innervation in the developing heart.