The study of neuro-vascular interactions in the developing heart

心脏发育中神经血管相互作用的研究

• 批准号: 10929142
• 负责人: Yoh-suke Mukouyama
• 金额: $ 71.86万
• 依托单位: NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10929142
• 关键词: 3-Dimensional; Adrenergic Agents; Affect; Axon; Biological Models; Blood Vessels; Cardiac; Cardiac Myocytes; Cells; Coculture Techniques; Connexin 43; Cyclic AMP; Data; Diameter; Endothelial Cells; Epicardium; Fibroblasts; Gap Junctions; Gene Expression; Genes; Goals; Heart; Imaging Techniques; Ion Channel; Laboratory Study; Modeling; Molecular; Myocardial; Nerve; Neurons; Organ; Organ Culture Techniques; Pattern; Play; Proliferating; Property; Regulation; Role; Sarcomeres; Signal Pathway; Signal Transduction; Smooth Muscle Myocytes; Structure; Structure of left gastric vein; System; Vascular Smooth Muscle; Venous; coronary vasculature; genetic manipulation; improved; induced pluripotent stem cell; nerve supply; neuronal guidance; neurovascular; postnatal

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.

心肌细胞分化和成熟的交感神经控制。 我们已经开发了一个3D共培养系统，该系统具有与交感神经元，内皮细胞和心外膜细胞的IPS衍生的IPS衍生的心肌细胞，并发现共培养的心肌细胞改善了功能，结构和基因表达性能（Kowalski et al an al an al an al.2022222）。具有交感神经元的共培养上调了多发性心脏结构和与心肌细胞成熟相关的离子通道基因，增加了肌节组织和连接蛋白43（CX43）-GAP连接，并显示出更大的Ca2+瞬态及时膨胀。有趣的是，将其他非心脏细胞（例如ECS和心外膜衍生的VSMC和成纤维细胞）纳入我们的共培养模型并未产生进一步的心肌细胞成熟。此外， - 肾上腺素信号的激活不足以上调心肌细胞成熟的基因。这些数据表明，交感神经元对发展心肌细胞有重大影响，并通过与心肌细胞直接关联在心肌细胞成熟中起重要作用。鉴于心肌细胞成熟主题的重要性以及我们在约翰·霍普金斯（Johns Hopkins）的合作者对交感神经神经元对心肌细胞对纳塔尔阶层后心肌细胞繁殖的影响的研究至关重要，研究自主神经支配对心肌细胞成熟的作用非常有趣且及时。我们目前正在尝试在交感神经元中为肾上腺能信号传导途径设置光激活的调节，并检查交感神经激活是否影响心肌细胞的成熟。这些研究将为发展心脏的交感神经的功能后果提供一个机械框架。

项目成果

Ultrahigh-Frequency Echocardiography of Autonomic Devoid Phox2B Homozygous Embryos Does Not Reveal a Significant Cardiac Phenotype before Embryo Death.

• DOI: 10.1016/j.ultrasmedbio.2020.11.008
• 发表时间: 2021-03
• 期刊: Ultrasound in medicine & biology
• 影响因子: 2.9
• 作者: Mokshagundam D;Kowalski W;Garcia-Pak I;Klaunberg B;Nam J;Mukouyama YS;Leatherbury L
• 通讯作者: Leatherbury L