Cardiac excitation–contraction coupling (ECC) is the orchestrated process of initial myocyte electrical excitation, which leads to calcium entry, intracellular trafficking, and subsequent sarcomere shortening and myofibrillar contraction. Neurohumoral β-adrenergic signaling is a well-established mediator of ECC; other signaling mechanisms, such as paracrine signaling, have also demonstrated significant impact on ECC but are less well understood. For example, resident heart endothelial cells are well-known physiological paracrine modulators of cardiac myocyte ECC mainly via NO and endothelin-1. Moreover, recent studies have demonstrated other resident noncardiomyocyte heart cells (eg, physiological fibroblasts and pathological myofibroblasts), and even experimental cardiotherapeutic cells (eg, mesenchymal stem cells) are also capable of altering cardiomyocyte ECC through paracrine mechanisms. In this review, we first focus on the paracrine-mediated effects of resident and therapeutic noncardiomyocytes on cardiomyocyte hypertrophy, electrophysiology, and calcium handling, each of which can modulate ECC, and then discuss the current knowledge about key paracrine factors and their underlying mechanisms of action. Next, we provide a case example demonstrating the promise of tissue-engineering approaches to study paracrine effects on tissue-level contractility. More specifically, we present new functional and molecular data on the effects of human adult cardiac fibroblast conditioned media on human engineered cardiac tissue contractility and ion channel gene expression that generally agrees with previous murine studies but also suggests possible species-specific differences. By contrast, paracrine secretions by human dermal fibroblasts had no discernible effect on human engineered cardiac tissue contractile function and gene expression. Finally, we discuss systems biology approaches to help identify key stem cell paracrine mediators of ECC and their associated mechanistic pathways. Such integration of tissue-engineering and systems biology methods shows promise to reveal novel insights into paracrine mediators of ECC and their underlying mechanisms of action, ultimately leading to improved cell-based therapies for patients with heart disease.

心脏兴奋－收缩偶联（ECC）是最初的心肌细胞电刺激的协调过程，可导致钙进入，细胞内运输以及随后的肌小节缩短和肌原纤维收缩。神经体液中的β-肾上腺素信号传导是一种公认​​的ECC介体。其他信号传导机制（例如旁分泌信号传导）也已显示出对ECC的显着影响，但人们对其了解较少。例如，驻留的心脏内皮细胞主要通过NO和内皮素-1是心肌细胞ECC的众所周知的生理旁分泌调节剂。此外，最近的研究表明，其他常驻非心肌细胞心脏细胞（例如，生理性成纤维细胞和病理性肌成纤维细胞），甚至是实验性心脏治疗细胞（例如，间充质干细胞）还能够通过旁分泌机制改变心肌细胞ECC。在这篇综述中，我们首先关注驻留和治疗性非心肌细胞在旁分泌介导的作用下对心肌肥大，电生理和钙处理的影响，它们均可以调节ECC，然后讨论有关关键旁分泌因子及其潜在机制的最新知识。行动。接下来，我们提供一个案例示例，展示组织工程方法研究旁分泌对组织水平收缩力的作用的希望。进一步来说，我们提供了有关人类成年心脏成纤维细胞条件培养基对人类工程心脏组织收缩力和离子通道基因表达的影响的新功能和分子数据，这些数据通常与以前的鼠类研究一致，但也暗示可能存在物种特异性差异。相比之下，人类皮肤成纤维细胞的旁分泌分泌对人类工程心脏组织的收缩功能和基因表达没有明显的影响。最后，我们讨论了系统生物学方法，以帮助确定ECC的关键干细胞旁分泌介质及其相关的机制途径。组织工程学和系统生物学方法的这种整合显示出有望揭示ECC旁分泌介质及其潜在作用机制的新颖见解，