Understanding the Consequences of Cell-to-Cell Mechanical Variation in the Heart

心脏由数百万个单独的肌肉细胞组成，它们必须以协调的方式收缩在一起以泵送血液。因为细胞必须一起工作，所以它们彼此电连接以同步跳动。人们可能已经预料到，收缩的强度和速度在相邻的细胞中是相同的。然而，当细胞分离时，它们的机械行为却惊人地不同。目前尚不清楚这些细胞，是如此不同的机械，仍然一起工作，以产生有效的泵。在这个项目中，将在心脏组织的小样本中测量细胞间的机械变化。根据这些信息，可以创建心脏组织的精确计算机模型。该模型将有助于解释细胞间变异如何影响整体组织功能。最后，该模型的预测将在工程心脏组织中进行测试，这允许调整和研究细胞变异性的数量。这项工作意义重大，因为细胞变异性往往会随着年龄的增长和某些疾病而增加。更清楚地了解变异如何影响正常和异常的心脏功能，最终可能会激发对目前无法治愈的心脏疾病的有效治疗。新的数据表明，来自健康心脏组织的相邻细胞显示出实质性的机械差异。这种“微尺度异质性”如何影响大块心肌的机械功能从未被研究过，但具有深远的意义。该项目通过检验两个假设来检验微尺度异质性的影响：（1）即使在正常心脏中，它也对心肌收缩有明显的影响，以及（2）超过正常限度的微尺度异质性增加会破坏组织功能。在测量微尺度不均匀性的性质和范围后，将使用一种新的多尺度计算模型预测其对组织力学行为的影响。该模型由嵌入有限元网格中的生物解剖学详细肌肉收缩模型组成，用于模拟三维组织力学。该模型产生的预测可以通过遗传操纵工程心肌组织模拟物中的细胞异质性并测量其生物力学特性来进行测试。相邻但功能不同的肌肉细胞网络的聚集行为具有显示新的和令人惊讶的涌现特性的潜力。如果被证明是正确的，这些假设将改变目前关于心肌松弛和组织稳态决定因素的观点，同时揭示疾病机制。

The heart is made of millions of individual muscle cells that must contract together in a coordinated way to pump blood. Because the cells must work together, they are electrically connected to one another to synchronize beating. It might have been expected that the strength and speed of contraction would be the same in neighboring cells. However, when cells are separate, their mechanical behavior is surprisingly different. It is not clear how these cells, being so different mechanically, still work together to produce efficient pumping. In this project, cell-to-cell mechanical variation will be measured in small samples of heart tissue. From this information, an accurate computer model of heart tissue can be created. The model will help explain how cell-to-cell variation impacts overall tissue function. Finally, the predictions made by the model will be tested in engineered heart tissues, which allow the amount of cell variability to be adjusted and studied. This work is significant because cell variability tends to increase with aging and in certain diseases. A clearer understanding of how variation contributes to normal and abnormal heart function could ultimately inspire effective treatments for cardiac disorders that are currently incurable. New data suggest that adjacent cells from healthy heart tissue display substantial mechanical differences. How this 'microscale heterogeneity' affects the mechanical function of bulk myocardium has never been studied, but has far-reaching implications. This project examines the impact of microscale heterogeneity by testing two hypotheses: (1) That it has an appreciable influence on myocardial contraction even in normal hearts, and (2) That increasing microscale heterogeneity beyond normal limits disrupts tissue function. After measuring the nature and scope of microscale heterogeneity, its effects on tissue mechanical behavior will be predicted using a novel multiscale computational model. This model is comprised of a biophysically detailed muscle contraction model embedded in a finite element mesh for simulation of three-dimensional tissue mechanics. The predictions produced by the model can be tested by genetically manipulating cellular heterogeneity in engineered myocardial tissue mimics and measuring their biomechanical characteristics. The aggregate behavior of a network of adjacent but functionally different muscle cells has the potential of displaying new and surprising emergent properties. If proven correct, these hypotheses would shift current opinion on the determinants of myocardial relaxation and tissue homeostasis while shedding light on disease mechanisms.