Majkut Stephanie, Dingal P C Dave P, Discher Dennis E
Biophysical Engineering Laboratory, University of Pennsylvania, Philadelphia, PA 19104, USA; Physics and Astronomy Graduate Group, University of Pennsylvania, Philadelphia, PA 19104, USA.
Biophysical Engineering Laboratory, University of Pennsylvania, Philadelphia, PA 19104, USA.
Curr Biol. 2014 May 19;24(10):R495-501. doi: 10.1016/j.cub.2014.04.027.
Early in embryogenesis, the heart begins its rhythmic contractions as a tube that helps perfuse the nascent vasculature, but the embryonic heart soon changes shape and mechanical properties, like many other developing organs. A key question in the field is whether stresses in development impact the underlying gene circuits and, if so, how? Here, we attempt to address this question as we review the mechanical maturation of heart - and, to a limited extent, lung and blood - with a focus on a few key abundant structural proteins whose expression dynamics have been suggested to be directly sensitive to mechanical stress. In heart maturation, proliferating fibroblasts deposit increasing amounts of collagenous matrix in parallel with cardiomyocytes expressing more sarcomeric proteins that increase the contractile stress and strength of the tissue, which in turn pumps more blood at higher stress throughout the developing vasculature. Feedback of beating cardiomyocytes on the expression of matrix by fibroblasts seems a reasonable model, with both synthesis and turnover of matrix and contractile elements achieving a suitable balance. Based on emerging evidence for coiled-coil biopolymers that are tension-stabilized against degradation, a minimal network model of a dynamic cell-matrix interaction is proposed. This same concept is extended to nuclear mechanics as regulated by stress on the nuclear structural proteins called lamins, which are examined in part because of the prominence of mutations in these coiled-coil proteins in diseases of the heart, amongst other organs/tissues. Variations in lamin levels during development and across adult tissues are to some extent known and appear to correlate with extracellular matrix mechanics, which we illustrate across heart, lung, and blood development. The formal perspective here on the mechanochemistry of tissue development and homeostasis could provide a useful framework for 'big data' quantitative biology, particularly of stress-sensitive differentiation, maturation, and disease processes.
在胚胎发育早期，心脏作为一根有助于为新生血管系统灌注血液的管道开始有节律地收缩，但与许多其他发育中的器官一样，胚胎心脏很快就会改变形状和力学特性。该领域的一个关键问题是发育过程中的应力是否会影响潜在的基因回路，如果是，又是如何影响的？在这里，我们试图回答这个问题，我们回顾了心脏以及在一定程度上肺和血液的力学成熟过程，重点关注一些关键的丰富结构蛋白，其表达动态已被认为对机械应力直接敏感。在心脏成熟过程中，增殖的成纤维细胞会沉积越来越多的胶原基质，与此同时，心肌细胞会表达更多肌节蛋白，从而增加组织的收缩应力和强度，进而在更高的应力下将更多的血液泵入整个发育中的血管系统。跳动的心肌细胞对成纤维细胞基质表达的反馈似乎是一个合理的模型，基质和收缩元件的合成与周转都达到了适当的平衡。基于对抵抗降解而张力稳定的卷曲螺旋生物聚合物的新证据，提出了一个动态细胞 - 基质相互作用的最小网络模型。这个相同的概念扩展到由称为核纤层蛋白的核结构蛋白上的应力调节的核力学，部分原因是这些卷曲螺旋蛋白的突变在心脏以及其他器官/组织的疾病中很突出，所以对其进行了研究。在发育过程中和成年组织中核纤层蛋白水平的变化在一定程度上是已知的，并且似乎与细胞外基质力学相关，我们在心脏、肺和血液发育过程中对此进行了说明。这里关于组织发育和稳态的机械化学的正式观点可以为“大数据”定量生物学提供一个有用的框架，特别是对于应力敏感的分化、成熟和疾病过程。
