Center for Cardiovascular Simulation, Institute for Computational Engineering and Sciences (ICES), Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX 78712, USA.
School of Aerospace and Mechanical Engineering, The University of Oklahoma, Norman, OK 73019, USA.
J R Soc Interface. 2017 Oct;14(135). doi: 10.1098/rsif.2017.0580.
Mechanical stress is one of the major aetiological factors underlying soft-tissue remodelling, especially for the mitral valve (MV). It has been hypothesized that altered MV tissue stress states lead to deviations from cellular homeostasis, resulting in subsequent cellular activation and extracellular matrix (ECM) remodelling. However, a quantitative link between alterations in the organ-level state and based mechanobiology studies has yet to be made. We thus developed an integrated experimental-computational approach to elucidate MV tissue and interstitial cell responses to varying tissue strain levels. Comprehensive results at different length scales revealed that normal responses are observed only within a defined range of tissue deformations, whereas deformations outside of this range lead to hypo- and hyper-synthetic responses, evidenced by changes in α-smooth muscle actin, type I collagen, and other ECM and cell adhesion molecule regulation. We identified MV interstitial cell deformation as a key player in leaflet tissue homeostatic regulation and, as such, used it as the metric that makes the critical link between responses to simulated equivalent behaviour. Results indicated that cell responses have a delimited range of deformations that maintain a homeostatic response, suggesting that deviations from this range may lead to deleterious tissue remodelling and failure.
机械应力是软组织重塑的主要病因之一，特别是对于二尖瓣 (MV)。人们假设 MV 组织的应力状态发生改变会导致细胞内稳态的偏离，从而导致随后的细胞激活和细胞外基质 (ECM)重塑。然而，器官水平状态的改变与基于机械生物学的研究之间的定量联系尚未建立。因此，我们开发了一种集成的实验计算方法来阐明 MV 组织和间质细胞对不同组织应变水平的反应。在不同的尺度上进行的综合结果表明，只有在组织变形的定义范围内才会观察到正常反应，而超出此范围的变形会导致低合成和高合成反应，这表现为 α-平滑肌肌动蛋白、I 型胶原和其他 ECM 及细胞黏附分子调节的变化。我们确定 MV 间质细胞的变形是小叶组织稳态调节的关键因素，因此将其用作模拟等效行为的响应之间建立关键联系的指标。结果表明，细胞的响应有一个限定的变形范围，以维持一个稳态响应，这表明超出这个范围可能导致有害的组织重塑和失效。
