Lee Chung-Hao, Carruthers Christopher A, Ayoub Salma, Gorman Robert C, Gorman Joseph H, Sacks Michael S
Center for Cardiovascular Simulation, Institute for Computational Engineering and Sciences (ICES), Department of Biomedical Engineering, The University of Texas at Austin, 201 East 24th Street, POB 5.236, 1 University Station C0200, Austin, TX 78712, USA.
Cardiac Rhythm Disease Management (CRDM) Clinical Specialist, Medtronic, Minneapolis, MN 55432, USA.
J Theor Biol. 2015 May 21;373:26-39. doi: 10.1016/j.jtbi.2015.03.004. Epub 2015 Mar 16.
Within each of the four layers of mitral valve (MV) leaflet tissues there resides a heterogeneous population of interstitial cells that maintain the structural integrity of the MV tissue via protein biosynthesis and enzymatic degradation. There is increasing evidence that tissue stress-induced MV interstitial cell (MVIC) deformations can have deleterious effects on their biosynthetic states that are potentially related to the reduction of tissue-level maintenance and to subsequent organ-level failure. To better understand the interrelationships between tissue-level loading and cellular responses, we developed the following integrated experimental-computational approach. Since in vivo cellular deformations are not directly measurable, we quantified the in-situ layer-specific MVIC deformations for each of the four layers under a controlled biaxial tension loading device coupled to multi-photon microscopy. Next, we explored the interrelationship between the MVIC stiffness and deformation to layer-specific tissue mechanical and structural properties using a macro-micro finite element computational model. Experimental results indicated that the MVICs in the fibrosa and ventricularis layers deformed significantly more than those in the atrialis and spongiosa layers, reaching a nucleus aspect ratio of 3.3 under an estimated maximum physiological tension of 150N/m. The simulated MVIC moduli for the four layers were found to be all within a narrow range of 4.71-5.35kPa, suggesting that MVIC deformation is primarily controlled by each tissue layer's respective structure and mechanical behavior rather than the intrinsic MVIC stiffness. This novel result further suggests that while the MVICs may be phenotypically and biomechanically similar throughout the leaflet, they experience layer-specific mechanical stimulatory inputs due to distinct extracellular matrix architecture and mechanical behaviors of the four MV leaflet tissue layers. This also suggests that MVICs may behave in a layer-specific manner in response to mechanical stimuli in both normal and surgically modified MVs.
在二尖瓣（MV）瓣叶组织的四层结构中，均存在着异质性的间质细胞群体，这些细胞通过蛋白质生物合成和酶促降解来维持MV组织的结构完整性。越来越多的证据表明，组织应力诱导的MV间质细胞（MVIC）变形会对其生物合成状态产生有害影响，这可能与组织水平维持功能的降低以及随后的器官水平功能衰竭有关。为了更好地理解组织水平负荷与细胞反应之间的相互关系，我们开发了以下综合实验-计算方法。由于体内细胞变形无法直接测量，我们在与多光子显微镜耦合的可控双轴拉伸加载装置下，对四层结构中每层的原位层特异性MVIC变形进行了量化。接下来，我们使用宏观-微观有限元计算模型，探究了MVIC刚度与变形之间的相互关系以及层特异性组织的力学和结构特性。实验结果表明，纤维层和心室层中的MVIC变形明显大于心耳层和海绵层中的MVIC变形，在估计的最大生理张力150N/m下，细胞核长宽比达到3.3。发现四层结构的模拟MVIC模量均在4.71-5.35kPa的狭窄范围内，这表明MVIC变形主要受每个组织层各自的结构和力学行为控制，而非MVIC的固有刚度。这一新颖的结果进一步表明，虽然MVIC在整个瓣叶中可能在表型和生物力学上相似，但由于四个MV瓣叶组织层不同的细胞外基质结构和力学行为，它们会经历层特异性的机械刺激输入。这也表明，在正常和手术改变的MV中，MVIC可能会以层特异性方式对机械刺激做出反应。
