PDF(Pubmed)
Abstract：
Within the aortic valve (AV) leaflet exists a population of interstitial cells (AVICs) that maintain the constituent tissues by extracellular matrix (ECM) secretion, degradation, and remodeling. AVICs can transition from a quiescent, fibroblast-like phenotype to an activated, myofibroblast phenotype in response to growth or disease. AVIC dysfunction has been implicated in AV disease processes, yet our understanding of AVIC function remains quite limited. A major characteristic of the AVIC phenotype is its contractile state, driven by contractile forces generated by the underlying stress fibers (SF). However, direct assessment of the AVIC SF contractile state and structure within physiologically mimicking three-dimensional environments remains technically challenging, as the size of single SFs are below the resolution of light microscopy. Therefore, in the present study, we developed a three-dimensional (3D) computational approach of AVICs embedded in 3D hydrogels to estimate their SF local orientations and contractile forces. One challenge with this approach is that AVICs will remodel the hydrogel, so that the gel moduli will vary spatially. We thus utilized our previous approach (Khang et al. 2023, \"Estimation of Aortic Valve Interstitial Cell-Induced 3D Remodeling of Poly (Ethylene Glycol) Hydrogel Environments Using an Inverse Finite Element Approach,\" Acta Biomater., 160, pp. 123-133) to define local hydrogel mechanical properties. The AVIC SF model incorporated known cytosol and nucleus mechanical behaviors, with the cell membrane assumed to be perfectly bonded to the surrounding hydrogel. The AVIC SFs were first modeled as locally unidirectional hyperelastic fibers with a contractile force component. An adjoint-based inverse modeling approach was developed to estimate local SF orientation and contractile force. Substantial heterogeneity in SF force and orientations were observed, with the greatest levels of SF alignment and contractile forces occurring in AVIC protrusions. The addition of a dispersed SF orientation to the modeling approach did not substantially alter these findings. To the best of our knowledge, we report the first fully 3D computational contractile cell models which can predict locally varying stress fiber orientation and contractile force levels.
摘要：
直接评估三维（3D）细胞单应力纤维（SF）的结构和功能在技术上仍然具有挑战性。由于SF特征尺寸远低于光学显微镜的分辨率。因此,需要计算方法来估计SFs在各种状态下的有效结构和收缩行为。在这里，我们开发了嵌入3D水凝胶中的收缩AVIC的3D计算模型，以估计其SF方向和收缩力。我们首先利用我们的水凝胶逆模型[1]来估计局部水凝胶的机械性能。接下来,我们开发了两个基于有限元的逆模型，利用单方向和分散方向的SF结构。两种模型都估计，最大的SF力发生在中航工业的突起处。第二个模型估计，最大程度的SF对齐发生在中航工业的突起处，而中航工业的中部显示出较少对齐的纤维。据我们所知,我们报告了第一个完全3D计算的收缩细胞模型，该模型可以预测局部变化的应力纤维方向和收缩力水平。展望未来,这些模型可以帮助我们在亚细胞长度尺度上加深对SF功能的理解,并且可以纳入组织/器官功能的多尺度模型.
