The Effects of the Extracellular Matrix Microstructural Deformation on the Nuclear Aspect Ratio of the Tricuspid Valve Interstitial Cells: A Computational Study

Objective: The normal function of the tricuspid valve interstitial cells (VICs) is essential for maintaining the biomechanical integrity of the valve, especially the production of collagen for the valve extracellular matrix (ECM). Researchers have shown that the VIC nuclear shape changes due to mechanical overloading. Nuclear shape alterations have also been associated to gene expressions and protein synthesis in many different types of cells. The objective of this study was to demonstrate how tissue-level mechanical overload can be transferred to sub-cellular level nuclear deformation. Methods: We employed a multiscale computational approach to predict ECM microstructural changes under different mechanical loading conditions. An ellipsoidal geometry was assumed for the cell nucleus and DAPI-stained images were used to reconstruct surfaces of the nuclei to obtain an average initial nuclear aspect ratio (NAR) of 2.20 for the tricuspid valve anterior leaflet. Three case studies were conducted with the initial configuration of the nuclei assumed to be inclined at 0º, 45º, and 90º to the main ECM fiber direction. Results: In all simulated cases, an initial rapid increase in NAR with the force was observed (Fig. 1). Such an increase can be associated to the gradual uncrimping of the ECM fibers. Once the majority of the fibers became straight, NAR response with load plateaued. The increase in NAR with tissue level mechanical loading was more pronounced in the nuclei that were more closely aligned with the ECM fibers. Conclusions: We observed a non-linear relation between the tissue-level mechanical loading and changes in the VIC NAR. Such NAR changes were affected by the relative orientation of the cells and the ECM microstructure. Since certain gene expression and protein syntheses have been linked directly to the nuclear shape alterations, we expect to employ this framework to predict VIC remodeling responses in physiological and pathological overloads.