A Multiscale Model to Predict Neuronal Cell Deformation with Varying Extracellular Matrix Stiffness and Topography

Neuronal cells are sensitive to mechanical properties of extracellular matrix (ECM) such as stiffness and topography. Cells contract and exert a force on ECM to detect the microenvironment, which activates the signaling pathway to influence the cell functions such as differentiation, migration, and proliferation. There are numerous transmembrane proteins that transmit signals; however, integrin and neural cellular adhesion molecules (NCAM) play an important role in sensing the ECM mechanical properties. Mechanotransduction of cell-ECM is the key to understand the influence of ECM stiffness and topography; therefore, in this study, we develop a multiscale computational model to investigate these properties.

This model couples the molecular behavior of integrin and NCAM to microscale interactions of neuronal cell and the ECM. We analyze the atomistic/molecular behavior of integrin and NCAM due to mechanical stimuli using steered molecular dynamics. The microscale properties of the neuronal cell and the ECM are simulated using non-linear finite element analysis by applying cell contractility.

We predict that by increasing the ECM stiffness, a neuronal cell exerts greater stress on the ECM. However, this stress reaches a saturation value for a threshold stiffness of ECM, and the saturation value is affected by the ECM thickness, topography, and clustering of integrin and NCAMs. Further, the ECM topography leads to asymmetric stress and deformation in the neuronal cell. Predicted stress distribution in neuronal cell and ECM are consistent with experimental results from the literature.

The multiscale computational model will guide in selecting the optimal ECM stiffness and topography range for in vitro studies.