A non-dimensional, two-parameter mechanical model reveals alterations in nuclear mechanics upon Hepatitis C Virus infection

Abstract

Morphology of the nucleus is an important regulator of gene-expression. Nuclear morphology is in turn a function of the forces acting on it and the mechanical properties of the nuclear envelope. Here, we present a two-parameter, non-dimensional mechanical model of the nucleus that reveals a relationship among nuclear shape parameters such as projected area, surface area and volume. Our model fits the morphology of individual nuclei and predicts the ratio between forces and modulus in each nucleus. We analyzed the changes in nuclear morphology of liver cells due to Hepatitis C Virus (HCV) infection using this model. The model predicted a decrease in the elastic modulus of the nuclear envelope and an increase in the pre-tension in cortical actin as the causes for the change in nuclear morphology. These predictions were validated biomechanically by showing that liver cells expressing HCV proteins possessed enhanced cellular stiffness and reduced nuclear stiffness. Concomitantly, cells expressing HCV proteins showed down-regulation of lamin-A,C and up-regulation of actin, corroborating the predictions of the model. Our modelling assumptions are broadly applicable to adherent, monolayer cell cultures making the model amenable to investigate changes in nuclear mechanics due to other stimuli by merely measuring nuclear morphology. Towards this, we present two techniques, graphical and numerical, to use our model for predicting physical changes in the nucleus.