Intranuclear mesoscale viscoelastic changes during osteoblastic differentiation of human mesenchymal stem cells

Cell nuclei behave as viscoelastic materials. Dynamic regulation of the viscoelastic properties of nuclei in living cells is crucial for diverse biological and biophysical processes, specifically for intranuclear mesoscale viscoelasticity, through modulation of the efficiency of force propagation to the nucleoplasm and gene expression patterns. However, how the intranuclear mesoscale viscoelasticity of stem cells changes with differentiation is unclear and so is its biological significance. Here, we quantified the changes in intranuclear mesoscale viscoelasticity during osteoblastic differentiation of human mesenchymal stem cells. This analysis revealed that the intranuclear region is a viscoelastic solid, probably with a higher efficiency of force transmission that results in high sensitivity to mechanical signals in the early stages of osteoblastic differentiation. The intranuclear region was noted to alter to a viscoelastic liquid with a lower efficiency, which is responsible for the robustness of gene expression toward terminal differentiation. Additionally, evaluation of changes in the mesoscale viscoelasticity due to chromatin decondensation and correlation between the mesoscale viscoelasticity and local DNA density suggested that size of gap and flexibility of chromatin meshwork structures, which are modulated depending on chromatin condensation state, determine mesoscale viscoelasticity, with various rates of contribution in different differentiation stages. Given that chromatin within the nucleus condenses into heterochromatin as stem cells adopt a specific lineage by restricting transcription, viscoelasticity is perhaps a key factor in cooperative regulation of the nuclear mechanosensitivity and gene expression pattern for stem cell differentiation.