Aging and Differentiation Alter Nuclear Mechanobiology

By studying dense connective tissue, scientists are discovering ways that the cell nucleus adapts and changes in response to the administration of force, time, and differentiation.

Robert Mauck, PhD, from the University of Pennsylvania, discussed how aging and differentiation alter nuclear mechanobiology at the 2014 American Society of Bone and Mineral Research Conference in Houston, Texas

By studying microarchitecture, dense connective tissue engineers are trying to understand how they can create engineered tissue that functions similarly to natural tissue. Scaffold architecture provides mechanical anisotropy and organizes cells into a matrix. Connective tissue engineers then attempt to build fibrous tissues, transforming aligned scaffolds into functionalized and anatomic assemblies.

In order to engineer tissues with mechanical properties that are similar to the tissues that they replace, in vivo stimuli must be taken into account. Scientists must replicate the mechanical stimuli that these tissues encounter and the various stresses and strains to which the cells and their microstructures are exposed.

Multi-scale and region-dependent strain transfers to the cellular microenvironment, transferring from the matrix to the nucleus. A force on the outside of the cell transmits from the contractile cytoskeleton (function in cell contractility) to lamins (function in nuclear deformation) to nesprins (link nucleus to the actin cytoskeleton). In nesprin knock-out animals, where the nucleus is disconnected from the actin cytoskeleton, the transfer of strain to the nucleus fails. Lamin level scales with tissue stiffness.

Knowing that Lamin A increases with tissue stiffness and meniscus stiffness increases with age, the researchers became interested in how lamin and nesprin change with age. They found that Lamin A and nesprin also increase with age in the meniscus, correlating with stiffness of tissue. When the cells are mechanically stretched, fetal, juvenile, and adult nuclei all deform to the same extent. This suggests that there is some coordination of nuclear mechanics and connectivity. It appears that strain transfer from the extracellular matrix to the nucleus utilizes established cellular machinery, and nuclear stiffness and nuclear connectivity scale with age.

Mesenchymal stem cells are widely used for tissue engineering. These cells are highly proliferative with multi-lineage potential, active differentiation and mechano-reponsive scaffolding.

The researchers began asking if cytoskeleton-to-nucleus strain transfer could be applied to mesenchymal stem cells. They found that these cells use established mechanisms to mediate nuclear strain transfer on aligned surfaces and the nuclei don’t deform like naïve cells when mesenchymal stem cells differentiate.

They did not discover a change in contractility or in connectivity, suggesting that there may be a difference in nuclear structure and content associated with differentiation. Dr Mauck said that he is currently exploring the ways that mechanically loading alone can cause nuclear re-organization in the previously undifferentiated cell.