Grant: Project Grant

All cells and tissues in our bodies all undergo change; two manifestations of this can be seen in cellular aging, and the ability of stem cells to differentiate into specialized cell types. These processes are ubiquitous in health physiology, yet in Hutchinson Gilford Progeria Syndrome (HGPS), accelerated cell aging is accompanied with a host of organ defects including a loss of fat tissue differentiation. While these processes are influenced by biochemical cues, they are also driven by mechanical stimuli and forces applied to cells. In particular we have found that compression of the cell nucleus by cell-driven or external mechanical forces is sufficient to trigger mechanotransduction pathways which dominate these processes. We have shown in our preliminary data that when the nucleus is compressed, a key factor known as Yes Associated Protein is more active, which retards cellular aging and induces the production of bone from stem cells. We hypothesize that as HGPS nuclei are stiffer, they are less easily compressed, leading to cellular aging and dysregulation of the differentiation process. This places the mechanical stiffness as an underexamined but crucial regulatory parameter in cellular aging and differentiation. In this study we will characterize the mechanical changes of the nucleus in healthy and HGPS cells during aging. We will examine how mechanics direct the biochemical nature of these processes, and tune them by modifying proteins which regulate the nuclear mechanics. Complementarily, we will apply varied forces to compress or swell the nucleus and bias these processes. We anticipate that mechanical manipulation of the nucleus will offer control of cellular aging and stem cell differentiation. The results from this study will help resolve mechanistic causes of aging and potential therapeutic targets as well as its impact on stem cell differentiation both in normal aging and in disease.