Nuclear stiffness regulates cellular senescence via YAP dependent mechanotransduction.

Abstract

The cellular nucleus is a critical mechanosensing organelle subjected to and integrating cytoskeletal forces for biochemical responses. Changes in nuclear stiffness influence this mechanotransduction, and pathologies involving accelerated cellular senescence such as Hutchison Gilford Progeria Syndrome (HGPS) have previously been shown to increase nuclear stiffness, but if this plays a causal role in cellular senescence is unclear. Here, we demonstrate that changes in nuclear stiffness directly influence accelerated or delayed cellular senescence through YAP-mediated modulation of human telomerase (hTERT) expression. To study how nuclear stiffness regulates hTERT expression, first, we established that the nuclear stiffness increases with culture age, observing that nuclear stiffening in time for progeria cells was approximately 40% faster than in wildtype (WT) human dermal fibroblast cells. hTERT is a downstream protein of YAP, and we hypothesized that nuclear stiffness regulates hTERT expression via YAP dependent mechanotransduction. By modulating nuclear stiffness via lamin A/C expression in WT and progeria cells, we then identified that nuclear stiffness directly influences YAP nuclear localization. Using both nuclear mechanics and chemical compounds to manipulate YAP shuttling, we found that YAP nuclear localization inversely influences the cellular senescence biomarker senescence-associated β-galactosidase (SA β-gal) and that in turn telomerase expression is inversely related to SA β-gal expression. These results identify new strategies for diagnosing aging disorders via nuclear mechanics and suggest possible future strategies that could mechanically correct dysfunctional nuclear mechanics.