Kavli Affiliate: Denis Wirtz
| Authors: Bartholomew Starich, Fan Yang, Derin Tanrioven, Heng-Chung Kung, Joanne Baek, Praful R. Nair, Pratik Kamat, Nico Macaluso, Joon Eoh, Kyu Sang Han, Luo Gu, Sean Sun, Pei-Hsun Wu, Denis Wirtz and Jude M. Phillip
| Summary:
Cellular senescence is a major driver of aging and disease. Here we show that substrate stiffness modulates the emergence and magnitude of senescence phenotypes post induction. Using a primary dermal fibroblast model of senescence, we show that decreased substrate stiffness accelerates cell-cycle arrest during senescence development and regulate expression of conventional protein-based biomarkers of senescence. We found that the expression of these senescence biomarkers, namely p21WAF1/CIP1 (CDKN1a) and p16INK4a (CDKN2a) are mechanosensitive and are in-part regulated by myosin contractility through focal adhesion kinase (FAK)-ROCK signaling. Interestingly, at the protein level senescence-induced dermal fibroblasts on soft substrates (0.5 kPa) do not express p21WAF1/CIP1 and p16INK4a at comparable levels to induced cells on stiff substrates (4GPa). However, cells do express CDKN1a, CDKN2a, and IL6 at the RNA level across both stiff and soft substrates. When cells were transferred from soft to stiff substrates, senescent cells recover an elevated expression expressing p21WAF1/CIP1 and p16INK4a at levels comparable to senescence cells on stiff substrates, pointing to a mechanosensitive regulation of the senescence phenotypes. Together, our results indicate that the induction of senescence programs depends critically on the mechanical environments of cells and that senescent cells actively respond and adapt to changing mechanical cues.