Skelton Mackenzie L, Bhat Tanvi, Yu Ethan, Ofori Afia, Caliari Steven R
Department of Biomedical Engineering, University of Virginia, Charlottesville, VA 22903, USA.
Department of Psychology, University of Virginia, Charlottesville, VA 22903, USA.
bioRxiv. 2025 Aug 27:2025.08.22.671571. doi: 10.1101/2025.08.22.671571.
Senescent cell accumulation has been implicated in aging and fibrotic disease, which are both characterized by increased tissue stiffness. However, the direct connection between tissue mechanics and senescence induction remains disputed in the literature. Thus, this work investigates the influence of hydrogel stiffness and viscoelasticity in promoting fibroblast senescence both in combination with genotoxic stress and independently. We show that while lung fibroblast YAP signaling declines with senescence induction, senescent fibroblasts maintain their mechanosensing capabilities with increased YAP nuclear localization on higher stiffness hydrogels. Most notably, we find a unique role for hydrogel viscoelasticity in senescence induction with soft (2 kPa) viscoelastic substrates promoting both the onset and amplification of senescence, even in the absence of genotoxic stress. These changes are not associated with a decline in YAP activity, but instead with a decline in nuclear DAPI intensity, suggesting a role of nuclear organization in driving this phenotype. Overall, this work highlights the influence of mechanics on the induction of senescence and supports the key role of viscoelasticity.
衰老细胞的积累与衰老和纤维化疾病有关，这两种疾病的特征都是组织硬度增加。然而，组织力学与衰老诱导之间的直接联系在文献中仍存在争议。因此，这项工作研究了水凝胶硬度和粘弹性在与基因毒性应激联合以及独立作用下对促进成纤维细胞衰老的影响。我们发现，虽然肺成纤维细胞YAP信号随着衰老诱导而下降，但衰老的成纤维细胞保持其机械传感能力，在更高硬度的水凝胶上YAP核定位增加。最值得注意的是，我们发现水凝胶粘弹性在衰老诱导中具有独特作用，柔软的（2 kPa）粘弹性底物即使在没有基因毒性应激的情况下也能促进衰老的起始和放大。这些变化与YAP活性下降无关，而是与细胞核DAPI强度下降有关，表明核组织在驱动这种表型中发挥作用。总体而言，这项工作突出了力学对衰老诱导的影响，并支持了粘弹性的关键作用。
