Substrate Stiffness and Viscoelasticity Influence Fibroblast Senescence

Area of Science:

• Biomedical Engineering
• Cell Biology
• Mechanobiology

Background:

• Senescent cell accumulation is linked to aging and fibrosis, conditions with increased tissue stiffness.
• The direct relationship between tissue mechanics and senescence induction is not fully understood.
• Fibroblasts play a key role in tissue structure and are susceptible to senescence.

Purpose of the Study:

• To investigate how hydrogel stiffness and viscoelasticity influence fibroblast senescence.
• To determine the combined effects of mechanical properties and genotoxic stress on senescence.
• To elucidate the role of YAP/TAZ signaling and nuclear organization in mechanically induced senescence.

Main Methods:

• Culturing human lung fibroblasts on hydrogels with varying stiffness (kPa) and viscoelastic properties.
• Inducing senescence using mechanical stimuli and/or genotoxic stress.
• Assessing senescence markers, YAP/TAZ localization, and nuclear morphology (DAPI intensity).

Main Results:

• Senescent fibroblasts retain mechanosensing capabilities, showing increased YAP/TAZ nuclear localization on stiffer hydrogels.
• Soft (2 kPa) viscoelastic substrates uniquely promote senescence onset and amplification, even without genotoxic stress.
• Mechanically induced senescence is linked to decreased nuclear DAPI intensity, not necessarily YAP/TAZ activity decline.

Conclusions:

• Hydrogel viscoelasticity, particularly softness, is a significant factor in inducing fibroblast senescence.
• Nuclear organization, indicated by DAPI intensity, may play a crucial role in mechanically driven senescence.
• This study underscores the importance of mechanical cues in cellular aging and fibrotic disease processes.