Substrate stiffness and viscoelasticity influence fibroblast senescence

Area of Science:

• Biomaterials Science
• Cellular Biology
• Tissue Engineering

Background:

• Cellular senescence is linked to aging and fibrosis, conditions associated with increased tissue stiffness.
• The direct impact of mechanical forces on senescence induction is not fully understood.
• Fibroblasts play a key role in tissue structure and are implicated in fibrotic diseases.

Purpose of the Study:

• To investigate how hydrogel stiffness and viscoelasticity influence fibroblast senescence.
• To determine if mechanical properties alone can induce senescence.
• To explore the role of YAP signaling and nuclear organization in mechanically induced senescence.

Main Methods:

• Utilized hydrogels with varying stiffness (kPa range) and viscoelastic properties.
• Exposed human lung fibroblasts to these hydrogels, with and without genotoxic stress.
• Analyzed fibroblast senescence markers, YAP localization, and nuclear morphology (DAPI intensity).

Main Results:

• Senescent fibroblasts retained mechanosensing, showing increased YAP nuclear localization on stiffer hydrogels.
• Soft (2 kPa) viscoelastic substrates uniquely induced and amplified senescence, independent of genotoxic stress.
• Mechanically induced senescence was linked to decreased nuclear DAPI intensity, not YAP activity decline.

Conclusions:

• Hydrogel viscoelasticity, particularly soft substrates, plays a significant role in inducing fibroblast senescence.
• Cellular mechanosensing and nuclear organization are critical in the response to mechanical cues.
• This study underscores the importance of material properties in cellular aging and fibrotic disease development.