Increased substrate stiffness disrupts nuclear-cytoskeletal mechanical coupling in senescent cells

Area of Science:

• Cell Biology
• Biophysics
• Mechanobiology

Background:

• Cellular adaptation to mechanical cues from the extracellular matrix (ECM) is vital.
• Aging impacts cellular and ECM mechanics, but how senescence affects mechano-adaptation is unclear.

Purpose of the Study:

• To investigate how cellular senescence affects the mechano-adaptive response to substrate stiffness.
• To elucidate the biophysical mechanisms underlying altered cell-ECM interactions in senescent cells.

Main Methods:

• Utilized three distinct senescence models in fibroblasts.
• Applied varying substrate stiffness as a mechanical stimulus.
• Analyzed nuclear deformation, cytoskeletal organization, focal adhesion maturation, and YAP localization.

Main Results:

• Senescent fibroblasts exhibited limited integration of increasing substrate stiffness.
• Nuclei deformed and flattened until decoupling from the cytoskeleton occurred on stiff substrates.
• This decoupling correlated with disrupted cytoskeleton, abnormal focal adhesions, nuclear softening, and altered YAP localization.

Conclusions:

• Senescent cells possess a fundamental biophysical limitation in adapting to high-stiffness environments.
• This impaired mechano-adaptation may contribute to altered nuclear mechanotransduction in aging and disease contexts like scarring.