Senescent cells secrete chromatin components via senescence-associated extracellular particles

Area of Science:

• Cellular senescence
• Extracellular vesicles
• Immunology

Background:

• Senescent cells secrete SASP, influencing surroundings.
• Cytoplasmic chromatin fragments (CCFs) drive SASP via cGAS/STING.
• Autophagy degrades CCFs, but their full fate is unknown.

Purpose of the Study:

• Investigate CCF extracellular release mechanisms.
• Characterize secreted CCF components and their effects.
• Explore the relationship between autophagy and CCF secretion.

Main Methods:

• Analysis of senescent cell secretions.
• Characterization of extracellular particle morphology.
• Inhibition of autophagy.
• cGAS/STING pathway activation assays.
• Analysis of aged mouse circulation.

Main Results:

• Senescent cells release CCF components (ɣH2AX, dsDNA) via multivesicular bodies.
• Secreted components form unique "popcorn"-like extracellular particles.
• Autophagy inhibition increases CCF component and particle secretion.
• Extracellular particles activate cGAS-STING in non-senescent cells.
• Particles are enriched in aged mouse circulation.

Conclusions:

• Senescent cells utilize a novel pathway for extracellular CCF release.
• Extracellular CCF particles represent a new mode of intercellular signaling.
• Autophagy plays a role in regulating CCF extracellular release.
• These findings suggest a link between senescence, inflammation, and aging.