Senescence-associated extracellular vesicles in skin aging and regeneration: from pathophysiology to therapeutic opportunities.

Cellular senescence is an important factor which significantly impairs the homeostasis and regeneration capability of skin through causing chronic inflammation, degradation of the extracellular matrix, depletion of stem cells, and angiogenesis impairment. In addition to the already known senescence associated secretory phenotype (SASP), senescent cells secrete senescence associated extracellular vesicles (SA-EVs) serving as powerful signalling molecules. SA-EVs are distinguished by the increased secretion rates, altered biogenesis and selective cargo loading which include proinflammatory microRNAs, cytokines, mitochondrial DNA, EphA2 protein and noncoding RNAs (tRNAs, lncRNAs, snoRNAs). SA-EVs promote senescence in a paracrine manner, impair the wound healing process and contribute to the development of chronic wounds, diabetic ulcers, burns, pathological scarring, skin ageing and other skin disorders. The treatment approaches which target the reduction of the SA-EV burden can be either senolytic or senomorphic while the application of regenerative mesenchymal stem cell-derived EVs and modified EV platforms as well as using the biomaterial assisted systems are promising therapeutic options.