Apoptotic cell-derived micro/nanosized extracellular vesicles in tissue regeneration

Extracellular vesicles (EVs), products released by cells in multiple biological activities, are currently widely accepted as functional particles and intercellular communicators. From the orthodox perspective, EVs derived from apoptotic cells (apoEVs) are responsible for cell debris clearance, while recent studies have demonstrated that apoEVs participate in tissue regeneration. However, the underlying mechanisms and particular functions in tissue regeneration promotion of apoEVs remain ambiguous. Some molecules active during apoptosis also function in tissue regeneration triggered by apoptosis, such as caspases. ApoEVs are generated in the process of apoptosis, carrying cell contents to manifest biological effects and possess biomarkers to target phagocytes. The regenerative effect of apoEVs might be due to their abilities to facilitate cell proliferation and regulate inflammation. Such regenerative effect has been observed in various tissues, including skin, bone, cardiovascular system, and kidneys. Engineered apoEVs are produced to amplify the biological benefits of apoEVs, rendering them optional for drug delivery. Meanwhile, challenges exist in thorough mechanistic exploration and standardization of production. In this review, we discussed the link between apoptosis and regeneration, current comprehension of the origination and investigation strategies of apoEVs, and mechanisms in tissue regeneration of apoEVs and their applications. Challenges and prospects are also addressed here.