hESC-derived extracellular vesicles enriched with MFGE-8 and the GSH redox system act as senotherapeutics for neural stem cells in ischemic stroke.

Youngseok Lee, Jihun Lee, Jeongjun Kim, Seunghyun Cho, Hye-Jin Lee, Dongho Geum, Dong-Hyuk Park, Jong-Hoon Kim

Laboratory of Stem Cells and Tissue Regeneration, Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, 02841, South Korea; Institute of Animal Molecular Biotechnology, Korea University, Seoul, 02841, South Korea. · pubmed

Paper

Abstract

Human embryonic stem cells (hESCs) and their extracellular vesicles (EVs) hold significant potential for tissue repair and regeneration. Neural stem cells (NSCs) in the adult brain often acquire senescent phenotypes after ischemic injuries, releasing neurodegenerative senescence-associated secretory phenotype factors. In this study, we investigated the senotherapeutic effects of hESC-EVs on NSCs and confirmed their neuroprotective effects in neurons via rejuvenation of NSC secretions. Proteomic profiling of hESC-EVs identified MFGE-8 as a critical bridging molecule to NSCs. We also found that the glutathione (GSH) redox system is a key contributor to the therapeutic antioxidant activity of hESC-EVs. Additionally, EVs produced by the hypoxic preconditioning of hESCs (hESC-HypoxEVs) exhibited reinforced GSH redox capacity and further enhanced the senotherapeutic effects on NSCs compared to naïve hESC-EVs. We also demonstrated that administration of hESC-HypoxEVs, precoated with MFGE-8, significantly increased the populations of NSCs and newborn neurons in the subventricular zone of the brain and improved sensorimotor functions in a rat model of ischemic stroke. Our study suggests that combining hESC-HypoxEVs with MFGE-8 may serve as an effective therapeutic modality for reversing senescence and enhancing the neurogenic potential of NSCs to treat neurodegenerative diseases.

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Research summary

The study claims that hESC-derived extracellular vesicles enriched with MFGE-8 and the GSH redox system can rejuvenate neural stem cells and improve outcomes in ischemic stroke. This research is relevant as it addresses mechanisms that may reverse cellular senescence, a key aspect of aging, and explores potential therapeutic strategies for age-related neurodegenerative conditions.

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