Kuihua Wang, Haizhen Xu, Xiaohui Ji, Shengjie Zhu, YanJun Lin, Hua Chen, Xiangping Chen, Xuyang Jiang, He Zhou, Jianxin Ye, Xiaoping Cui
Our findings demonstrate that exosomes derived from NRG1β-overexpressing mesenchymal stem cells (MSCs) exert neuroprotective effects against ischemic injury by upregulating miR-296-3p. This microRNA targets MAOA, leading to a reduction in apoptosis, oxidative stress, and inflammation. These results highlight the therapeutic potential of MSC/NRG1β-exosomes and the miR-296-3p/MAOA signaling axis in the treatment of ischemic brain injury.
BACKGROUND: Cerebral ischemic injury is a severe neurological disorder necessitating effective therapeutic strategies. Neuregulin-1β (NRG1β) and microRNAs are critical for neuroprotection, but the mechanisms by which NRG1β regulates microRNAs in neuronal injury are not fully understood.
METHODS: We characterized mesenchymal stem cells (MSCs) through their phenotypic markers and multilineage differentiation potential, confirming NRG1β overexpression in engineered MSCs. Transmission electron microscopy and nanoparticle tracking analysis were used to isolate and characterize exosomes. In vitro studies evaluated the effects of MSC/NRG1β-exosomes on OGD-treated HT-22 neuronal cells.
RESULTS: Mesenchymal stem cells/NRG1β-exosomes significantly enhanced HT-22 neuronal survival while reducing apoptosis and reactive oxygen species (ROS). The treatment reduced oxidative stress by lowering malondialdehyde (MDA) levels and boosting superoxide dismutase (SOD) activity. It also inhibited inflammatory cytokines such as IL-1β, TNF-α, and IL-6. Studies conducted in vivo with a middle cerebral artery occlusion model demonstrated that MSC/NRG1β-exosomes led to a reduction in infarct size, enhanced histopathological results 24 h after injury. Mechanistically, these exosomes were enriched with miR-296-3p, targeting monoamine oxidase A (MAOA) for downregulation. Inhibition of miR-296-3p or MAOA overexpression negated the protective effects of MSC/NRG1β-exosomes.
CONCLUSION: Our findings demonstrate that exosomes derived from NRG1β-overexpressing mesenchymal stem cells (MSCs) exert neuroprotective effects against ischemic injury by upregulating miR-296-3p. This microRNA targets MAOA, leading to a reduction in apoptosis, oxidative stress, and inflammation. These results highlight the therapeutic potential of MSC/NRG1β-exosomes and the miR-296-3p/MAOA signaling axis in the treatment of ischemic brain injury.