Mesenchymal Stem Cell-derived Exosomes Alleviate Oxidative Stress and Brain Injuries Through Promoting OPA1 Mediated Mitochondrial Fusion After Intracerebral Hemorrhage

Oxidative stress (OS) is a hallmark of secondary brain damage after intracerebral hemorrhage (ICH), contributing to the progression of neurological damage and poor clinical outcomes. While mesenchymal stem cell-derived exosomes (MSC-Exo) demonstrate antioxidative potential, the specific mechanisms underlying their protective effects, particularly concerning mitochondrial dynamics, remain unclear. This study identifies OPA1-mediated mitochondrial fusion as a novel mechanism through which MSC-Exo alleviates oxidative stress and brain injury after ICH. In vivo fluorescence imaging and immunofluorescence assay revealed that intravenously injected MSC-Exo could be effectively internalized by neuronal cells in ICH mice. MRI assay indicated that although MSC-Exo had little effect on the volume of hematoma, it significantly relieved brain edema and improved the neurological outcomes. MSC-Exo effectively reduced oxidative stress and neuronal apoptosis in the peri-hematoma tissues. Notably, both in vivo and in vitro studies showed that MSC-Exo significantly alleviated mitochondrial morphological damage following ICH. MSC-Exo substantially reversed the downregulation of OPA1 after ICH but showed no significant impact on other proteins associated with mitochondrial dynamics. Neuron-specific knockout of OPA1 (Opa1cko) aggravated the impairment of mitochondrial morphology, the accumulation of superoxide production, and the deficits of mitochondrial respiratory capacities following ICH. Moreover, MSC-Exo failed to restore mitochondrial morphology and functionality, alleviate oxidative stress-induced damage, enhance neuronal viability, and facilitate functional recovery subsequent to ICH in Opa1cko mice models.