Theranostics · 2026
Ultra-high-field magnetic resonance imaging reveals sex-specific recovery after ischemic stroke following treatment with three-dimensional human mesenchymal stem cell-derived extracellular vesicles.
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Bhagu Jamini, Arbabian Arshia, Lobo Thurston Da Vitoria, Martinez Katherine, Richter Dayna L, Bryant Hannah, Elumalai Malathy, Li Yan, Grant Samuel C
Аннотация
RATIONALE: Ischemic stroke is sexually dimorphic. Biological sex can influence injury progression and response to treatment. Extracellular vesicles (EV) derived from three-dimensional (3D) human mesenchymal stem cell aggregates (3D-EV) are a promising candidate as a treatment, but their efficacy across these biological variables and in vivo behavior needs to be characterized. This study evaluated whether 3D-EV therapy enhances recovery following ischemic stroke in female and male models using ultra-high-field MRI and their influence on structural, ionic, and metabolic recovery.
METHODS: A preclinical model of transient middle cerebral artery occlusion was used to longitudinally evaluate the efficacy of ultrasmall superparamagnetic iron oxide (USPIO)-labeled 3D-EV or saline at reperfusion through intra-arterial injection. MRI was performed at 21.1 T, which included T2-weighted, diffusion-weighted imaging, gradient-recalled echo imaging, and ²³Na chemical shift imaging. Proton magnetic resonance spectroscopy (¹H-MRS) was used to quantify changes in lactate, N-acetylaspartate, creatine, and choline within peri-infarct tissue. Imaging and behavioral outcomes were assessed over 21 days.
RESULTS: USPIO-labeled 3D-EV resulted in localized hypointense contrast in the ischemic striatum, indicating delivery of treatment. T2-weighted MRI showed progressive lesion reduction, with a trend toward better recovery in females. ²³Na MRI revealed reduced sodium accumulation, with earlier ionic normalization in 3D-EV-treated animals. Diffusion recovery was observed with sex-dependent trajectories. ¹H-MRS showed lower lactate concentrations and preservation of other metabolites in EV-treated females. Behavioral differences were not significant.
CONCLUSIONS: 3D-EV therapy showed trends toward structural, ionic, and metabolic recovery following an ischemic insult. Ultra-high-field MRI and MRS can provide sensitive biomarkers to resolve these differences and support 3D-EV as a potential cell-free therapeutic candidate for ischemic stroke.
METHODS: A preclinical model of transient middle cerebral artery occlusion was used to longitudinally evaluate the efficacy of ultrasmall superparamagnetic iron oxide (USPIO)-labeled 3D-EV or saline at reperfusion through intra-arterial injection. MRI was performed at 21.1 T, which included T2-weighted, diffusion-weighted imaging, gradient-recalled echo imaging, and ²³Na chemical shift imaging. Proton magnetic resonance spectroscopy (¹H-MRS) was used to quantify changes in lactate, N-acetylaspartate, creatine, and choline within peri-infarct tissue. Imaging and behavioral outcomes were assessed over 21 days.
RESULTS: USPIO-labeled 3D-EV resulted in localized hypointense contrast in the ischemic striatum, indicating delivery of treatment. T2-weighted MRI showed progressive lesion reduction, with a trend toward better recovery in females. ²³Na MRI revealed reduced sodium accumulation, with earlier ionic normalization in 3D-EV-treated animals. Diffusion recovery was observed with sex-dependent trajectories. ¹H-MRS showed lower lactate concentrations and preservation of other metabolites in EV-treated females. Behavioral differences were not significant.
CONCLUSIONS: 3D-EV therapy showed trends toward structural, ionic, and metabolic recovery following an ischemic insult. Ultra-high-field MRI and MRS can provide sensitive biomarkers to resolve these differences and support 3D-EV as a potential cell-free therapeutic candidate for ischemic stroke.