Jamini Bhagu, Arshia Arbabian, Thurston Da Vitoria Lobo, Katherine Martinez, Dayna L Richter, Hannah Bryant, Malathy Elumalai, Yan Li, Samuel C Grant
{"title":"超高场磁共振成像揭示了三维人间充质干细胞来源的细胞外囊泡治疗后缺血性卒中后的性别特异性恢复。","authors":"Jamini Bhagu, Arshia Arbabian, Thurston Da Vitoria Lobo, Katherine Martinez, Dayna L Richter, Hannah Bryant, Malathy Elumalai, Yan Li, Samuel C Grant","doi":"10.7150/thno.129188","DOIUrl":null,"url":null,"abstract":"<p><strong>Rationale: </strong>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 <i>in vivo</i> 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.</p><p><strong>Methods: </strong>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 T<sub>2</sub>-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.</p><p><strong>Results: </strong>USPIO-labeled 3D-EV resulted in localized hypointense contrast in the ischemic striatum, indicating delivery of treatment. T<sub>2</sub>-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.</p><p><strong>Conclusions: </strong>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.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"16 13","pages":"7698-7714"},"PeriodicalIF":14.9000,"publicationDate":"2026-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13295759/pdf/","citationCount":"0","resultStr":"{\"title\":\"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.\",\"authors\":\"Jamini Bhagu, Arshia Arbabian, Thurston Da Vitoria Lobo, Katherine Martinez, Dayna L Richter, Hannah Bryant, Malathy Elumalai, Yan Li, Samuel C Grant\",\"doi\":\"10.7150/thno.129188\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Rationale: </strong>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 <i>in vivo</i> 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.</p><p><strong>Methods: </strong>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 T<sub>2</sub>-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.</p><p><strong>Results: </strong>USPIO-labeled 3D-EV resulted in localized hypointense contrast in the ischemic striatum, indicating delivery of treatment. T<sub>2</sub>-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.</p><p><strong>Conclusions: </strong>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.</p>\",\"PeriodicalId\":22932,\"journal\":{\"name\":\"Theranostics\",\"volume\":\"16 13\",\"pages\":\"7698-7714\"},\"PeriodicalIF\":14.9000,\"publicationDate\":\"2026-06-17\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13295759/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Theranostics\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.7150/thno.129188\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2026/1/1 0:00:00\",\"PubModel\":\"eCollection\",\"JCR\":\"Q1\",\"JCRName\":\"MEDICINE, RESEARCH & EXPERIMENTAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Theranostics","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.7150/thno.129188","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2026/1/1 0:00:00","PubModel":"eCollection","JCR":"Q1","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}
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.
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.
期刊介绍：
Theranostics serves as a pivotal platform for the exchange of clinical and scientific insights within the diagnostic and therapeutic molecular and nanomedicine community, along with allied professions engaged in integrating molecular imaging and therapy. As a multidisciplinary journal, Theranostics showcases innovative research articles spanning fields such as in vitro diagnostics and prognostics, in vivo molecular imaging, molecular therapeutics, image-guided therapy, biosensor technology, nanobiosensors, bioelectronics, system biology, translational medicine, point-of-care applications, and personalized medicine. Encouraging a broad spectrum of biomedical research with potential theranostic applications, the journal rigorously peer-reviews primary research, alongside publishing reviews, news, and commentary that aim to bridge the gap between the laboratory, clinic, and biotechnology industries.
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