Eun Hee Kim, Jeong Pyo Son, Gyun Sik Oh, Suji Park, Eunchong Hong, Kyoung-Sun Lee, Michael Chopp, Oh Young Bang
{"title":"临床规模的msc来源的细胞外囊泡增强啮齿动物和非人类灵长类动物中风后的神经可塑性","authors":"Eun Hee Kim, Jeong Pyo Son, Gyun Sik Oh, Suji Park, Eunchong Hong, Kyoung-Sun Lee, Michael Chopp, Oh Young Bang","doi":"10.1002/jev2.70110","DOIUrl":null,"url":null,"abstract":"<p>Stroke is a leading cause of death and disability. The therapeutic potential of mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) has shown considerable promise in rodent models of stroke. However, the therapeutic efficacy and safety of clinical-scale MSC-EVs for ischemic stroke are not well elucidated, especially in non-human primates. We developed a scalable production method for MSC-EVs using a 3D bioprocessing platform. EVs were isolated with a filter and tangential flow filtration and characterized using electron microscopy, nanoparticle tracking analysis, nanoflow cytometry analysis, proteomic and lipidomic analysis using mass spectrometry, and RNA sequencing. We determined the appropriate dosage and frequency of intravenous administration of EVs in a mouse stroke model. A biodistribution study of the selected dose regimen was performed using the internal cargo of EVs, human mitochondrial DNA. We then confirmed the efficacy of EVs in a marmoset stroke model. Improvement in behavioural tests and MRI-based neuroplasticity were compared between the control and EV groups through blinded evaluation. The proteome profiles of the infarcted hemisphere were also evaluated. EV products showed suitable lot-to-lot consistency. In a mouse stroke model, intravenous administration of a dose of 6 × 10<sup>8</sup> EVs for 5 days resulted in the smallest infarct volume and improvement in motor function. A biodistribution study showed that EVs were rapidly distributed into systemic organs and were relatively specifically distributed to the infarcted brain areas. Intravenous administration of an equivalent dose (3.5 × 10<sup>9</sup> EVs for 5 days) in a marmoset stroke model significantly improved motor functions and anatomical connectivity on diffusion MRI, and significantly reduced infarct volume. Proteomics analyses indicated that EV treatment promoted neurogenesis, synapse organization, and vascular development. In conclusion, this study is the first to demonstrate that a clinical-scale EV product is safe and significantly enhances function recovery and neuroplasticity in a non-human primate stroke model, offering a promising treatment for human stroke.</p>","PeriodicalId":15811,"journal":{"name":"Journal of Extracellular Vesicles","volume":"14 6","pages":""},"PeriodicalIF":14.5000,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jev2.70110","citationCount":"0","resultStr":"{\"title\":\"Clinical Scale MSC-Derived Extracellular Vesicles Enhance Poststroke Neuroplasticity in Rodents and Non-Human Primates\",\"authors\":\"Eun Hee Kim, Jeong Pyo Son, Gyun Sik Oh, Suji Park, Eunchong Hong, Kyoung-Sun Lee, Michael Chopp, Oh Young Bang\",\"doi\":\"10.1002/jev2.70110\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p>Stroke is a leading cause of death and disability. The therapeutic potential of mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) has shown considerable promise in rodent models of stroke. However, the therapeutic efficacy and safety of clinical-scale MSC-EVs for ischemic stroke are not well elucidated, especially in non-human primates. We developed a scalable production method for MSC-EVs using a 3D bioprocessing platform. EVs were isolated with a filter and tangential flow filtration and characterized using electron microscopy, nanoparticle tracking analysis, nanoflow cytometry analysis, proteomic and lipidomic analysis using mass spectrometry, and RNA sequencing. We determined the appropriate dosage and frequency of intravenous administration of EVs in a mouse stroke model. A biodistribution study of the selected dose regimen was performed using the internal cargo of EVs, human mitochondrial DNA. We then confirmed the efficacy of EVs in a marmoset stroke model. Improvement in behavioural tests and MRI-based neuroplasticity were compared between the control and EV groups through blinded evaluation. The proteome profiles of the infarcted hemisphere were also evaluated. EV products showed suitable lot-to-lot consistency. In a mouse stroke model, intravenous administration of a dose of 6 × 10<sup>8</sup> EVs for 5 days resulted in the smallest infarct volume and improvement in motor function. A biodistribution study showed that EVs were rapidly distributed into systemic organs and were relatively specifically distributed to the infarcted brain areas. Intravenous administration of an equivalent dose (3.5 × 10<sup>9</sup> EVs for 5 days) in a marmoset stroke model significantly improved motor functions and anatomical connectivity on diffusion MRI, and significantly reduced infarct volume. Proteomics analyses indicated that EV treatment promoted neurogenesis, synapse organization, and vascular development. In conclusion, this study is the first to demonstrate that a clinical-scale EV product is safe and significantly enhances function recovery and neuroplasticity in a non-human primate stroke model, offering a promising treatment for human stroke.</p>\",\"PeriodicalId\":15811,\"journal\":{\"name\":\"Journal of Extracellular Vesicles\",\"volume\":\"14 6\",\"pages\":\"\"},\"PeriodicalIF\":14.5000,\"publicationDate\":\"2025-06-23\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jev2.70110\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Extracellular Vesicles\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://onlinelibrary.wiley.com/doi/10.1002/jev2.70110\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CELL BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Extracellular Vesicles","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/jev2.70110","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
Clinical Scale MSC-Derived Extracellular Vesicles Enhance Poststroke Neuroplasticity in Rodents and Non-Human Primates
Stroke is a leading cause of death and disability. The therapeutic potential of mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) has shown considerable promise in rodent models of stroke. However, the therapeutic efficacy and safety of clinical-scale MSC-EVs for ischemic stroke are not well elucidated, especially in non-human primates. We developed a scalable production method for MSC-EVs using a 3D bioprocessing platform. EVs were isolated with a filter and tangential flow filtration and characterized using electron microscopy, nanoparticle tracking analysis, nanoflow cytometry analysis, proteomic and lipidomic analysis using mass spectrometry, and RNA sequencing. We determined the appropriate dosage and frequency of intravenous administration of EVs in a mouse stroke model. A biodistribution study of the selected dose regimen was performed using the internal cargo of EVs, human mitochondrial DNA. We then confirmed the efficacy of EVs in a marmoset stroke model. Improvement in behavioural tests and MRI-based neuroplasticity were compared between the control and EV groups through blinded evaluation. The proteome profiles of the infarcted hemisphere were also evaluated. EV products showed suitable lot-to-lot consistency. In a mouse stroke model, intravenous administration of a dose of 6 × 108 EVs for 5 days resulted in the smallest infarct volume and improvement in motor function. A biodistribution study showed that EVs were rapidly distributed into systemic organs and were relatively specifically distributed to the infarcted brain areas. Intravenous administration of an equivalent dose (3.5 × 109 EVs for 5 days) in a marmoset stroke model significantly improved motor functions and anatomical connectivity on diffusion MRI, and significantly reduced infarct volume. Proteomics analyses indicated that EV treatment promoted neurogenesis, synapse organization, and vascular development. In conclusion, this study is the first to demonstrate that a clinical-scale EV product is safe and significantly enhances function recovery and neuroplasticity in a non-human primate stroke model, offering a promising treatment for human stroke.
期刊介绍:
The Journal of Extracellular Vesicles is an open access research publication that focuses on extracellular vesicles, including microvesicles, exosomes, ectosomes, and apoptotic bodies. It serves as the official journal of the International Society for Extracellular Vesicles and aims to facilitate the exchange of data, ideas, and information pertaining to the chemistry, biology, and applications of extracellular vesicles. The journal covers various aspects such as the cellular and molecular mechanisms of extracellular vesicles biogenesis, technological advancements in their isolation, quantification, and characterization, the role and function of extracellular vesicles in biology, stem cell-derived extracellular vesicles and their biology, as well as the application of extracellular vesicles for pharmacological, immunological, or genetic therapies.
The Journal of Extracellular Vesicles is widely recognized and indexed by numerous services, including Biological Abstracts, BIOSIS Previews, Chemical Abstracts Service (CAS), Current Contents/Life Sciences, Directory of Open Access Journals (DOAJ), Journal Citation Reports/Science Edition, Google Scholar, ProQuest Natural Science Collection, ProQuest SciTech Collection, SciTech Premium Collection, PubMed Central/PubMed, Science Citation Index Expanded, ScienceOpen, and Scopus.