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Stroke Res."],"published-print":{"date-parts":[[2025,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:p>Small extracellular vesicles (sEVs) obtained from mesenchymal stromal cells (MSCs) have shown considerable promise as restorative stroke treatment. In a head-to-head comparison in mice exposed to transient proximal middle cerebral artery occlusion (MCAO), sEVs obtained from MSCs cultured under hypoxic conditions particularly potently enhanced long-term brain tissue survival, microvascular integrity, and angiogenesis. These observations suggest that hypoxic preconditioning might represent the strategy of choice for harvesting MSC-sEVs for clinical stroke trials. To test the efficacy of\u00a0hypoxic MSCs in a second stroke model in an additional species, we now exposed 6\u20138-month-old Sprague\u2013Dawley rats to permanent distal MCAO and intravenously administered vehicle, platelet sEVs, or sEVs obtained from hypoxic MSCs (1% O<jats:sub>2<\/jats:sub>; 2\u2009\u00d7\u200910<jats:sup>6<\/jats:sup> or 2\u2009\u00d7\u200910<jats:sup>7<\/jats:sup> cell equivalents\/kg) at 24\u00a0h, 3, 7, and 14\u00a0days post-MCAO. Over 28\u00a0days, motor-coordination recovery was evaluated by rotating pole and cylinder tests. Ischemic injury, brain inflammatory responses, and peri-infarct angiogenesis were assessed by infarct volumetry and immunohistochemistry. sEVs obtained from hypoxic MSCs did not influence infarct volume in this permanent MCAO model, but promoted motor-coordination recovery over 28\u00a0days at both sEV doses. Ischemic injury was associated with brain ED1<jats:sup>+<\/jats:sup> macrophage infiltrates and Iba1<jats:sup>+<\/jats:sup> microglia accumulation in the peri-infarct cortex of vehicle-treated rats. Hypoxic MSC-sEVs reduced brain macrophage infiltrates and microglia accumulation in the peri-infarct cortex. In vehicle-treated rats, CD31<jats:sup>+<\/jats:sup>\/BrdU<jats:sup>+<\/jats:sup> proliferating endothelial cells were found in the peri-infarct cortex. Hypoxic MSC-sEVs increased the number of CD31<jats:sup>+<\/jats:sup>\/BrdU<jats:sup>+<\/jats:sup> proliferating endothelial cells. Our results provide evidence that hypoxic MSC-derived sEVs potently enhance neurological recovery, reduce neuroinflammation. and increase angiogenesis in rat permanent distal MCAO.<\/jats:p>","DOI":"10.1007\/s12975-024-01266-5","type":"journal-article","created":{"date-parts":[[2024,9,7]],"date-time":"2024-09-07T07:02:03Z","timestamp":1725692523000},"page":"817-830","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Extracellular Vesicles Obtained from Hypoxic Mesenchymal Stromal Cells Induce Neurological Recovery, Anti-inflammation, and Brain Remodeling After Distal Middle Cerebral Artery Occlusion in Rats"],"prefix":"10.1007","volume":"16","author":[{"given":"Mihaela","family":"Abuzan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roxana","family":"Surugiu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayan","family":"Mohamud-Yusuf","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tobias","family":"Tertel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bogdan","family":"Catalin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thorsten R.","family":"Doeppner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernd","family":"Giebel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0198-3152","authenticated-orcid":false,"given":"Dirk M.","family":"Hermann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4574-8605","authenticated-orcid":false,"given":"Aurel","family":"Popa-Wagner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,9,7]]},"reference":[{"issue":"5\u20136","key":"1266_CR1","first-page":"467","volume":"25","author":"B Buchhold","year":"2007","unstructured":"Buchhold B, Mogoanta L, Suofu Y, Hamm A, Walker L, Kessler C, Popa-Wagner A. 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J Extracell Vesicles. 2015;4:27066. https:\/\/doi.org\/10.3402\/jev.v4.27066.","DOI":"10.3402\/jev.v4.27066"}],"container-title":["Translational Stroke Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s12975-024-01266-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s12975-024-01266-5\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s12975-024-01266-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,5,1]],"date-time":"2025-05-01T03:41:11Z","timestamp":1746070871000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s12975-024-01266-5"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,9,7]]},"references-count":24,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2025,6]]}},"alternative-id":["1266"],"URL":"https:\/\/doi.org\/10.1007\/s12975-024-01266-5","relation":{},"ISSN":["1868-4483","1868-601X"],"issn-type":[{"value":"1868-4483","type":"print"},{"value":"1868-601X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,9,7]]},"assertion":[{"value":"4 March 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 May 2024","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"30 May 2024","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"7 September 2024","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"DMH and BG hold patents for the application of extracellular vesicles for the treatment of inflammatory conditions (EP2687219A1; US9877989B2).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"The experiments conducted at the University of Medicine and Pharmacy Craiova received approval from the Institutional Animal Care and Use Committee (#112\u201315-11\u20132017). The experiments were carried out in accordance with national regulations in accordance with the EU Directive 2010\/63\/EU on the care and use of laboratory animals. Randomization of experiments was strictly implemented following the ARRIVE criteria to ensure unbiased data analysis, including behavioral tests, while the examiners involved were kept completely blinded to the experimental conditions. The authors will provide supporting data upon reasonable request to support the conclusions derived from this study.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics Approval"}},{"value":"N\/A.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Informed Consent"}},{"value":"DMH and BG hold patents for the application of extracellular vesicles for the treatment of inflammatory conditions (EP2687219A1; US9877989B2).","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of Interest"}}]}}