{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T22:16:19Z","timestamp":1788387379117,"version":"build-2803163510"},"reference-count":20,"publisher":"Journal of Neurosurgery Publishing Group (JNSPG)","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,10,1]]},"abstract":"\nOBJECTIVE<\/jats:title>\nRecent randomized clinical trials of a single infusion of mesenchymal stem cells (MSCs) for acute cerebral stroke revealed a limited functional recovery outcome. Conversely, animal studies suggest that multiple MSC infusions may enhance functional recovery by inducing neural plasticity, which indicates that a multiple-infusion approach might be effective for stroke treatment in humans. The objective of this study was to investigate whether multiple infusions of MSCs enhance functional outcomes during the acute phase of cerebral ischemia.<\/jats:p>\n<\/jats:sec>\n\nMETHODS<\/jats:title>\nRats subjected to permanent middle cerebral artery occlusion (MCAO) were randomized into four groups: 1) vehicle group (infusion of vehicle only), 2) MSC-1 group (single administration of the standard MSC dose on day 3), 3) high-dose MSC group (single administration of three times the standard MSC dose on day 3), and 4) MSC-3 group (multiple administrations of the standard MSC dose on days 3, 10, and 17). MSCs were administered via the femoral vein. Behavioral performance and ischemic lesion volume were examined using in vivo MRI every 7 days from day 3 to day 45 after MCAO induction. The thickness of the corpus callosum (CC) was determined using Nissl staining, and the area of the CC was measured using ex vivo MRI. Interhemispheric connections within the CC were assessed using ex vivo MRI diffusion tensor imaging.<\/jats:p>\n<\/jats:sec>\n\nRESULTS<\/jats:title>\nThe MSC-3 group exhibited the most significant motor recovery and increased CC thickness and area among all groups. Increased CC thickness and area were correlated with improved behavioral function 45 days after MCAO induction. Neural tracts through interhemispheric connections via the CC were most pronounced in the MSC-3 group, and this anatomical change showed a positive relationship with behavioral function.<\/jats:p>\n<\/jats:sec>\n\nCONCLUSIONS<\/jats:title>\nMultiple infusions of MSCs led to histological changes in the CC and neural tracts within the CC. These results indicate that multiple systemic infusions of MSCs had a greater beneficial effect in the acute phase of MCAO than a single standard or high-dose infusion of MSCs.<\/jats:p>\n<\/jats:sec>","DOI":"10.3171\/2024.6.jns241111","type":"journal-article","created":{"date-parts":[[2024,10,26]],"date-time":"2024-10-26T01:29:01Z","timestamp":1729906141000},"page":"1-9","source":"Crossref","is-referenced-by-count":3,"title":["Multiple intravenous infusions versus a single infusion of mesenchymal stem cells in a rat model of cerebral ischemia"],"prefix":"10.3171","author":[{"given":"Takahiro","family":"Yokoyama","sequence":"first","affiliation":[{"name":"Department of Neural Regenerative Medicine, Institute of Regenerative Medicine, School of Medicine, Sapporo Medical University, Sapporo, Hokkaido, Japan;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masanori","family":"Sasaki","sequence":"additional","affiliation":[{"name":"Department of Neural Regenerative Medicine, Institute of Regenerative Medicine, School of Medicine, Sapporo Medical University, Sapporo, Hokkaido, Japan;"},{"name":"Departments of Neurology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroshi","family":"Nagahama","sequence":"additional","affiliation":[{"name":"Department of Neural Regenerative Medicine, Institute of Regenerative Medicine, School of Medicine, Sapporo Medical University, Sapporo, Hokkaido, Japan;"},{"name":"Division of Radioisotope Research, Biomedical Research, Education and Instrumentation Center, School of Medicine, Sapporo Medical University, Sapporo, Hokkaido, Japan;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuko","family":"Kataoka-Sasaki","sequence":"additional","affiliation":[{"name":"Department of Neural Regenerative Medicine, Institute of Regenerative Medicine, School of Medicine, Sapporo Medical University, Sapporo, Hokkaido, Japan;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryo","family":"Ukai","sequence":"additional","affiliation":[{"name":"Department of Neural Regenerative Medicine, Institute of Regenerative Medicine, School of Medicine, Sapporo Medical University, Sapporo, Hokkaido, Japan;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shinichi","family":"Oka","sequence":"additional","affiliation":[{"name":"Department of Neural Regenerative Medicine, Institute of Regenerative Medicine, School of Medicine, Sapporo Medical University, Sapporo, Hokkaido, Japan;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffery D.","family":"Kocsis","sequence":"additional","affiliation":[{"name":"Departments of Neurology and"},{"name":"Neuroscience, School of Medicine, Yale University, New Haven, Connecticut; and"},{"name":"Center for Neuroscience and Regeneration Research, VA Connecticut Healthcare System, West Haven, Connecticut"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Osamu","family":"Honmou","sequence":"additional","affiliation":[{"name":"Department of Neural Regenerative Medicine, Institute of Regenerative Medicine, School of Medicine, Sapporo Medical University, Sapporo, Hokkaido, Japan;"},{"name":"Departments of Neurology and"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1754","reference":[{"issue":"1","key":"b1","series-title":"Neurol Sci","first-page":"55","article-title":"New approaches to recovery after stroke","volume":"45","author":"Mar\u00edn-Medina DS","year":"2024","unstructured":"Mar\u00edn-Medina DS, Arenas-Vargas PA, Arias-Botero JC, G\u00f3mez-V\u00e1squez M, Jaramillo-L\u00f3pez MF, Gaspar-Toro JM. New approaches to recovery after stroke. Neurol Sci. 2024;45(1):55\u201363."},{"issue":"12","key":"b2","series-title":"Stroke","first-page":"3618","article-title":"Intravenous autologous bone marrow mononuclear stem cell therapy for ischemic stroke: a multicentric, randomized trial","volume":"45","author":"Prasad K","year":"2014","unstructured":"Prasad K, Sharma A, Garg A, Intravenous autologous bone marrow mononuclear stem cell therapy for ischemic stroke: a multicentric, randomized trial. 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Cytotherapy. 2021;23(9):833\u2013840."},{"key":"b4","first-page":"e160","article-title":"Intravenous infusion of mesenchymal stem cells enhances therapeutic efficacy of reperfusion therapy in cerebral ischemia","volume":"149","author":"Kiyose R","year":"2021","unstructured":"Kiyose R, Sasaki M, Kataoka-Sasaki Y, Intravenous infusion of mesenchymal stem cells enhances therapeutic efficacy of reperfusion therapy in cerebral ischemia. World Neurosurg. 2021;149:e160\u2013e169."},{"issue":"4","key":"b5","series-title":"J Neurosurg","first-page":"1308","article-title":"Intravenous infusion of mesenchymal stem cells for protection against brainstem infarction in a persistent basilar artery occlusion model in the adult rat","volume":"131","author":"Namioka A","year":"2018","unstructured":"Namioka A, Namioka T, Sasaki M, Intravenous infusion of mesenchymal stem cells for protection against brainstem infarction in a persistent basilar artery occlusion model in the adult rat. J Neurosurg. 2018;131(4):1308\u20131316."},{"key":"b6","series-title":"Brain Res","first-page":"37","article-title":"Preservation of interhemispheric cortical connections through corpus callosum following intravenous infusion of mesenchymal stem cells in a rat model of cerebral infarction","volume":"1695","author":"Nagahama H","year":"2018","unstructured":"Nagahama H, Nakazaki M, Sasaki M, Preservation of interhemispheric cortical connections through corpus callosum following intravenous infusion of mesenchymal stem cells in a rat model of cerebral infarction. Brain Res. 2018;1695:37\u201344."},{"issue":"4","key":"b7","series-title":"J Neurosurg","first-page":"917","article-title":"Intravenous infusion of mesenchymal stem cells inhibits intracranial hemorrhage after recombinant tissue plasminogen activator therapy for transient middle cerebral artery occlusion in rats","volume":"127","author":"Nakazaki M","year":"2017","unstructured":"Nakazaki M, Sasaki M, Kataoka-Sasaki Y, Intravenous infusion of mesenchymal stem cells inhibits intracranial hemorrhage after recombinant tissue plasminogen activator therapy for transient middle cerebral artery occlusion in rats. 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