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Increasing evidence indicates that peripheral immune responses contribute to secondary brain injury after stroke. The impact of the splenic response on brain injury has been well documented in animal models. This phenomenon remains poorly defined in the clinical situation. Through a retrospective analysis of 76 patients with acute anterior circulation large-vessel occlusion, we provide novel evidence that post-stroke spleen volume reduction is an outstanding risk factor for cerebral edema expansion, an association partially explained by a concomitant decrease in peripheral lymphocytes. Previous studies have shown that bone marrow-derived mesenchymal stem cells (BMSCs) improve stroke outcomes through immunomodulation peripherally. Nonetheless, efforts to identify more potent MSCs have never ceased. Antler stem cells, known for their potent regenerative and anti-inflammatory properties, represent promising candidates for stroke treatment. Using the transient middle cerebral artery occlusion (tMCAO) model rats, we found that intravenous administration of antler reserve mesenchymal cells (aRMCs, one type of antler stem cells) significantly improved motor function and reduced both cerebral edema and infarct volume, effects that were superior to those observed with BMSC treatment. Notably, these beneficial effects of aRMCs were attenuated in the splenectomized animals. Compared with the model and BMSC groups, the spleens of aRMC-treated rats exhibited increased weight, restored T cell populations, reduced lymphocyte activity, and downregulated expression of T cell migration-related genes. Additionally, these rats displayed decreased T cell infiltration into the cerebral infarct region. Mechanistically, the inhibitory effect of aRMCs on tMCAO-induced splenic T-cell migration is highly likely to be achieved via downregulation of CCR5 expression. These findings demonstrate a causal link between the degree of splenic contraction and the severity of brain edema, suggest spleen-to-brain T-cell migration as a therapeutic target, and position aRMCs as a promising and novel stem cell type for post-stroke neuroprotection with superior efficacy over BMSCs.<\/jats:p>","DOI":"10.1038\/s41420-026-03218-4","type":"journal-article","created":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T15:36:34Z","timestamp":1782315394000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Antler stem cells effectively alleviate the symptoms of cerebral ischemic injury via immunomodulation of the spleen"],"prefix":"10.1038","volume":"12","author":[{"given":"Si","family":"Wu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shunshun","family":"Zhong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7983-3731","authenticated-orcid":false,"given":"Qianqian","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huiying","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiping","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huiling","family":"Luo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongyu","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing","family":"Leng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yufang","family":"Shi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5551-7603","authenticated-orcid":false,"given":"Zhonghui","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7275-4440","authenticated-orcid":false,"given":"Chunyi","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7427-6892","authenticated-orcid":false,"given":"Guangxian","family":"Nan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,24]]},"reference":[{"key":"3218_CR1","doi-asserted-by":"publisher","DOI":"10.1016\/j.eclinm.2024.102758","volume":"75","author":"XY Li","year":"2024","unstructured":"Li XY, Kong XM, Yang CH, Cheng ZF, Lv JJ, Guo H, et al. 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J Antimicrob Chemother. 2013;68:577\u201386.","journal-title":"J Antimicrob Chemother"}],"container-title":["Cell Death Discovery"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41420-026-03218-4","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41420-026-03218-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41420-026-03218-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T00:02:18Z","timestamp":1788912138000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41420-026-03218-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,24]]},"references-count":53,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["3218"],"URL":"https:\/\/doi.org\/10.1038\/s41420-026-03218-4","relation":{},"ISSN":["2058-7716"],"issn-type":[{"value":"2058-7716","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,24]]},"assertion":[{"value":"9 April 2026","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"31 May 2026","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 June 2026","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 June 2026","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Ethics"}},{"value":"The clinical study protocol was approved by the local Ethics Committee of China-Japan Union Hospital of Jilin University (Approval No. 2025121102). All methods and procedures performed in this study involving human participants were in accordance with relevant guidelines and regulations. Informed consent was waived by the ethics committee for this retrospective study. All experimental procedures were approved by the Animal Ethics Committee of Jilin University (Approval No. 2025708) and performed in accordance with China\u2019s national standard GB\/T 35892\u20132018 \u201cGuidelines for Ethical Review of Laboratory Animal Welfare\u201d.","order":2,"name":"Ethics","label":"Ethical approval","group":{"name":"EthicsHeading","label":"Ethics"}}],"article-number":"359"}}