{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T05:05:30Z","timestamp":1789362330855,"version":"build-2803163510"},"reference-count":48,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T00:00:00Z","timestamp":1789344000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82472238"],"award-info":[{"award-number":["82472238"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004826","name":"Natural Science Foundation of Beijing Municipality","doi-asserted-by":"publisher","award":["7254419"],"award-info":[{"award-number":["7254419"]}],"id":[{"id":"10.13039\/501100004826","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Central nervous system (CNS) injury is a major determinant of mortality and persistent disability after heat stroke. Mesenchymal stromal\/stem cell-derived extracellular vesicles (MSC-EVs) are candidate cell-free immunomodulatory therapeutics, but their effects and molecular correlates in heat stroke-associated brain injury remain incompletely defined. We investigated whether MSC-EVs attenuate hippocampal inflammation and alter microglial phenotype-associated markers after heat stroke.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Human umbilical cord MSC-EVs were isolated by differential ultracentrifugation and characterized by transmission electron microscopy, nanoparticle tracking analysis, and immunoblotting for EV-enriched and non-EV markers. In a mouse heat stroke model, MSC-EVs (200 \u03bcg total protein per mouse) were administered intravenously. Neurological outcomes, hippocampal pathology, inflammatory mediators, IBA1 immunoreactivity, and phenotype-associated markers were evaluated. BV2 heat-stress and MSC co-culture experiments were used to examine VIM-AS1-associated miR-34a-5p\/Per2 signaling.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      MSC-EV treatment improved survival and neurological scores and reduced hippocampal injury and inflammatory readouts after heat stroke. In mouse brain and BV2 models, treatment was associated with lower expression of inflammatory-associated markers and higher expression of repair-associated markers. EV RNA sequencing identified abundant VIM-AS1. VIM-AS1 gain- and loss-of-function experiments altered miR-34a-5p and Per2 expression, while miR-34a-5p directly repressed a conserved mouse Per2 3\u2032UTR reporter. VIM-AS1 overexpression also improved inflammatory and neurological readouts\n                      <jats:italic>in vivo<\/jats:italic>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>MSC-EVs attenuated heat stroke-induced hippocampal injury and were associated with coordinated changes in VIM-AS1, miR-34a-5p, and Per2. These findings support MSC-EVs and VIM-AS1-associated signaling as candidates for further mechanistic investigation, while not establishing VIM-AS1 as the sole or dominant active EV cargo.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1873819","type":"journal-article","created":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T04:37:25Z","timestamp":1789360645000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Mesenchymal stem cell-derived extracellular vesicles ameliorate heat stroke-induced hippocampal injury and modulate VIM-AS1-associated miR-34a-5p\/Per2 signaling"],"prefix":"10.3389","volume":"17","author":[{"given":"Lu","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Critical Care Medicine, the Fifth Medical Centre, Chinese PLA General Hospital","place":["Beijing, China"]},{"name":"National Key Laboratory of Kidney Diseases, Beijing Key Laboratory of Kidney 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