{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T16:33:27Z","timestamp":1787848407021,"version":"build-2784847793"},"reference-count":92,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2025,8,22]],"date-time":"2025-08-22T00:00:00Z","timestamp":1755820800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Department of Veterans\u2019 Affairs (VHA)","award":["I01BX005708"],"award-info":[{"award-number":["I01BX005708"]}]},{"name":"Department of Veterans\u2019 Affairs (VHA)","award":["IK6BX004214"],"award-info":[{"award-number":["IK6BX004214"]}]},{"name":"Department of Veterans\u2019 Affairs (VHA)","award":["IK6BX005387"],"award-info":[{"award-number":["IK6BX005387"]}]},{"name":"Department of Veterans\u2019 Affairs (VHA)","award":["I0BX005591"],"award-info":[{"award-number":["I0BX005591"]}]},{"name":"VHA Research Career Scientist","award":["I01BX005708"],"award-info":[{"award-number":["I01BX005708"]}]},{"name":"VHA Research Career Scientist","award":["IK6BX004214"],"award-info":[{"award-number":["IK6BX004214"]}]},{"name":"VHA Research Career Scientist","award":["IK6BX005387"],"award-info":[{"award-number":["IK6BX005387"]}]},{"name":"VHA Research Career Scientist","award":["I0BX005591"],"award-info":[{"award-number":["I0BX005591"]}]},{"name":"VHA","award":["I01BX005708"],"award-info":[{"award-number":["I01BX005708"]}]},{"name":"VHA","award":["IK6BX004214"],"award-info":[{"award-number":["IK6BX004214"]}]},{"name":"VHA","award":["IK6BX005387"],"award-info":[{"award-number":["IK6BX005387"]}]},{"name":"VHA","award":["I0BX005591"],"award-info":[{"award-number":["I0BX005591"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Traumatic brain injury (TBI) is a major cause of long-term neurological impairment, with aging amplifying vulnerability and worsening recovery. Older individuals face greater cognitive and motor deficits post-TBI and respond less effectively to treatments, as both aging and TBI independently elevate neuroinflammation and cognitive decline. This study evaluated the therapeutic effects of human adipose-derived stem cell small extracellular vesicles (hASC-sEVs) on neurological recovery and neuroinflammation in a mouse model of TBI. Male C57BL\/6 mice (3, 15, and 20 months old) underwent controlled cortical impact (CCI) and received intranasal hASC-sEVs 48 h post-injury; control groups received PBS. A dose\u2013response study at 7 days post injury (dpi) identified 20 \u00b5g as the optimal therapeutic dose, improving motor function, reducing neuroinflammation, and enhancing neurogenesis. This was followed by a 30-dpi study assessing cognitive function, neuroinflammation, neurogenesis, and proteomic changes in microglia and astrocytes via mass spectrometry. hASC-sEV treatment significantly improved behavioral outcomes and reduced neuroinflammatory markers (GFAP, IBA-1, and MHC-II), with reduced efficacy observed in older mice. Proteomics revealed that hASC-sEVs reduce inflammatory proteins (TNF-\u03b1, IL-1\u03b2, IFNG, CCL2) and modulated mitochondrial dysfunction and reactive oxygen species. These results highlight hASC-sEVs as a promising cell-free therapy for improving TBI outcomes, especially in aging populations.<\/jats:p>","DOI":"10.3390\/cells14171304","type":"journal-article","created":{"date-parts":[[2025,8,22]],"date-time":"2025-08-22T12:31:26Z","timestamp":1755865886000},"page":"1304","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Human Adipose-Stem-Cell-Derived Small Extracellular Vesicles Modulate Behavior and Glial Cells in Young and Aged Mice Following TBI"],"prefix":"10.3390","volume":"14","author":[{"given":"Salma S.","family":"Abdelmaboud","sequence":"first","affiliation":[{"name":"Department of Molecular Pharmacology and Physiology, University of South Florida Morsani College of Medicine, Tampa, FL 33612, USA"},{"name":"Department of Neurosurgery, Brain and Spine, University of South Florida Morsani College of Medicine, Tampa, FL 33612, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauren D.","family":"Moss","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Brain and Spine, University of South Florida Morsani College of Medicine, Tampa, FL 33612, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles","family":"Hudson","sequence":"additional","affiliation":[{"name":"James A. Haley Veterans Hospital, Research Service, Tampa, FL 33637, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rekha","family":"Patel","sequence":"additional","affiliation":[{"name":"James A. Haley Veterans Hospital, Research Service, Tampa, FL 33637, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Avlas","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Brain and Spine, University of South Florida Morsani College of Medicine, Tampa, FL 33612, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-7785-3051","authenticated-orcid":false,"given":"Jessica","family":"Wohlfahrt","sequence":"additional","affiliation":[{"name":"Department of Molecular Biosciences, University of South Florida, Tampa, FL 33620, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-4274-9843","authenticated-orcid":false,"given":"Tiara","family":"Wolf","sequence":"additional","affiliation":[{"name":"Department of Molecular Biosciences, University of South Florida, Tampa, FL 33620, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Guergues","sequence":"additional","affiliation":[{"name":"Department of Molecular Biosciences, University of South Florida, Tampa, FL 33620, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1399-0256","authenticated-orcid":false,"suffix":"Jr.","given":"Stanley M.","family":"Stevens","sequence":"additional","affiliation":[{"name":"Department of Molecular Biosciences, University of South Florida, Tampa, FL 33620, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4811-8596","authenticated-orcid":false,"given":"Niketa A.","family":"Patel","sequence":"additional","affiliation":[{"name":"James A. Haley Veterans Hospital, Research Service, Tampa, FL 33637, USA"},{"name":"Department of Molecular Medicine, University of South Florida Morsani College of Medicine, Tampa, FL 33612, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9657-7725","authenticated-orcid":false,"given":"Paula C.","family":"Bickford","sequence":"additional","affiliation":[{"name":"Department of Molecular Pharmacology and Physiology, University of South Florida Morsani College of Medicine, Tampa, FL 33612, USA"},{"name":"Department of Neurosurgery, Brain and Spine, University of South Florida Morsani College of Medicine, Tampa, FL 33612, USA"},{"name":"James A. Haley Veterans Hospital, Research Service, Tampa, FL 33637, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1016\/S1474-4422(17)30279-X","article-title":"The chronic and evolving neurological consequences of traumatic brain injury","volume":"16","author":"Wilson","year":"2017","journal-title":"Lancet Neurol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1080","DOI":"10.3171\/2017.10.JNS17352","article-title":"Estimating the global incidence of traumatic brain injury","volume":"130","author":"Dewan","year":"2018","journal-title":"J. Neurosurg."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"602","DOI":"10.1097\/00001199-199912000-00009","article-title":"Traumatic brain injury in the United States: A public health perspective","volume":"14","author":"Thurman","year":"1999","journal-title":"J. Head. 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