{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T22:48:54Z","timestamp":1792795734208,"version":"4.5.0"},"reference-count":36,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,11,12]],"date-time":"2025-11-12T00:00:00Z","timestamp":1762905600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003593","name":"Conselho Nacional de Desenvolvimento Cient\u00edfico e Tecnol\u00f3gico","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003593","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Spinal cord injury (SCI) is a devastating condition with high mortality and limited treatment options. Mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) have emerged as promising cell-free therapies due to their immunomodulatory and neuroprotective properties. Here, we evaluated the therapeutic potential of EVs derived from human umbilical cord MSCs in a rat model of SCI.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Adult male Wistar rats were randomized into three groups: control, SCI, and SCI treated with a single intralesional dose of EVs. Locomotor recovery was assessed by the Basso, Beattie &amp;amp; Bresnahan (BBB) score, while survival, neuroinflammation, histological alterations, and biodistribution were systematically analyzed.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      EV administration improved 30-day survival, and locomotor performance from day 7, and was associated with sustained reductions in pro-inflammatory cytokines (IL-1\u03b2, TNF-\u03b1) alongside increased levels of anti-inflammatory cytokines (IL-10) and neurotrophic factors (BDNF). Histological and immunofluorescence analyses showed attenuated microglial activation and astrocytic reactivity, accompanied by reduced lesion size and glial scar formation.\n                      <jats:italic>In vivo<\/jats:italic>\n                      imaging demonstrated accumulation of labeled EVs at the injury site, with peak retention at day 7 post-injection.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>Together, these findings demonstrate that early intralesional delivery of MSC-EVs enhances survival, modulates the inflammatory response, and promotes functional recovery after SCI, supporting further translational development of EV-based interventions for SCI.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2025.1695914","type":"journal-article","created":{"date-parts":[[2025,11,12]],"date-time":"2025-11-12T05:19:24Z","timestamp":1762924764000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Early intervention with extracellular vesicles derived from human umbilical cord mesenchymal stem cells enhances survival and functional recovery after spinal cord injury in rats"],"prefix":"10.3389","volume":"16","author":[{"given":"Barbara Porto","family":"Cipriano","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel Santana","family":"Cunha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tha\u00eds Alves de","family":"Santana","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K\u00e1tia Nunes da","family":"Silva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erick Correia","family":"Loiola","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00falio C\u00e9sar Queiroz","family":"Figueiredo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisama Ara\u00fajo da","family":"Silva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adne Vit\u00f3ria Rocha de","family":"Lima","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erik Aranha","family":"Rossi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Igor Campos da","family":"Silva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ravena Pereira do","family":"Nascimento","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia Lima","family":"Costa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zaquer Suzana Munhoz","family":"Costa-Ferro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruno Solano de Freitas","family":"Souza","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,11,12]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"17018","DOI":"10.1038\/NRDP.2017.18","article-title":"Traumatic spinal cord injury","volume":"3","author":"Ahuja","year":"2017","journal-title":"Nat. Rev. Dis. Prim."},{"key":"B2","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1089\/NEU.1995.12.1","article-title":"A sensitive and reliable locomotor rating scale for open field testing in rats","volume":"12","author":"Basso","year":"1995","journal-title":"J. Neurotrauma"},{"key":"B3","doi-asserted-by":"publisher","first-page":"eads3398","DOI":"10.1126\/sciadv.ads3398","article-title":"An engineering-reinforced extracellular vesicle\u2013integrated hydrogel with an ROS-Responsive release pattern mitigates spinal cord injury","volume":"11","author":"Cao","year":"2025","journal-title":"Sci. Adv."},{"key":"B4","doi-asserted-by":"publisher","first-page":"1013","DOI":"10.1016\/j.jcyt.2024.04.074","article-title":"GMP-compliant extracellular vesicles derived from umbilical cord mesenchymal stromal cells: manufacturing and pre-clinical evaluation in ARDS treatment","volume":"26","author":"Costa-Ferro","year":"2024","journal-title":"Cytotherapy"},{"key":"B5","doi-asserted-by":"publisher","first-page":"123479","DOI":"10.1016\/j.lfs.2025.123479","article-title":"Extracellular vesicles derived from mesenchymal stem cells alleviate depressive-like behavior in a rat model of chronic stress","author":"Costa-Ferro","year":"2025","journal-title":"Life Sci."},{"key":"B6","doi-asserted-by":"publisher","first-page":"898","DOI":"10.1038\/S41591-019-0475-6","article-title":"Spinal cord repair: advances in biology and technology","volume":"25","author":"Courtine","year":"2019","journal-title":"Nat. Med."},{"key":"B7","doi-asserted-by":"publisher","first-page":"471","DOI":"10.1016\/J.NCL.2021.02.004","article-title":"Acute traumatic spinal cord injury","volume":"39","author":"Eli","year":"2021","journal-title":"Neurol. Clin."},{"key":"B8","doi-asserted-by":"publisher","first-page":"1612","DOI":"10.1177\/09603271211003311","article-title":"Bone marrow mesenchymal stem cells-derived exosomes reduce apoptosis and inflammatory response during spinal cord injury by inhibiting the TLR4\/MyD88\/NF-\u03baB signaling pathway","volume":"40","author":"Fan","year":"2021","journal-title":"Hum. Exp. Toxicol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1016\/0014-4886(85)90118-9","article-title":"Spinal cord contusion in the rat: behavioral analysis of functional neurologic impairment","volume":"88","author":"Gale","year":"1985","journal-title":"Exp. Neurol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"S50","DOI":"10.1038\/D41586-017-07551-8","article-title":"Repairing the neural highway","volume":"552","author":"Holmes","year":"2017","journal-title":"Nature"},{"key":"B11","doi-asserted-by":"publisher","first-page":"3388","DOI":"10.1089\/NEU.2017.5063","article-title":"Systemic administration of exosomes released from mesenchymal stromal cells attenuates apoptosis, inflammation, and promotes angiogenesis after spinal cord injury in rats","volume":"34","author":"Huang","year":"2017","journal-title":"J. Neurotrauma"},{"key":"B12","doi-asserted-by":"publisher","first-page":"385","DOI":"10.4252\/WJSC.V15.I5.385","article-title":"Cell transplantation therapies for spinal cord injury focusing on bone marrow mesenchymal stem cells: advances and challenges","volume":"15","author":"Huang","year":"2023","journal-title":"World J. Stem Cells"},{"key":"B13","doi-asserted-by":"publisher","first-page":"251","DOI":"10.1007\/S12035-012-8287-4","article-title":"Reactive astrogliosis after spinal cord injury-beneficial and detrimental effects","volume":"46","author":"Karimi-Abdolrezaee","year":"2012","journal-title":"Mol. Neurobiol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"487","DOI":"10.1186\/S13287-022-03116-3","article-title":"miR-146a-5p-modified hUCMSC-derived exosomes facilitate spinal cord function recovery by targeting neurotoxic astrocytes","volume":"13","author":"Lai","year":"2022","journal-title":"Stem Cell Res. Ther."},{"key":"B15","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1016\/J.BIOMATERIALS.2017.05.027","article-title":"Cetuximab modified collagen scaffold directs neurogenesis of injury-activated endogenous neural stem cells for acute spinal cord injury repair","volume":"137","author":"Li","year":"2017","journal-title":"Biomaterials"},{"key":"B16","doi-asserted-by":"publisher","first-page":"1447414","DOI":"10.3389\/fneur.2025.1447414","article-title":"Stem cell-derived exosome treatment for acute spinal cord injury: a systematic review and meta-analysis based on preclinical evidence","volume":"16","author":"Mou","year":"2025","journal-title":"Front. Neurology"},{"key":"B17","doi-asserted-by":"publisher","first-page":"121526","DOI":"10.1016\/j.biomaterials.2022.121526","article-title":"Dual-functional hydrogel system for spinal cord regeneration with sustained release of arylsulfatase B alleviates fibrotic microenvironment and promotes axonal regeneration","volume":"284","author":"Park","year":"2022","journal-title":"Biomaterials"},{"key":"B18","doi-asserted-by":"publisher","first-page":"36405","DOI":"10.31083\/FBL36405","article-title":"Extracellular vesicles: recent advances and perspectives","volume":"30","author":"Ragni","year":"2025","journal-title":"Front. Biosci. Landmark Ed."},{"key":"B19","doi-asserted-by":"publisher","first-page":"1225","DOI":"10.3389\/FNEUR.2019.01225","article-title":"Extracellular vesicles can deliver anti-inflammatory and anti-scarring activities of mesenchymal stromal cells after spinal cord injury","volume":"10","author":"Romanelli","year":"2019","journal-title":"Front. Neurology"},{"key":"B20","doi-asserted-by":"publisher","first-page":"150","DOI":"10.3390\/CELLS13020150","article-title":"Involvement of astrocytes in the formation, maintenance, and function of the blood\u2013brain barrier","volume":"13","author":"Schiera","year":"2024","journal-title":"Cells"},{"key":"B21","doi-asserted-by":"publisher","first-page":"555","DOI":"10.1179\/2045772311Y.0000000024","article-title":"Factors associated with early mortality after cervical spinal cord injury","volume":"34","author":"Shao","year":"2011","journal-title":"J. Spinal Cord. Med."},{"key":"B22","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/S13287-024-04086-4\/FIGURES\/6","article-title":"Functional heterogeneity of mesenchymal stem cells and their therapeutic potential in the K18-hACE2 mouse model of SARS-CoV-2 infection","volume":"16","author":"Silva","year":"2025","journal-title":"Stem Cell Res. Ther."},{"key":"B23","doi-asserted-by":"publisher","first-page":"1105","DOI":"10.1038\/S41417-022-00427-8","article-title":"Mesenchymal stem cell (MSC)-derived exosomes as novel vehicles for delivery of miRNAs in cancer therapy","volume":"29","author":"Sohrabi","year":"2022","journal-title":"Cancer Gene Ther."},{"key":"B24","doi-asserted-by":"publisher","first-page":"1084101","DOI":"10.3389\/FIMMU.2022.1084101","article-title":"Immune response following traumatic spinal cord injury: pathophysiology and therapies","volume":"13","author":"Sterner","year":"2023","journal-title":"Front. Immunol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"194","DOI":"10.1016\/j.msec.2018.04.006","article-title":"hucMSC derived exosomes promote functional recovery in spinal cord injury mice via attenuating inflammation","volume":"89","author":"Sun","year":"2018","journal-title":"Mater. Sci. Eng. C"},{"key":"B26","doi-asserted-by":"publisher","first-page":"E256","DOI":"10.1097\/MAT.0000000000001938","article-title":"Application of human umbilical cord mesenchymal stem cells in rat spinal cord injury model","volume":"69","author":"Sun","year":"2023","journal-title":"ASAIO J."},{"key":"B27","doi-asserted-by":"publisher","first-page":"881","DOI":"10.1152\/PHYSREV.00017.2017","article-title":"The biology of regeneration failure and success after spinal cord injury","volume":"98","author":"Tran","year":"2018","journal-title":"Physiol. Rev."},{"key":"B28","doi-asserted-by":"publisher","first-page":"1399","DOI":"10.1089\/08977150152725687","article-title":"A simple and reproducible model of spinal cord injury induced by epidural balloon inflation in the rat","volume":"18","author":"Vanick\u00fd","year":"2001","journal-title":"J. Neurotrauma"},{"key":"B29","doi-asserted-by":"publisher","first-page":"1394","DOI":"10.3390\/BIOMEDICINES11051394","article-title":"Human adipose-derived stem cells reduce cellular damage after experimental spinal cord injury in rats","volume":"11","author":"Vialle","year":"2023","journal-title":"Biomedicines"},{"key":"B30","doi-asserted-by":"publisher","first-page":"633","DOI":"10.1002\/BIOF.1374","article-title":"Mesenchymal stem cell-derived factors: immuno-modulatory effects and therapeutic potential","volume":"43","author":"Volarevic","year":"2017","journal-title":"BioFactors"},{"key":"B31","doi-asserted-by":"publisher","first-page":"101497","DOI":"10.1016\/j.bbrep.2023.101497","article-title":"Umbilical mesenchymal stem cell-derived exosomes promote spinal cord functional recovery through the miR-146b\/TLR4 -mediated NF-\u03baB p65 signaling pathway in rats","volume":"35","author":"Wang","year":"2023","journal-title":"Biochem. Biophysics Rep."},{"key":"B32","doi-asserted-by":"publisher","first-page":"e12404","DOI":"10.1002\/JEV2.12404","article-title":"Minimal information for studies of extracellular vesicles (MISEV2023): from basic to advanced approaches","volume":"13","author":"Welsh","year":"2024","journal-title":"J. Extracell. Vesicles"},{"key":"B33","doi-asserted-by":"publisher","first-page":"124","DOI":"10.1016\/j.ejphar.2016.08.020","article-title":"Activation of the niacin receptor HCA2reduces demyelination and neurofilament loss, and promotes functional recovery after spinal cord injury in mice","volume":"791","author":"Yang","year":"2016","journal-title":"Eur. J. Pharmacol."},{"key":"B34","doi-asserted-by":"publisher","first-page":"822","DOI":"10.23736\/S1973-9087.24.08462-4","article-title":"Life expectancy and long-term survival after traumatic spinal cord injury: a systematic review","volume":"60","author":"Zadra","year":"2024","journal-title":"Eur. J. Phys. Rehabilitation Med."},{"key":"B35","doi-asserted-by":"publisher","first-page":"301","DOI":"10.1007\/S10735-020-09950-0","article-title":"Exosomes with high level of miR-181c from bone marrow-derived mesenchymal stem cells inhibit inflammation and apoptosis to alleviate spinal cord injury","volume":"52","author":"Zhang","year":"2021","journal-title":"J. Mol. Histology"},{"key":"B36","doi-asserted-by":"publisher","first-page":"417","DOI":"10.3892\/MMR.2021.12056","article-title":"Acute spinal cord injury: pathophysiology and pharmacological intervention","volume":"23","author":"Zhang","year":"2021","journal-title":"Mol. Med. Rep."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2025.1695914\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,12]],"date-time":"2025-11-12T05:19:26Z","timestamp":1762924766000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2025.1695914\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,12]]},"references-count":36,"alternative-id":["10.3389\/fphar.2025.1695914"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2025.1695914","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,12]]},"article-number":"1695914"}}