{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T10:19:29Z","timestamp":1788430769348,"version":"build-2803163510"},"reference-count":41,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T00:00:00Z","timestamp":1788393600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T00:00:00Z","timestamp":1788393600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100012443","name":"MSCRF","doi-asserted-by":"publisher","award":["2022\u2010MSCRFD\u20105886"],"award-info":[{"award-number":["2022\u2010MSCRFD\u20105886"]}],"id":[{"id":"10.13039\/100012443","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["R01 DA056739"],"award-info":[{"award-number":["R01 DA056739"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["S10OD030430"],"award-info":[{"award-number":["S10OD030430"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Neuroprotection"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Traumatic brain injury (TBI) causes long\u2010term disability, with inflammation contributing to both primary and secondary brain damage. Extracellular adenosine triphosphate (ATP) and its receptor purinergic receptor X7 (P2X7) drive neuroinflammation and represent promising therapeutic targets. Therefore, we developed a strategy to mitigate acute post\u2010TBI inflammation using mesenchymal stem cells (MSCs) engineered to deliver a P2X7\u2010blocking nanobody (P2X7nb).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Primary MSCs were transfected in vitro with bicistronic messenger RNA (mRNA) encoding P2X7nb and a haloalkane dehalogenase Tag reporter, with nanobody secretion confirmed by enzyme\u2010linked immunosorbent assay (ELISA). In vivo, TBI was induced in mice using the closed\u2010head injury model. Twenty\u20104 hours post\u2010TBI, MSCs labeled with iron oxide nanoparticles were administered via intra\u2010arterial injection into the internal carotid artery. Dynamic 9.4\u2009T magnetic resonance imaging (MRI) using susceptibility\u2010weighted imaging (SWI) allowed real\u2010time monitoring of cellular accumulation. Behavioral performance was assessed using the beam walk test, while mice were euthanized on Day 4 post\u2010TBI for immunofluorescence analysis of cell localization. Data were analyzed using either an unpaired\n                      <jats:italic>t<\/jats:italic>\n                      \u2010test or Mann\u2013Whitney\n                      <jats:italic>U<\/jats:italic>\n                      test, depending on data distribution, with statistical significance set at\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Transfection (38.9% efficiency) and release of P2X7nb were confirmed, with a peak secretion of 17.29\u2009\u00b1\u20091.84\u2009ng\/mL. SWI MRI revealed accumulation of labeled MSCs in the brain post\u2010injection, with a persistent hypointense signal ranging from 2.45%\u2009\u00b1\u20092.93% to 0.77%\u2009\u00b1\u20090.88% of cell area (% of right hemisphere) over 3 days. Behavioral assessment using the beam walk test revealed no cell transplantation\u2010related motor impairment, while histology confirmed the presence of transfected MSCs in injured brain tissue.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>MSCs expressing a P2X7nb are detectable in the injured brain following intra\u2010arterial delivery for at least 3 days, without producing adverse effects. These findings provide insights into cell\u2010based immunomodulatory therapies targeting neuroinflammation in TBI and highlight the utility of noninvasive MRI to monitor therapeutic cell biodistribution and persistence.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/nep3.70055","type":"journal-article","created":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T09:55:41Z","timestamp":1788429341000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Mesenchymal stem cells as cellular factories for targeted P2X7 blockade after traumatic brain injury"],"prefix":"10.1002","author":[{"given":"Lucia","family":"Fadon\u2010Padilla","sequence":"first","affiliation":[{"name":"Department of Diagnostic Radiology and Nuclear Medicine University of Maryland School of Medicine Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chengyan","family":"Chu","sequence":"additional","affiliation":[{"name":"Department of Diagnostic Radiology and Nuclear Medicine University of Maryland School of Medicine Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorissa","family":"McDougall","sequence":"additional","affiliation":[{"name":"Department of Diagnostic Radiology and Nuclear Medicine University of Maryland School of Medicine Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4798-4882","authenticated-orcid":false,"given":"Yajie","family":"Liang","sequence":"additional","affiliation":[{"name":"Department of Diagnostic Radiology and Nuclear Medicine University of Maryland School of Medicine Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chinmoy","family":"Sarkar","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology University of Maryland School of Medicine Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Lipinski","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology University of Maryland School of Medicine Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tim","family":"Magnus","sequence":"additional","affiliation":[{"name":"Department of Neurology University Medical Center Hamburg\u2010Eppendorf Hamburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5261-7975","authenticated-orcid":false,"given":"Miroslaw","family":"Janowski","sequence":"additional","affiliation":[{"name":"Department of Diagnostic Radiology and Nuclear Medicine University of Maryland School of Medicine Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3733-3322","authenticated-orcid":false,"given":"Piotr","family":"Walczak","sequence":"additional","affiliation":[{"name":"Department of Diagnostic Radiology and Nuclear Medicine University of Maryland School of Medicine Baltimore Maryland USA"},{"name":"Research and Development Service VA Maryland Health Care System Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,3]]},"reference":[{"issue":"1","key":"e_1_2_11_2_1","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1089\/neu.2015.4322","article-title":"Human mesenchymal stem cell treatment normalizes cortical gene expression after traumatic brain injury","volume":"34","author":"Darkazalli A","year":"2017","journal-title":"J 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rats","volume":"12","author":"Wang YC","year":"2015","journal-title":"Mol Med Rep"},{"issue":"4","key":"e_1_2_11_23_1","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1007\/s11302-017-9579-y","article-title":"Inhibition of P2X7 receptors improves outcomes after traumatic brain injury in rats","volume":"13","author":"Liu X","year":"2017","journal-title":"Purinergic Signal"},{"issue":"9","key":"e_1_2_11_24_1","doi-asserted-by":"crossref","first-page":"1073","DOI":"10.5966\/sctm.2015-0023","article-title":"Intracarotid infusion of mesenchymal stem cells in an animal model of Parkinson's disease, focusing on cell distribution and neuroprotective and behavioral effects","volume":"4","author":"Cerri S","year":"2015","journal-title":"Stem Cells Transl Med"},{"key":"e_1_2_11_25_1","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1016\/j.neulet.2013.08.058","article-title":"Mannitol enhances therapeutic effects of intra\u2010arterial transplantation of mesenchymal stem cells into the brain after traumatic brain injury","volume":"554","author":"Okuma Y","year":"2013","journal-title":"Neurosci Lett"},{"issue":"9","key":"e_1_2_11_26_1","doi-asserted-by":"crossref","first-page":"1940","DOI":"10.1007\/s00259-019-04347-y","article-title":"PET imaging of distinct brain uptake of a nanobody and similarly\u2010sized PAMAM dendrimers after intra\u2010arterial administration","volume":"46","author":"Lesniak WG","year":"2019","journal-title":"Eur J Nucl Med Mol Imaging"},{"issue":"4","key":"e_1_2_11_27_1","doi-asserted-by":"crossref","first-page":"1399","DOI":"10.7150\/thno.97254","article-title":"P2X7R antagonism suppresses long\u2010lasting brain hyperexcitability following traumatic brain injury in mice","volume":"15","author":"Alves M","year":"2025","journal-title":"Theranostics"},{"issue":"3","key":"e_1_2_11_28_1","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1002\/nep3.70006","article-title":"A comprehensive review on adaptive plasticity and recovery 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