{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:59:03Z","timestamp":1792789143363,"version":"4.5.0"},"reference-count":38,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2022,5,11]],"date-time":"2022-05-11T00:00:00Z","timestamp":1652227200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Basic Public Welfare Plan Project of Zhejiang Province, China","award":["LGF19H090016"],"award-info":[{"award-number":["LGF19H090016"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brain Sciences"],"abstract":"<jats:p>Mesenchymal stem cells (MSCs) have great application prospects in the treatment of ischemic injury. However, their long-time cultivation before transplantation and poor survival after transplantation greatly limit the therapeutic effect and applications. This study aimed to investigate whether MSCs under the ischemic microenvironment could improve their survival and better alleviate cerebral ischemic injury. Firstly, we used ischemic brain tissue to culture MSCs and evaluated the functional changes of MSCs. Then a middle cerebral artery occlusion (MCAO) model was induced in rats, and the pretreated MSCs were injected via the tail vein. The adhesive removal test, rotarod test, modified neurological severity score, and pathological analyses were applied to assess the rats\u2019 neurological function. Then the expression of neuron and apoptosis related markers was detected. The results indicated that ischemic brain tissue pretreated MSCs promoted the proliferation and the release of the growth factors of MSCs. Meanwhile, in MCAO model rats, transplantation of pretreated MSCs enhanced the neurogenesis, attenuated behavioral changes, reduced infarct size, and inhibited apoptosis. The expression of B-cell lymphoma-2 (Bcl-2), brain-derived neurotrophic factor (BDNF), glial fibrillary acidic protein (GFAP), NF-L, and NeuN were increased, while BCL2-Associated X (Bax) and Caspase-3 decreased. Our results suggest that MSCs pretreatment with stroke brain tissue could be an effective strategy in treating cerebral ischemic injury.<\/jats:p>","DOI":"10.3390\/brainsci12050631","type":"journal-article","created":{"date-parts":[[2022,5,11]],"date-time":"2022-05-11T10:19:46Z","timestamp":1652264386000},"page":"631","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Preconditioned MSCs Alleviate Cerebral Ischemia-Reperfusion Injury in Rats by Improving the Neurological Function and the Inhibition of Apoptosis"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8145-698X","authenticated-orcid":false,"given":"Jin","family":"Zheng","sequence":"first","affiliation":[{"name":"Department of Neurology, Tongde Hospital of Zhejiang Province, Hangzhou 310012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xueyu","family":"Mao","sequence":"additional","affiliation":[{"name":"Department of Neurology, Minhang Hospital, Fudan University, Shanghai 201199, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Delong","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Neurology, Minhang Hospital, Fudan University, Shanghai 201199, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiliang","family":"Xia","sequence":"additional","affiliation":[{"name":"Department of Neurology, Minhang Hospital, Fudan University, Shanghai 201199, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,5,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e56","DOI":"10.1161\/CIR.0000000000000659","article-title":"Heart disease and stroke statistics\u20142019 update: A report from the American heart association","volume":"139","author":"Benjamin","year":"2019","journal-title":"Circulation"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1016\/j.brainresbull.2020.09.018","article-title":"Mesenchymal stem cells-derived mitochondria transplantation mitigates I\/R-induced injury, abolishes I\/R-induced apoptosis, and restores motor function in acute ischemia stroke rat model","volume":"165","author":"Roushandeh","year":"2020","journal-title":"Brain Res. Bull."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"3517","DOI":"10.1182\/blood-2007-03-079616","article-title":"Gambogic acid, a novel ligand for transferrin receptor, potentiates TNF-induced apoptosis through modulation of the nuclear factor-kappaB signaling pathway","volume":"110","author":"Pandey","year":"2007","journal-title":"Blood"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"874","DOI":"10.1002\/ana.20501","article-title":"Autologous mesenchymal stem cell transplantation in stroke patients","volume":"57","author":"Bang","year":"2005","journal-title":"Ann. Neurol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1428","DOI":"10.1111\/jcmm.13492","article-title":"Preconditioning influences mesenchymal stem cell properties in vitro and in vivo","volume":"22","author":"Hu","year":"2018","journal-title":"J. Cell Mol. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1186\/s13287-018-1031-x","article-title":"LincRNA-p21 promotes mesenchymal stem cell migration capacity and survival through hypoxic preconditioning","volume":"9","author":"Meng","year":"2018","journal-title":"Stem Cell Res. Ther."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1038\/sj.jcbfm.9600311","article-title":"Therapeutic Benefit of Bone Marrow Stromal Cells Administered 1 Month after Stroke","volume":"27","author":"Shen","year":"2006","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1045","DOI":"10.3727\/096368908786991551","article-title":"Mesenchymal Stem Cells for Ischemic Stroke: Changes in Effects after Ex Vivo Culturing","volume":"17","author":"Li","year":"2008","journal-title":"Cell Transplant."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1683","DOI":"10.1142\/S0192415X17500914","article-title":"Angelica sinensis Exerts Angiogenic and Anti-apoptotic Effects Against Cerebral Ischemia-Reperfusion Injury by Activating p38MAPK\/HIF-1[Formula: See text]\/VEGF-A Signaling in Rats","volume":"45","author":"Cheng","year":"2017","journal-title":"Am. J. Chin. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1005","DOI":"10.1161\/01.STR.32.4.1005","article-title":"Therapeutic Benefit of Intravenous Administration of Bone Marrow Stromal Cells After Cerebral Ischemia in Rats","volume":"32","author":"Chen","year":"2001","journal-title":"Stroke"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/j.jneumeth.2012.12.021","article-title":"Characterization of long-term functional outcome in a murine model of mild brain ischemia","volume":"213","author":"Balkaya","year":"2013","journal-title":"J. Neurosci. Methods"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1016\/j.jneumeth.2010.03.026","article-title":"A rotarod test for evaluation of motor skill learning","volume":"189","author":"Shiotsuki","year":"2010","journal-title":"J. Neurosci. Methods"},{"key":"ref_13","first-page":"3099","article-title":"Concentration-dependent effects of fullerenol on cultured hippocampal neuron viability","volume":"7","author":"Zha","year":"2012","journal-title":"Int. J. Nanomed."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"586541","DOI":"10.3389\/fcell.2020.586541","article-title":"Olfactory Mucosa Mesenchymal Stem Cells Alleviate Cerebral Ischemia\/Reperfusion Injury Via Golgi Apparatus Secretory Pathway Ca2+ -ATPase Isoform1","volume":"8","author":"He","year":"2020","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_15","first-page":"394","article-title":"Functional recovery after hematic administration of allogenic mesenchymal stem cells in acute ischemic stroke in rats","volume":"175","author":"Merino","year":"2010","journal-title":"Neuroscience"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/scrt34","article-title":"New concepts on the immune modulation mediated by mesenchymal stem cells","volume":"1","author":"Bunnell","year":"2010","journal-title":"Stem Cell Res. Ther."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.expneurol.2008.11.010","article-title":"Therapeutic benefits of angiogenetic gene-modified human mesenchymal stem cells after cerebral ischemia","volume":"216","author":"Toyama","year":"2009","journal-title":"Exp. Neurol."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Coppin, L., Sokal, E., and St\u00e9phenne, X. (2019). Thrombogenic Risk Induced by Intravascular Mesenchymal Stem Cell Therapy: Current Status and Future Perspectives. Cells, 8.","DOI":"10.3390\/cells8101160"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1046\/j.1440-1789.2002.00450.x","article-title":"Ischemic rat brain extracts induce human marrow stromal cell growth factor production","volume":"22","author":"Chen","year":"2002","journal-title":"Neuropathology"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1951","DOI":"10.1159\/000489384","article-title":"Intravenously Delivered Allogeneic Mesenchymal Stem Cells Bidirectionally Regulate Inflammation and Induce Neurotrophic Effects in Distal Middle Cerebral Artery Occlusion Rats Within the First 7 Days After Stroke","volume":"46","author":"Li","year":"2018","journal-title":"Cell. Physiol. Biochem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2703","DOI":"10.1089\/scd.2011.0604","article-title":"Hypoxia-Inducible Factor 1-alpha-AA-Modified Bone Marrow Stem Cells Protect PC12 Cells from Hypoxia-Induced Apoptosis, Partially Through VEGF\/PI3K\/Akt\/FoxO1 Pathway","volume":"21","author":"Zhong","year":"2012","journal-title":"Stem Cells Dev."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1038\/pr.2017.243","article-title":"Promoting neuroregeneration after perinatal arterial ischemic stroke: Neurotrophic factors and mesenchymal stem cells","volume":"83","author":"Wagenaar","year":"2017","journal-title":"Pediatr. Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1007\/s12031-013-0119-0","article-title":"Update on Therapeutic Mechanism for Bone Marrow Stromal Cells in Ischemic Stroke","volume":"52","author":"Wan","year":"2013","journal-title":"J. Mol. Neurosci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1711","DOI":"10.1038\/jcbfm.2013.152","article-title":"Systemic administration of exosomes released from mesenchymal stromal cells promote functional recovery and neurovascular plasticity after stroke in rats","volume":"33","author":"Xin","year":"2013","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/j.neulet.2007.10.046","article-title":"Intravenous administration of bone marrow stromal cells increases survivin and Bcl-2 protein expression and improves sensorimotor function following ischemia in rats","volume":"430","author":"Okazaki","year":"2008","journal-title":"Neurosci. Lett."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Zhu, T., Wang, L., Xie, W., Meng, X., Feng, Y., Sun, G., and Sun, X. (2021). Notoginsenoside R1 Improves Cerebral Ischemia\/Reperfusion Injury by Promoting Neurogenesis via the BDNF\/Akt\/CREB Pathway. Front. Pharmacol., 12.","DOI":"10.3389\/fphar.2021.615998"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"111021","DOI":"10.1016\/j.biopha.2020.111021","article-title":"Protection against acute cerebral ischemia\/reperfusion injury by Leonuri Herba Total Alkali via modulation of BDNF-TrKB-PI3K\/Akt signaling pathway in rats","volume":"133","author":"Li","year":"2021","journal-title":"Biomed Pharmacother."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1201","DOI":"10.3892\/ijmm.2017.3106","article-title":"Endothelial cell-derived exosomes protect SH-SY5Y nerve cells against ischemia\/reperfusion injury","volume":"40","author":"Xiao","year":"2017","journal-title":"Int. J. Mol. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1007\/s10571-017-0490-4","article-title":"Effects of SDF-1\/CXCR4 on the Repair of Traumatic Brain Injury in Rats by Mediating Bone Marrow Derived Mesenchymal Stem Cells","volume":"38","author":"Deng","year":"2018","journal-title":"Cell Mol. Neurobiol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1186\/s12974-019-1597-y","article-title":"Astrocytic endothelin-1 overexpression promotes neural progenitor cells proliferation and differentiation into astrocytes via the Jak2\/Stat3 pathway after stroke","volume":"16","author":"Cheng","year":"2019","journal-title":"J. Neuroinflamm."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1161\/STROKEAHA.111.632943","article-title":"Ischemic Cerebral Damage An Appraisal of Synaptic Failure","volume":"43","author":"Hofmeijer","year":"2012","journal-title":"Stroke"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"826","DOI":"10.1007\/s10753-018-0937-x","article-title":"Honokiol Attenuates Sepsis-Associated Acute Kidney Injury via the Inhibition of Oxidative Stress and Inflammation","volume":"42","author":"Xia","year":"2019","journal-title":"Inflammation"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1186\/1479-5876-8-63","article-title":"Adipose-derived mesenchymal stem cells markedly attenuate brain infarct size and improve neurological function in rats","volume":"8","author":"Leu","year":"2010","journal-title":"J. Transl. Med."},{"key":"ref_34","first-page":"400","article-title":"Reactive Astrocytes in Neural Repair and Protection","volume":"11","author":"Sofroniew","year":"2005","journal-title":"Neurosci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"103","DOI":"10.3171\/jns.1989.70.1.0103","article-title":"Degradation of neurofilament protein in cerebral ischemia","volume":"70","author":"Ogata","year":"1989","journal-title":"J. Neurosurg."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Mages, B., Aleithe, S., Altmann, S., Blietz, A., Nitzsche, B., Barthel, H., Horn, A.K.E., Hobusch, C., H\u00e4rtig, W., and Krueger, M. (2018). Impaired Neurofilament Integrity and Neuronal Morphology in Different Models of Focal Cerebral Ischemia and Human Stroke Tissue. Front. Cell. Neurosci., 12.","DOI":"10.3389\/fncel.2018.00161"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1016\/j.brainres.2015.02.042","article-title":"Coupling of neurogenesis and angiogenesis after ischemic stroke","volume":"1623","author":"Ruan","year":"2015","journal-title":"Brain Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2449","DOI":"10.3727\/096368914X679354","article-title":"BDNF Pretreatment of Human Embryonic-Derived Neural Stem Cells Improves Cell Survival and Functional Recovery After Transplantation in Hypoxic-Ischemic Stroke","volume":"24","author":"Rosenblum","year":"2015","journal-title":"Cell Transpl."}],"container-title":["Brain Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3425\/12\/5\/631\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:09:22Z","timestamp":1760137762000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3425\/12\/5\/631"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,5,11]]},"references-count":38,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2022,5]]}},"alternative-id":["brainsci12050631"],"URL":"https:\/\/doi.org\/10.3390\/brainsci12050631","relation":{},"ISSN":["2076-3425"],"issn-type":[{"value":"2076-3425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,5,11]]}}}