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dc.contributor.authorWang, Rui
dc.contributor.authorChu, Chengyan
dc.contributor.authorWei, Zhiliang
dc.contributor.authorChen, Lin
dc.contributor.authorXu, Jiadi
dc.contributor.authorLiang, Yajie
dc.contributor.authorJanowski, Miroslaw
dc.contributor.authorStevens, Robert D
dc.contributor.authorWalczak, Piotr
dc.date.accessioned2021-05-03T18:32:13Z
dc.date.available2021-05-03T18:32:13Z
dc.date.issued2021-04-30
dc.identifier.urihttp://hdl.handle.net/10713/15558
dc.description.abstractBACKGROUND: Cell transplantation-based treatments for neurological disease are promising, yet graft rejection remains a major barrier to successful regenerative therapies. Our group and others have shown that long-lasting tolerance of transplanted stem cells can be achieved in the brain with systemic application of monoclonal antibodies blocking co-stimulation signaling. However, it is unknown if subsequent injury and the blood-brain barrier breach could expose the transplanted cells to systemic immune system spurring fulminant rejection and fatal encephalitis. Therefore, we investigated whether delayed traumatic brain injury (TBI) could trigger graft rejection. METHODS: Glial-restricted precursor cells (GRPs) were intracerebroventricularly transplanted in immunocompetent neonatal mice and co-stimulation blockade (CoB) was applied 0, 2, 4, and 6 days post-grafting. Bioluminescence imaging (BLI) was performed to monitor the grafted cell survival. Mice were subjected to TBI 12 weeks post-transplantation. MRI and open-field test were performed to assess the brain damage and behavioral change, respectively. The animals were decapitated at week 16 post-transplantation, and the brains were harvested. The survival and distribution of grafted cells were verified from brain sections. Hematoxylin and eosin staining (HE) was performed to observe TBI-induced brain legion, and neuroinflammation was evaluated immunohistochemically. RESULTS: BLI showed that grafted GRPs were rejected within 4 weeks after transplantation without CoB, while CoB administration resulted in long-term survival of allografts. BLI signal had a steep rise following TBI and subsequently declined but remained higher than the preinjury level. Open-field test showed TBI-induced anxiety for all animals but neither CoB nor GRP transplantation intensified the symptom. HE and MRI demonstrated a reduction in TBI-induced lesion volume in GRP-transplanted mice compared with non-transplanted mice. Brain sections further validated the survival of grafted GRPs and showed more GRPs surrounding the injured tissue. Furthermore, the brains of post-TBI shiverer mice had increased activation of microglia and astrocytes compared to post-TBI wildtype mice, but infiltration of CD45+ leukocytes remained low. CONCLUSIONS: CoB induces sustained immunological tolerance towards allografted cerebral GRPs which is not disrupted following TBI, and unexpectedly TBI may enhance GRPs engraftment and contribute to post-injury brain tissue repair.en_US
dc.description.urihttps://doi.org/10.1186/s12974-021-02152-9en_US
dc.language.isoenen_US
dc.publisherSpringer Natureen_US
dc.relation.ispartofJournal of Neuroinflammationen_US
dc.subjectCo-stimulation blockadeen_US
dc.subjectGlial-restricted progenitorsen_US
dc.subjectImmunological toleranceen_US
dc.subjectNeuroinflammationen_US
dc.subjectTraumatic brain injuryen_US
dc.titleTraumatic brain injury does not disrupt costimulatory blockade-induced immunological tolerance to glial-restricted progenitor allograftsen_US
dc.typeArticleen_US
dc.identifier.doi10.1186/s12974-021-02152-9
dc.identifier.pmid33931070
dc.source.volume18
dc.source.issue1
dc.source.beginpage104
dc.source.endpage
dc.source.countryEngland


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