Transplanted human iPSC-derived vascular endothelial cells promote functional recovery by recruitment of regulatory T cells to ischemic white matter in the brain
Abstract Background Ischemic stroke in white matter of the brain induces not only demyelination, but also neuroinflammation. Peripheral T lymphocytes, especially regulatory T cells (Tregs), are known to infiltrate into ischemic brain and play a crucial role in modulation of inflammatory response the...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2023-01-01
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| Series: | Journal of Neuroinflammation |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12974-023-02694-0 |
| _version_ | 1828056687084306432 |
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| author | Bin Xu Hiroya Shimauchi-Ohtaki Yuhei Yoshimoto Tetsushi Sadakata Yasuki Ishizaki |
| author_facet | Bin Xu Hiroya Shimauchi-Ohtaki Yuhei Yoshimoto Tetsushi Sadakata Yasuki Ishizaki |
| author_sort | Bin Xu |
| collection | DOAJ |
| description | Abstract Background Ischemic stroke in white matter of the brain induces not only demyelination, but also neuroinflammation. Peripheral T lymphocytes, especially regulatory T cells (Tregs), are known to infiltrate into ischemic brain and play a crucial role in modulation of inflammatory response there. We previously reported that transplantation of vascular endothelial cells generated from human induced pluripotent stem cells (iVECs) ameliorated white matter infarct. The aim of this study is to investigate contribution of the immune system, especially Tregs, to the mechanism whereby iVEC transplantation ameliorates white matter infarct. Methods iVECs and human Tregs were transplanted into the site of white matter lesion seven days after induction of ischemia. The egress of T lymphocytes from lymph nodes was sequestered by treating the animals with fingolimod (FTY720). The infarct size was evaluated by magnetic resonance imaging. Immunohistochemistry was performed to detect the activated microglia and macrophages, T cells, Tregs, and oligodendrocyte lineage cells. Remyelination was examined by Luxol fast blue staining. Results iVEC transplantation reduced ED-1+ inflammatory cells and CD4+ T cells, while increased Tregs in the white matter infarct. Treatment of the animals with FTY720 suppressed neuroinflammation and reduced the number of both CD4+ T cells and Tregs in the lesion, suggesting the importance of infiltration of these peripheral immune cells into the lesion in aggravation of neuroinflammation. Suppression of neuroinflammation by FTY720 per se, however, did not promote remyelination in the infarct. FTY720 treatment negated the increase in the number of Tregs by iVEC transplantation in the infarct, and attenuated remyelination promoted by transplanted iVECs, while it did not affect the number of oligodendrocyte lineage cells increased by iVEC transplantation. Transplantation of Tregs together with iVECs into FTY720-treated ischemic white matter did not affect the number of oligodendrocyte lineage cells, while it remarkably promoted myelin regeneration. Conclusions iVEC transplantation suppresses neuroinflammation, but suppression of neuroinflammation per se does not promote remyelination. Recruitment of Tregs by transplanted iVECs contributes significantly to promotion of remyelination in the injured white matter. |
| first_indexed | 2024-04-10T21:00:36Z |
| format | Article |
| id | doaj.art-04b0447fa7a64439b6be2d574ddaee17 |
| institution | Directory Open Access Journal |
| issn | 1742-2094 |
| language | English |
| last_indexed | 2024-04-10T21:00:36Z |
| publishDate | 2023-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj.art-04b0447fa7a64439b6be2d574ddaee172023-01-22T12:20:25ZengBMCJournal of Neuroinflammation1742-20942023-01-0120111310.1186/s12974-023-02694-0Transplanted human iPSC-derived vascular endothelial cells promote functional recovery by recruitment of regulatory T cells to ischemic white matter in the brainBin Xu0Hiroya Shimauchi-Ohtaki1Yuhei Yoshimoto2Tetsushi Sadakata3Yasuki Ishizaki4Department of Molecular and Cellular Neurobiology, Gunma University Graduate School of Medicine, MaebashiDepartment of Neurosurgery, Gunma University Graduate School of MedicineDepartment of Neurosurgery, Gunma University Graduate School of MedicineEducation and Research Support Center, Gunma University Graduate School of MedicineDepartment of Molecular and Cellular Neurobiology, Gunma University Graduate School of Medicine, MaebashiAbstract Background Ischemic stroke in white matter of the brain induces not only demyelination, but also neuroinflammation. Peripheral T lymphocytes, especially regulatory T cells (Tregs), are known to infiltrate into ischemic brain and play a crucial role in modulation of inflammatory response there. We previously reported that transplantation of vascular endothelial cells generated from human induced pluripotent stem cells (iVECs) ameliorated white matter infarct. The aim of this study is to investigate contribution of the immune system, especially Tregs, to the mechanism whereby iVEC transplantation ameliorates white matter infarct. Methods iVECs and human Tregs were transplanted into the site of white matter lesion seven days after induction of ischemia. The egress of T lymphocytes from lymph nodes was sequestered by treating the animals with fingolimod (FTY720). The infarct size was evaluated by magnetic resonance imaging. Immunohistochemistry was performed to detect the activated microglia and macrophages, T cells, Tregs, and oligodendrocyte lineage cells. Remyelination was examined by Luxol fast blue staining. Results iVEC transplantation reduced ED-1+ inflammatory cells and CD4+ T cells, while increased Tregs in the white matter infarct. Treatment of the animals with FTY720 suppressed neuroinflammation and reduced the number of both CD4+ T cells and Tregs in the lesion, suggesting the importance of infiltration of these peripheral immune cells into the lesion in aggravation of neuroinflammation. Suppression of neuroinflammation by FTY720 per se, however, did not promote remyelination in the infarct. FTY720 treatment negated the increase in the number of Tregs by iVEC transplantation in the infarct, and attenuated remyelination promoted by transplanted iVECs, while it did not affect the number of oligodendrocyte lineage cells increased by iVEC transplantation. Transplantation of Tregs together with iVECs into FTY720-treated ischemic white matter did not affect the number of oligodendrocyte lineage cells, while it remarkably promoted myelin regeneration. Conclusions iVEC transplantation suppresses neuroinflammation, but suppression of neuroinflammation per se does not promote remyelination. Recruitment of Tregs by transplanted iVECs contributes significantly to promotion of remyelination in the injured white matter.https://doi.org/10.1186/s12974-023-02694-0Ischemic strokeDemyelinationCell transplantationiPS cellsEndothelial cellsNeuroinflammation |
| spellingShingle | Bin Xu Hiroya Shimauchi-Ohtaki Yuhei Yoshimoto Tetsushi Sadakata Yasuki Ishizaki Transplanted human iPSC-derived vascular endothelial cells promote functional recovery by recruitment of regulatory T cells to ischemic white matter in the brain Journal of Neuroinflammation Ischemic stroke Demyelination Cell transplantation iPS cells Endothelial cells Neuroinflammation |
| title | Transplanted human iPSC-derived vascular endothelial cells promote functional recovery by recruitment of regulatory T cells to ischemic white matter in the brain |
| title_full | Transplanted human iPSC-derived vascular endothelial cells promote functional recovery by recruitment of regulatory T cells to ischemic white matter in the brain |
| title_fullStr | Transplanted human iPSC-derived vascular endothelial cells promote functional recovery by recruitment of regulatory T cells to ischemic white matter in the brain |
| title_full_unstemmed | Transplanted human iPSC-derived vascular endothelial cells promote functional recovery by recruitment of regulatory T cells to ischemic white matter in the brain |
| title_short | Transplanted human iPSC-derived vascular endothelial cells promote functional recovery by recruitment of regulatory T cells to ischemic white matter in the brain |
| title_sort | transplanted human ipsc derived vascular endothelial cells promote functional recovery by recruitment of regulatory t cells to ischemic white matter in the brain |
| topic | Ischemic stroke Demyelination Cell transplantation iPS cells Endothelial cells Neuroinflammation |
| url | https://doi.org/10.1186/s12974-023-02694-0 |
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