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Neurovascular recovery via co-transplanted neural and vascular progenitors leads to improved functional restoration after ischemic stroke in rats.

ABSTRACT: The concept of the "neurovascular unit," emphasizing the interactions between neural and vascular components in the brain, raised the notion that neural progenitor cell (NPC) transplantation therapy aimed at neural repair may be insufficient for the treatment of ischemic stroke. Here, we demonstrate that enhanced neurovascular recovery via cotransplantation of NPCs and embryonic stem cell-derived vascular progenitor cells (VPCs) in a rat stroke model is correlated with improved functional recovery after stroke. We found that cotransplantation promoted the survival, migration, differentiation, and maturation of neuronal and vascular cells derived from the cotransplanted progenitors. Furthermore, it triggered an increased generation of VEGF-, BDNF-, and IGF1-expressing neural cells derived from the grafted NPCs. Consistently, compared with transplantation of NPCs alone, cotransplantation more effectively improved the neurobehavioral deficits and attenuated the infarct volume. Thus, cotransplantation of NPCs and VPCs represents a more effective therapeutic strategy for the treatment of stroke than transplantation of NPCs alone.

SUBMITTER: Li J

PROVIDER: S-EPMC4110773 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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Neurovascular recovery via co-transplanted neural and vascular progenitors leads to improved functional restoration after ischemic stroke in rats.

Li Jia J Tang Yaohui Y Wang Yongting Y Tang Rongbiao R Jiang Weifang W Yang Guo-Yuan GY Gao Wei-Qiang WQ

Stem cell reports 20140619 1

The concept of the "neurovascular unit," emphasizing the interactions between neural and vascular components in the brain, raised the notion that neural progenitor cell (NPC) transplantation therapy aimed at neural repair may be insufficient for the treatment of ischemic stroke. Here, we demonstrate that enhanced neurovascular recovery via cotransplantation of NPCs and embryonic stem cell-derived vascular progenitor cells (VPCs) in a rat stroke model is correlated with improved functional recove ...[more]

PMID: 25068125

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Project description:BackgroundIschemic 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.MethodsiVECs 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.ResultsiVEC 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.ConclusionsiVEC 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.

Dataset Information

Neurovascular recovery via co-transplanted neural and vascular progenitors leads to improved functional restoration after ischemic stroke in rats.

Publications

Neurovascular recovery via co-transplanted neural and vascular progenitors leads to improved functional restoration after ischemic stroke in rats.

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