Bone Marrow Stromal Cell Transplantation Attenuates Cognitive Dysfunction due to Chronic Cerebral Ischemia in Rats

Shichinohe, Hideo; Kuroda, Satoshi; Sugiyama, Taku; Ito, Masaki; Kawabori, Masahito

doi:10.1159/000320486

Cited by 15 publications

(11 citation statements)

References 78 publications

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“…Pathophysiological mechanism of post-stroke cognitive impairment is quite complicated [ 30 ]. However, recent studies have shown that the engrafted BMSCs may contribute to improve cognitive function in rodent models of chronic cerebral ischemia, although the underlying mechanisms are still unclear [ 10 ]. Indeed, both the BMSCs and non-Muse cells significantly increase the correct choice and decrease the error choice at 28 days after transplantation.…”

Section: Discussionmentioning

confidence: 99%

“…For the decades, numerous numbers of studies have indicated that the transplanted BMSCs enhance motor function recovery after the insults in animal models of various neurological disorders, including cerebral infarct [ 3 , 6 – 9 ]. They also have the potential to ameliorate cognitive dysfunction under certain conditions in diffuse axonal injury and chronic cerebral ischemia models [ 10 , 11 ]. However, there are many variables that may affect the efficacy of BMSC transplantation in the clinical setting.…”

Section: Introductionmentioning

confidence: 99%

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Therapeutic Effects of Human Multilineage-Differentiating Stress Enduring (MUSE) Cell Transplantation into Infarct Brain of Mice

et al. 2015

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ObjectiveBone marrow stromal cells (BMSCs) are heterogeneous and their therapeutic effect is pleiotropic. Multilineage-differentiating stress enduring (Muse) cells are recently identified to comprise several percentages of BMSCs, being able to differentiate into triploblastic lineages including neuronal cells and act as tissue repair cells. This study was aimed to clarify how Muse and non-Muse cells in BMSCs contribute to functional recovery after ischemic stroke.MethodsHuman BMSCs were separated into stage specific embryonic antigen-3-positive Muse cells and -negative non-Muse cells. Immunodeficient mice were subjected to permanent middle cerebral artery occlusion and received transplantation of vehicle, Muse, non-Muse or BMSCs (2.5×104 cells) into the ipsilateral striatum 7 days later.ResultsMotor function recovery in BMSC and non-Muse groups became apparent at 21 days after transplantation, but reached the plateau thereafter. In Muse group, functional recovery was not observed for up to 28 days post-transplantation, but became apparent at 35 days post-transplantation. On immunohistochemistry, only Muse cells were integrated into peri-infarct cortex and differentiate into Tuj-1- and NeuN-expressing cells, while negligible number of BMSCs and non-Muse cells remained in the peri-infarct area at 42 days post-transplantation.ConclusionsThese findings strongly suggest that Muse cells and non-Muse cells may contribute differently to tissue regeneration and functional recovery. Muse cells may be more responsible for replacement of the lost neurons through their integration into the peri-infarct cortex and spontaneous differentiation into neuronal marker-positive cells. Non-Muse cells do not remain in the host brain and may exhibit trophic effects rather than cell replacement.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Therapeutic Effects of Human Multilineage-Differentiating Stress Enduring (MUSE) Cell Transplantation into Infarct Brain of Mice

et al. 2015

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“…The QD800‐labeled BMSC were stereotactically or intravenously transplanted at 7 days after the onset of permanent MCA occlusion. In the intracerebral group ( n = 8), the QD800‐labeled BMSC were stereotactically transplanted into the right striatum, as reported previously 16,19–25 . Briefly, the animals were anesthetized under the above‐mentioned conditions.…”

Section: Methodsmentioning

confidence: 99%

Intracerebral, but not intravenous, transplantation of bone marrow stromal cells enhances functional recovery in rat cerebral infarct: An optical imaging study

Kawabori¹,

Kuroda²,

Sugiyama³

et al. 2011

Neuropathology

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Recent studies have indicated that bone marrow stromal cells (BMSC) may improve neurological function when transplanted into an animal model of CNS disorders, including cerebral infarct. However, there are few studies that evaluate the therapeutic benefits of intracerebral and intravenous BMSC transplantation for cerebral infarct. This study was aimed to clarify the favorable route of cell delivery for cerebral infarct in rats. The rats were subjected to permanent middle cerebral artery occlusion. The BMSC were labeled with near infrared (NIR)-emitting quantum dots and were transplanted stereotactically (1 × 10⁶ cells) or intravenously (3 × 10⁶ cells) at 7 days after the insult. Using in vivo NIR fluorescence imaging technique, the behaviors of BMSC were serially visualized during 4 weeks after transplantation. Motor function was also assessed. Immunohistochemistry was performed to evaluate the fate of the engrafted BMSC. Intracerebral, but not intravenous, transplantation of BMSC significantly enhanced functional recovery. In vivo NIR fluorescence imaging could clearly visualize their migration toward the cerebral infarct during 4 weeks after transplantation in the intracerebral group, but not in the intravenous, group. The BMSC were widely distributed in the ischemic brain and some of them expressed neural cell markers in the intracerebral group, but not in the intravenous group. These findings strongly suggest that intravenous administration of BMSC has limited effectiveness at clinically relevant timing and intracerebral administration should be chosen for patients with ischemic stroke, although further studies would be warranted to establish the treatment protocol.

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“…However, there are few reports on the combination of the two different neuroprotective strategies for the treatment of cerebral ischemia. Coupled with the other manuscript demonstrating its neuroprotective role on ischemic stroke[ 20 – 23 ], it is strongly suggested that combination of BMSCs transplantation and MH can significantly reduce infarction size and improve functional recovery by promoting neurogenesis and angiogenesis, which may be a beneficial treatment for cerebral ischemia.…”

Section: Discussionmentioning

confidence: 98%

Bone mesenchymal stem cells transplantation combined with mild hypothermia improves the prognosis of cerebral ischemia in rats

Wang

Zhang

et al. 2018

PLoS ONE

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Bone marrow mesenchymal stem cells (BMSCs) are used as a great promising choice for the treatment of cerebral ischemia. Herein, we discuss the neuroprotective effects of the combination of BMSCs transplantation and mild hypothermia (MH) in an ischemia-reperfusion rat model. First, BMSCs were isolated using density gradient centrifugation and the adherent screening method, followed by culture, identification and labeling with DAPI. Second, adult male SD rats were divided into 5 groups: sham group (surgery without blockage of middle cerebral artery), model group (middle cerebral artery occlusion (MCAO) was established 2h prior to reperfusion), BMSCs group (injection of BMSCs via the lateral ventricle 24h after MCAO), MH group (mild hypothermia for 3h immediately after MCAO) and combination therapy group (combination of BMSCs and MH). Finally, the modified neurological severity score (mNSS) test was performed to assess behavioral function at different time points (before MCAO, before transplantation, at day 1, day 5 and day 10 after transplantation). After that, the brain was subjected to TTC staining, and the homing and angiogenesis were evaluated by immumofluorescence and immunohistochemistry. Immunofluorescence staining and Western Blot analysis were performed to calculate the percentage of the infarct area and explore glial fibrillary acidic protein (GFAP) and vascular endothelial growth factor (VEGF). Our results showed that the combination therapy significantly decreased mNSS scores (P<0.01) and reduced the percentage of the infarct area (P<0.01) than a single treatment. Moreover, the expression of GFAP and VEGF increased significantly in the combination therapy group (at day 5, day 10 after transplantation; at all time points after transplantation, respectively) compared to the single treatment groups. Taken together, it was suggested that the combination of BMSCs transplantation and MH can significantly reduce the percentage of the infarct area and improve functional recovery by promoting homing and angiogenesis, which may be a beneficial treatment for cerebral ischemia.

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Bone Marrow Stromal Cell Transplantation Attenuates Cognitive Dysfunction due to Chronic Cerebral Ischemia in Rats

Cited by 15 publications

References 78 publications

Therapeutic Effects of Human Multilineage-Differentiating Stress Enduring (MUSE) Cell Transplantation into Infarct Brain of Mice

Therapeutic Effects of Human Multilineage-Differentiating Stress Enduring (MUSE) Cell Transplantation into Infarct Brain of Mice

Intracerebral, but not intravenous, transplantation of bone marrow stromal cells enhances functional recovery in rat cerebral infarct: An optical imaging study

Bone mesenchymal stem cells transplantation combined with mild hypothermia improves the prognosis of cerebral ischemia in rats

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