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Protective effects of primary neural stem cell treatment in ischemic stroke models.

ABSTRACT: Strokes are a major cause of neurological disability. Stem cell replacement therapy is a potential novel strategy of treating patients that have experienced strokes. The present study examined the protective role of neural stem cell (NSC) administration in oxygen-glucose deprivation (OGD) injury and ischemic stroke animal models. Primary cultured embryonic NSCs and brain microvascular endothelial cells were indirectly co-cultured for in vitro testing. A rat model of embolic middle cerebral artery occlusion (MCAO) was used to assess the morphological and functional changes that occur following treatment with NSCs. The role of the phosphoinositide 3-kinase/protein kinase b/glycogen synthase kinase 3? (PI3K/Akt/GSK-3?) signaling pathway in the neuroprotective effects of NSC treatment was also determined. It was demonstrated in vivo and in vitro that NSC administration may attenuate the brain injury caused by stroke. Furthermore, the results suggest that activation of PI3k/Akt/GSK-3? signaling pathway serves a role in attenuating OGD injury. Inflammation, synaptic remodeling and autophagy may be improved following NSC treatment and behavioral testing suggests that treatment with NSCs improves functional recovery in rats following MCAO.

SUBMITTER: Yu X

PROVIDER: S-EPMC6122422 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Protective effects of primary neural stem cell treatment in ischemic stroke models.

Yu Xiaowen X Wang Xiaoqing X Zeng Shuxiong S Tuo Xiping X

Experimental and therapeutic medicine 20180718 3

Strokes are a major cause of neurological disability. Stem cell replacement therapy is a potential novel strategy of treating patients that have experienced strokes. The present study examined the protective role of neural stem cell (NSC) administration in oxygen-glucose deprivation (OGD) injury and ischemic stroke animal models. Primary cultured embryonic NSCs and brain microvascular endothelial cells were indirectly co-cultured for in vitro testing. A rat model of embolic middle cerebral arter ...[more]

PMID: 30186461

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Project description:Transplantation of neural stem cells (NSCs) has been proposed as an alternative novel therapy to replace damaged neural circuitry after ischemic stroke onset. Nonetheless, albeit the potential of these cells for stroke therapy, many critical challenges are yet to be overcome to reach clinical applications. The major limitation of the NSC-based therapy is its inability to retain most of the donor stem cells after grafting into an ischemic brain area which is lacking of essential oxygen and nutrients for the survival of transplanted cells. Low cell survival rate limits the capacity of NSCs to repair the injured area and this poses a much more difficult challenge to the NSC-based therapy for ischemic stroke. In order to enhance the survival of transplanted cells, several stem cell culture preconditioning strategies have been employed. For ischemic diseases, hypoxic preconditioning is the most commonly applied strategy since the last few decades. Now, the preconditioning strategies have been developed and expanded enormously throughout years of efforts. This review systematically presented studies searched from PubMed, ScienceDirect, Web of Science, Scopus and the Google Scholar database up to 31 March 2020 based on search words containing the following terms: "precondition" or "pretreatment" and "neural stem cell" and "ischemic stroke". The searched data comprehensively reported seven major NSC preconditioning strategies including hypoxic condition, small drug molecules such as minocycline, doxycycline, interleukin-6, adjudin, sodium butyrate and nicorandil, as well as electrical stimulation using conductive polymer for ischemic stroke treatment. We discussed therapeutic benefits gained from these preconditioned NSC for in vitro and in vivo stroke studies and the detailed insights of the mechanisms underlying these preconditioning approaches. Nonetheless, we noticed that there was a scarcity of evidence on the efficacy of these preconditioned NSCs in human clinical studies, therefore, it is still too early to draw a definitive conclusion on the efficacy and safety of this active compound for patient usage. Thus, we suggest for more in-depth clinical investigations of this cell-based therapy to develop into more conscientious and judicious evidence-based therapy for clinical application in the future.

Project description:JOURNAL/nrgr/04.03/01300535-202408000-00031/figure1/v/2023-12-16T180322Z/r/image-tiff Proliferation of neural stem cells is crucial for promoting neuronal regeneration and repairing cerebral infarction damage. Transcranial magnetic stimulation (TMS) has recently emerged as a tool for inducing endogenous neural stem cell regeneration, but its underlying mechanisms remain unclear. In this study, we found that repetitive TMS effectively promotes the proliferation of oxygen-glucose deprived neural stem cells. Additionally, repetitive TMS reduced the volume of cerebral infarction in a rat model of ischemic stroke caused by middle cerebral artery occlusion, improved rat cognitive function, and promoted the proliferation of neural stem cells in the ischemic penumbra. RNA-sequencing found that repetitive TMS activated the Wnt signaling pathway in the ischemic penumbra of rats with cerebral ischemia. Furthermore, PCR analysis revealed that repetitive TMS promoted AKT phosphorylation, leading to an increase in mRNA levels of cell cycle-related proteins such as Cdk2 and Cdk4. This effect was also associated with activation of the glycogen synthase kinase 3β/β-catenin signaling pathway, which ultimately promotes the proliferation of neural stem cells. Subsequently, we validated the effect of repetitive TMS on AKT phosphorylation. We found that repetitive TMS promoted Ca2+ influx into neural stem cells by activating the P2 calcium channel/calmodulin pathway, thereby promoting AKT phosphorylation and activating the glycogen synthase kinase 3β/β-catenin pathway. These findings indicate that repetitive TMS can promote the proliferation of endogenous neural stem cells through a Ca2+ influx-dependent phosphorylated AKT/glycogen synthase kinase 3β/β-catenin signaling pathway. This study has produced pioneering results on the intrinsic mechanism of repetitive TMS to promote neural function recovery after ischemic stroke. These results provide a strong scientific foundation for the clinical application of repetitive TMS. Moreover, repetitive TMS treatment may not only be an efficient and potential approach to support neurogenesis for further therapeutic applications, but also provide an effective platform for the expansion of neural stem cells.

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Protective effects of primary neural stem cell treatment in ischemic stroke models.

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Protective effects of primary neural stem cell treatment in ischemic stroke models.

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