Adenosine potentiates the therapeutic effects of neural stem cells expressing cytosine deaminase against metastatic brain tumors

Hyperbaric oxygen (HBO) therapy may promote neurological recovery from hypoxic-ischemic encephalopathy (HIE). However, the therapeutic effects of HBO and its associated mechanisms remain unknown. The canonical Wnt/β-catenin signaling pathways and bone morphogenetic protein (BMP) play important roles in mammalian nervous system development. The present study examined whether HBO stimulates the differentiation of neural stem cells (NSCs) and its effect on Wnt3/β-catenin and BMP2 signaling pathways. We showed HBO treatment (2 ATA, 60 min) promoted differentiation of NSCs into neurons and oligodendrocytes in vitro. In addition, rat hypoxic-ischemic brain damage (HIBD) tissue extracts also promoted the differentiation of NSCs into neurons and oligodendrocytes, with the advantage of reducing the number of astrocytes. These effects were most pronounced when these two were combined together. In addition, the expression of Wnt3a, BMP2, and β-catenin nuclear proteins were increased after HBO treatment. However, blockade of Wnt/β-catenin or BMP signaling inhibited NSC differentiation and reduced the expression of Wnt3a, BMP2, and β-catenin nuclear proteins. In conclusion, HBO promotes differentiation of NSCs into neurons and oligodendrocytes and reduced the number of astrocytes in vitro possibly through regulation of Wnt3/β-catenin and BMP2 signaling pathways. HBO may serve as a potential therapeutic strategy for treating HIE.

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Vascular Transdifferentiation in the CNS: A Focus on Neural and Glioblastoma Stem-Like Cells

Stem Cells International ◽

10.1155/2016/2759403 ◽

2016 ◽

Vol 2016 ◽

pp. 1-13 ◽

Cited By ~ 7

Author(s):

Sophie Guelfi ◽

Hugues Duffau ◽

Luc Bauchet ◽

Bernard Rothhut ◽

Jean-Philippe Hugnot

Keyword(s):

Stem Cells ◽

Brain Tumors ◽

Neural Stem Cells ◽

Vascular Cells ◽

Therapeutic Approaches ◽

Tumorigenic Potential ◽

New Directions ◽

Functional Analyses

Glioblastomas are devastating and extensively vascularized brain tumors from which glioblastoma stem-like cells (GSCs) have been isolated by many groups. These cells have a high tumorigenic potential and the capacity to generate heterogeneous phenotypes. There is growing evidence to support the possibility that these cells are derived from the accumulation of mutations in adult neural stem cells (NSCs) as well as in oligodendrocyte progenitors. It was recently reported that GSCs could transdifferentiate into endothelial-like and pericyte-like cells bothin vitroandin vivo, notably under the influence of Notch and TGFβsignaling pathways. Vascular cells derived from GBM cells were also observed directly in patient samples. These results could lead to new directions for designing original therapeutic approaches against GBM neovascularization but this specific reprogramming requires further molecular investigations. Transdifferentiation of nontumoral neural stem cells into vascular cells has also been described and conversely vascular cells may generate neural stem cells. In this review, we present and discuss these recent data. As some of them appear controversial, further validation will be needed using new technical approaches such as high throughput profiling and functional analyses to avoid experimental pitfalls and misinterpretations.

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From Blood to the Brain: Can Systemically Transplanted Mesenchymal Stem Cells Cross the Blood-Brain Barrier?

Stem Cells International ◽

10.1155/2013/435093 ◽

2013 ◽

Vol 2013 ◽

pp. 1-7 ◽

Cited By ~ 34

Author(s):

Linan Liu ◽

Mark A. Eckert ◽

Hamidreza Riazifar ◽

Dong-Ku Kang ◽

Dritan Agalliu ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Brain Tumors ◽

Blood Brain Barrier ◽

Inflammatory Diseases ◽

Neurological Diseases ◽

Brain Barrier ◽

Therapeutic Effects ◽

Blood Brain ◽

The Brain

Systemically infused mesenchymal stem cells (MSCs) are emerging therapeutics for treating stroke, acute injuries, and inflammatory diseases of the central nervous system (CNS), as well as brain tumors due to their regenerative capacity and ability to secrete trophic, immune modulatory, or other engineered therapeutic factors. It is hypothesized that transplanted MSCs home to and engraft at ischemic and injured sites in the brain in order to exert their therapeutic effects. However, whether MSCs possess the ability to migrate across the blood-brain barrier (BBB) that separates the blood from the brain remains unresolved. This review analyzes recent advances in this area in an attempt to elucidate whether systemically infused MSCs are able to actively transmigrate across the CNS endothelium, particularly under conditions of injury or stroke. Understanding the fate of transplanted MSCs and their CNS trafficking mechanisms will facilitate the development of more effective stem-cell-based therapeutics and drug delivery systems to treat neurological diseases and brain tumors.

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Sustained correction of hippocampal neurogenic and cognitive deficits after a brief treatment by Nutlin-3 in a mouse model of Fragile X Syndrome

10.1101/2022.01.14.476402 ◽

2022 ◽

Author(s):

Sahar Javadi ◽

Yue Li ◽

Jie Shen ◽

Lucy Zhao ◽

Yao Fu ◽

...

Keyword(s):

Stem Cells ◽

Young Adult ◽

Neural Stem Cells ◽

Fragile X Syndrome ◽

Cognitive Deficits ◽

Fragile X ◽

Therapeutic Effects ◽

Mature Adult ◽

Mature Adults ◽

Deficient Mice

Background: Fragile X syndrome (FXS), the most prevalent inherited intellectual disability and one of the most common monogenic form of autism, is caused by a loss of FMRP translational regulator 1 (FMR1). We have previously shown that FMR1 represses the levels and activities of ubiquitin ligase MDM2 in young adult FMR1-deficient mice and treatment by a MDM2 inhibitor Nutlin-3 rescues both hippocampal neurogenic and cognitive deficits in FMR1-deficient mice when analyzed shortly after the administration. However, it is unknown whether Nutlin-3 treatment can have long-lasting therapeutic effects. Methods: We treated 2-month-old young adult FMR1-deficient mice with Nutlin-3 for 10 days and then assessed the persistent effect of Nutlin-3 on both cognitive functions and adult neurogenesis when mice were 6-month-old mature adults. To investigate the mechanisms underlying persistent effects of Nutlin-3, we analyzed proliferation and differentiation of neural stem cells isolated from these mice and assessed the transcriptome of the hippocampal tissues of treated mice. Results: We found that transient treatment with Nutlin-3 of 2-month-old young adult FMR1-deficient mice prevents the emergence of neurogenic and cognitive deficits in mature adult FXS mice at 6-month of age. We further found that the long-lasting restoration of neurogenesis and cognitive function might not be mediated by changing intrinsic properties of adult neural stem cells. Transcriptomic analysis of the hippocampal tissue demonstrated that transient Nultin-3 treatment leads to significant expression changes in genes related to extracellular matrix, secreted factors, and cell membrane proteins in FMR1-deficient hippocampus.

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ID: 1084 Proliferative and differentiative effects of the Panax vietnamensis ethanol fraction on murine neural stem cells

Biomedical Research and Therapy ◽

10.15419/bmrat.v4is.358 ◽

2017 ◽

Vol 4 (S) ◽

pp. 172

Author(s):

Huy Quang Do ◽

Nhung Hai Truong ◽

Thanh Thai Lam ◽

Linh Thuy Nguyen ◽

Dung Minh Le ◽

...

Keyword(s):

Stem Cells ◽

Neural Stem Cells ◽

Raw Material ◽

Therapeutic Effects ◽

Sphere Diameter ◽

Rt Pcr ◽

Potential Toxicity ◽

Pathological Conditions ◽

Successive Extraction ◽

Ethanol Fraction

Background:Ginseng has been known since ancient time for its unique pharmaceutical effects on human health. Modern studies indicated that extracts of ginseng could improve a broad range of pathological conditions including neurodegenerative diseases such as Alzheimer’s or Parkinson’s disease. Panax vietnamensis, a new ginseng species recently discovered in Vietnam, has received much interest due to its high composition of both known and new saponins whose therapeutic effects have not yet fully evaluated. In this study, the proliferative and differentiative effects of different fractions of the extract of Panax vietnamensis on cultured neural stem cells would be assessed. Materials and methods: Fractions from the Panax vietnamensis were prepared following a successive extraction of the raw material using ethanol, n-butanol, ether ethylic, and water, respectively. Potential toxicity and proliferative effects of each fraction were assessed based on the increase in the sphere diameter in before further analyses. The percentage of cells in active phases, cell cycle- or differentiation-associated genes were analyzed using flow cytometry and real-time RT-PCR. Results:Our results revealed that supplementing media with 200 µg/ml of ethanol Panax vietnamensis fraction significantly increased diameters of neurospheres, also maintained the growth rate of the neurospheres compared with the control within the five-day period. Moreover, the results also demonstrated that the ginseng ethanol fraction and a known neurotrophic protein, NGF, affected the differentiation of the neural stem cells. Conclusion:200 µg/ml ethanol fraction from the extract of Panax vietnamensis most significantly induced the proliferation of cultured neural stem cells. However, the higher concentration of the fraction seemed not to maintain the growth of neurospheres. Regarding differentiation, the ethanol fraction of Vietnamese ginseng possibly shared similar mechanisms with the neurotrophic growth factor.

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