Regulation Of Neural Stem Cells Research Articles

Abstract 4968: Msi2 directly linked to Hedgehog and Wnt signaling in non-triple negative breast cancer

Abstract Introduction: Previously, we have shown that a gain on 17q22.24.2 was a predictor of invasiveness when found in duct carcinoma in situ (DCIS) and of nodal metastasis when found in invasive duct carcinoma (IDC). Within this amplicon, we have identified a gene that is a likely driver of breast tumorigenesis and progression: Musashi homolog 2 (Msi2). Msi2 has a functional role in neural stem cell maintenance and regulation of hematopoietic stem cells. Previously, Msi2 has been implicated in Notch and Hedgehog signaling in leukemia, and here we link Msi2 to an increase in Wnt activation. Methodology: To understand the expression of Msi2 in patient tissue, tissue microarrays (TMAs) containing 232 breast cancers were analyzed by immunohistochemistry. MDA-MB-231 and MCF7 cells expressing Msi2-GFP and GFP clones were plated on transwells to examine cell migration and invasiveness. Proliferation was analyzed by the MTS assay. TOP-FOP and Gli1 Luciferase assays were used to confirm activation of Hedgehog and Wnt signaling. Western blots were used to assess total beta-catenin levels in the cell lines. Analysis of publicly available expression microarray databases and RT-PCR of the over-expression cell lines validated the proposed mechanism of action. Results: Tissue microarrays confirmed that Allred scores for Msi2 significantly correlated with grade, size stage, and non-triple negative receptor status. Over-expression of Msi2, in MDA-MB-231 (triple negative) and MCF7 (luminal cell type with epithelial morphology) cell lines, caused an increase in proliferation, migration and invasion. The knockdowns demonstrated the reverse effect. As determined by the TOP-FOP luciferase assay and RT-PCR, Msi2 leads to increased signaling of Hedgehog and Wnt. Furthermore, Msi2-mediated activation of Wnt occurs independently of total beta-catenin levels. Microarray analysis of breast cancer cell lines and patients' tumors supports this mechanism of action for Msi2 in non-triple negative cell lines (as assessed by Pearson's correlation coefficient of pathway interactions). Conclusion: When overexpressed in a cancerous cell system in vitro, Msi2 levels correlate with increased migratory and invasive capabilities. Furthermore, its implication in Notch, Hedgehog, and Wnt Signaling, make Msi2 a likely driver of the 17q22-24.2 amplicon in breast cancer. This study furthers our understanding of Msi2, and hints at the possibility that Msi2 plays a more significant role in cellular events and tumorigenesis than previously thought. Citation Format: Moustafa Abdalla, Nisha Kanwar, Yanglong Zhu, Ranju Nair, Bruce J. Youngson, Naomi A. Miller, Tianyu Liu, Susan J. Done. Msi2 directly linked to Hedgehog and Wnt signaling in non-triple negative breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4968. doi:10.1158/1538-7445.AM2014-4968

Adult neurogenesis: taking stock in Stockholm.

In May this year, Stockholm hosted a Keystone Symposium on Adult Neurogenesis, attracting scientists from around the world despite the lack of customary snow. The symposium offered an extraordinary program, covering diverse topics that ranged from the neural stem cell lineage and regulation of neurogenesis to functional aspects of neurogenesis in homeostasis and disease, and even computational modeling. This Meeting Review describes some of the exciting presentations and emerging themes from the symposium, which reveal how much this young field has matured.

Notch intracellular domain deficiency in nuclear localization activity retains the ability to enhance neural stem cell character and block neurogenesis in mammalian brain development.

Notch has a broad range of regulatory functions in many developmental processes, including hematopoiesis, neurogenesis, and angiogenesis. Notch has several key functional regions such as the RBP-Jκ/CBF1 association module (RAM) domain, nuclear localization signals (NLS), and ankyrin (ANK) repeats. However, previous reports assessing the level of importance of these domains in the Notch signaling pathway are controversial. In this study, we have assessed the level of contribution of each Notch domain to the regulation of mammalian neural stem cells in vivo as well as in vitro. Reporter assays and real-time polymerase chain reactions show that the ANK repeats and RAM domain are indispensable to the transactivation of Notch target genes, whereas a nuclear export signal (NES)-fused Notch intracellular domain (NICD) mutant defective in nuclear localization exerts a level of activity comparable to unmodified NICD. Transactivational ability appears to be tightly coupled to Notch functions during brain development. Unlike ANK repeats and RAM domain deletion mutants, NES-NICD recapitulates NICD features such as promotion of astrogenesis at the expense of neurogenesis in vitro and enhancement of neural stem cell character in vivo. Our data support the previous observation that intranuclear localization is not essential to the oncogenesis of Notch1 in certain types of cells and imply the importance of the noncanonical Notch signaling pathway in the regulation of mammalian neural stem cells.

A Time and Place for Understanding Neural Stem Cell Specification

The regulation of neural stem cells is key to their use for repair. Reporting in this issue of Developmental Cell, Dirian et al. (2014) identify an adult neural stem cell population surprisingly distinct in Notch independence, lack of radial glia hallmarks, and late contribution to neurogenesis in a strikingly region-specific manner.

EPHRINA2 RECEPTOR IN HUMAN GLIOBLASTOMA CANCER STEM CELLS AND IDENTIFICATION OF NEW, PUTATIVE THERAPEUTIC TARGETS

BACKGROUND: Human glioblastomas (hGBMs) have been shown to embody a relatively small subset of cells which bear the defining features of somatic stem cells and the ability to establish, expand and perpetuate these tumors. They are defined cancer stem cell or tumor propagating cells (TPCs). This has caused a paradigmatic shift in the way we interpret hGBM physiology, for it identifies TPCs as a major culprit to be tackled for the development of novel therapeutics. Hence, we inferred that the study of regulatory mechanisms of normal neurogenesis may lead us to identify specific inhibitors of TPCs. METHODS: TPCs from human GBMs were used to determine the role of a neural stem cell regulator, the EphA2 receptor, in modulating self-renewal and tumorigenicity. We used a combined series of in vitro experiments which include primary tissue cultures, FACS analysis, next generation sequencing screening and in vivo, orthotopic xenografting experiments entailing the intracerebral delivery of putative therapeutic agents. RESULTS: We determined the over-expression of the Ephrin receptor type A2 (EphA2) in hGBM TPCs. EphA2 upregulation causally underlies self-renewal and expansion of the TPCs pool. Most important, both the EphA2 cognate ligand ephrinA1-Fc causes EphA2 downregulation in TPCs and suppress TPC self-renewal and intracranial tumorigenicity. This points to EphA2 as a key effector in TPCs self-renewal and tumorigenicity. Notably, intracranial administration of ephrinA1-Fc causes both down-regulation of EphA2 in hGBMs orthotopic xenografts pre-established in mice, whose growth and expansion throughout the brain parenchyma is significantly hindered in the absence of cytotoxic effects. CONCLUSIONS: We identify TPCs as a major target of EphA2 overexpression in hGBM, that drives their self-renewal and tumorigenicity. We propose TPCs as a specific cellular target in which enforced down-regulation of a molecular target such as EphA2 may be exploited for therapeutic purposes, under therapy-like scenarios. In addition cytofluorimetric sorting into EphA2-high and EphA2-low populations demonstrates that EphA2 expression correlates with the size of the hGBM, TPC pool and that this can be used to purify TPCs. We have exploited this technique in a comparative next generation sequencing approach, in which the transcriptomic profile of purified TPCs was compared to that of their non-tumorigenic siblings from the same FACS preparation. We identified a series of putative TPC critical regulators involved in self-renewal and invasion. This investigation is being deepened and the most cogent findings on this subject will be discussed in our presentation. SECONDARY CATEGORY: Preclinical Experimental Therapeutics.

MRNA-Seq and microRNA-Seq whole-transcriptome analyses of rhesus monkey embryonic stem cell neural differentiation revealed the potential regulators of rosette neural stem cells.

Rosette neural stem cells (R-NSCs) represent early stage of neural development and possess full neural differentiation and regionalization capacities. R-NSCs are considered as stem cells of neural lineage and have important implications in the study of neurogenesis and cell replacement therapy. However, the molecules regulating their functional properties remain largely unknown. Rhesus monkey is an ideal model to study human neural degenerative diseases and plays intermediate translational roles as therapeutic strategies evolved from rodent systems to human clinical applications. In this study, we derived R-NSCs from rhesus monkey embryonic stem cells (ESCs) and systematically investigated the unique expressions of mRNAs, microRNAs (miRNAs), and signalling pathways by genome-wide comparison of the mRNA and miRNA profilings of ESCs, R-NSCs at early (R-NSCP1) and late (R-NSCP6) passages, and neural progenitor cells. Apart from the R-NSCP1-specific protein-coding genes and miRNAs, we identified several pathways including Hedgehog and Wnt highly activated in R-NSCP1. The possible regulatory interactions among the miRNAs, protein-coding genes, and signalling pathways were proposed. Besides, many genes with alternative splicing switch were identified at R-NSCP1. These data provided valuable resource to understand the regulation of early neurogenesis and to better manipulate the R-NSCs for cell replacement therapy.

Performance and Mechanism of Neuroleukin in the Growth and Survival of Sertoli Cell-Induced Neurons in a Coculture System

Sertoli cells (SCs), which are recognized as the "nurse cells" of the testis due to their important biofunctions, have been used in cotransplantation with neurons in cell therapy. However, it is not clear whether SCs influence neuronal communication and survival. In this study, we showed that approximately 60% of cortical neural stem cells (NSCs) cocultured with SCs differentiated into mature neurons. In addition, the neurite outgrowth and neuronal survival rates were significantly enhanced in the coculture system compared with differentiated neurons induced by a differentiation medium. The neuroleukin (NLK) secretion of SCs was also identified at the RNA and protein level, and the roles of NLK in neuromorphology and physiological regulation were systematically investigated for the first time. These results not only highlight the significance of paracrine regulation of NSCs by SCs but also confirm the role NLK plays in the differentiation and survival of NSCs. Finally, we proposed a possible hypothesis for the mechanism of NLK in the growth and survival of SC-induced neurons based on Western blotting results, which is that NLK secreted by SCs activates the Ras/Raf/MEK/Erk, Jak/Stat, and PI3K/Akt pathways, but not the NF-κB pathway, in neurons resulting in their growth and survival.

Complex Roles of Notch Signaling in the Development of Temporal Lobe Epilepsy: Evidence and Speculation

The Notch pathway is well known as a master regulator of neural stem cells, but accumulating evidence suggest both novel and sophisticated roles for Notch signaling in adult brain. In the postnatal hippocampus, the regulatory function of Notch signaling on synaptic plasticity has been studied extensively. Mice with germline deletion of Notch1 or presenilins exhibited impaired long-term potentiation (LTP) and working memory, which could be understood as a consequence of disruptions in Notch-dependent neurite development and neuronal migration. Compared with long-term synaptic plasticity, recent studies have shown that Notch pathway is induced instantly by neuronal activity, suggesting a correlate of stimulus-dependent Notch activity and synaptic transmission. However, the role of those non-canonical functions of Notch signaling in neurological disorders has not been characterized so far. More recently, we have reported that Notch signaling activation led to an increase in epileptiform discharges in a mouse model of acute seizures. Temporal lobe epilepsy (TLE) is among the most frequent types of drug-resistant epilepsy, and the reorganization of neural circuits underlying the generation of recurrent seizures has been demonstrated, including impaired long-term potentiation of synaptic networks and disordered short-term synaptic responses. Here, focusing on the primary and new-emerging functions of Notch signaling, we review the complicated roles of Notch in the development of TLE and speculate some potential neuropathogenic mechanisms.

Epigenetic regulation of adult neural stem cells: implications for Alzheimer's disease.

Experimental evidence has demonstrated that several aspects of adult neural stem cells (NSCs), including their quiescence, proliferation, fate specification and differentiation, are regulated by epigenetic mechanisms. These control the expression of specific sets of genes, often including those encoding for small non-coding RNAs, indicating a complex interplay between various epigenetic factors and cellular functions.Previous studies had indicated that in addition to the neuropathology in Alzheimer’s disease (AD), plasticity-related changes are observed in brain areas with ongoing neurogenesis, like the hippocampus and subventricular zone. Given the role of stem cells e.g. in hippocampal functions like cognition, and given their potential for brain repair, we here review the epigenetic mechanisms relevant for NSCs and AD etiology. Understanding the molecular mechanisms involved in the epigenetic regulation of adult NSCs will advance our knowledge on the role of adult neurogenesis in degeneration and possibly regeneration in the AD brain.

Chapter Two - MicroRNAs and Epigenetics in Adult Neurogenesis

Neurogenesis occurs throughout adulthood in the mammalian brain. Neural stem cells (NSCs) exist in three distinct areas of the brain: the subventricular zone, the olfactory bulb, and the dentate gyrus of the hippocampus. MicroRNAs (miRNAs) are small noncoding RNA molecules that posttranscriptionally regulate gene expression. Epigenetic regulation of gene expression, which includes DNA methylation and histone modification, plays a significant role in modulating NSC proliferation and differentiation. However, the functions of miRNAs in neurogenesis are just beginning to be understood. Based on the recent literature, miRNAs are suggested to play an important role in the epigenetic regulation of NSCs and differentiation of lineage populations, which include neurons, astrocytes, and oligodendrocytes. Recent studies have elucidated the roles of miRNAs in embryonic and adult neurogenesis, specifically, their involvement in stem cell maintenance and differentiation, neuronal maturation and neurite outgrowth, dendritogenesis, and spine formation. The cross-talk between miRNAs and epigenetic regulators appears to modulate neurogenesis in the adult mammalian brain. Since the dysfunction in miRNA machinery contributes to many types of neurodegenerative disorders, a better understanding of how miRNAs influence the neurogenesis and differentiation may offer novel targets for therapeutic application.

Roles of PINK1, mTORC2, and mitochondria in preserving brain tumor-forming stem cells in a noncanonical Notch signaling pathway

The self-renewal versus differentiation choice of Drosophila and mammalian neural stem cells (NSCs) requires Notch (N) signaling. How N regulates NSC behavior is not well understood. Here we show that canonical N signaling cooperates with a noncanonical N signaling pathway to mediate N-directed NSC regulation. In the noncanonical pathway, N interacts with PTEN-induced kinase 1 (PINK1) to influence mitochondrial function, activating mechanistic target of rapamycin complex 2 (mTORC2)/AKT signaling. Importantly, attenuating noncanonical N signaling preferentially impaired the maintenance of Drosophila and human cancer stem cell-like tumor-forming cells. Our results emphasize the importance of mitochondria to N and NSC biology, with important implications for diseases associated with aberrant N signaling.

Shifts in the vascular endothelial growth factor isoforms result in transcriptome changes correlated with early neural stem cell proliferation and differentiation in mouse forebrain

Regulation of neural stem cell (NSC) fate decisions is critical during the transition from a multicellular mammalian forebrain neuroepithelium to the multilayered neocortex. Forebrain development requires coordinated vascular investment alongside NSC differentiation. Vascular endothelial growth factor A (Vegf) has proven to be a pleiotrophic gene whose multiple protein isoforms regulate a broad range of effects in neurovascular systems. To test the hypothesis that the Vegf isoforms (120, 164, and 188) are required for normal forebrain development, we analyzed the forebrain transcriptome of mice expressing specific Vegf isoforms, Vegf120, VegfF188, or a combination of Vegf120/188. Transcriptome analysis identified differentially expressed genes in embryonic day (E) 9.5 forebrain, a time point preceding dramatic neuroepithelial expansion and vascular investment in the telencephalon. Meta-analysis identified gene pathways linked to chromosome-level modifications, cell fate regulation, and neurogenesis that were altered in Vegf isoform mice. Based on these gene network shifts, we predicted that NSC populations would be affected in later stages of forebrain development. In the E11.5 telencephalon, we quantified mitotic cells [Phospho-Histone H3 (pHH3)-positive] and intermediate progenitor cells (Tbr2/Eomes-positive), observing quantitative and qualitative shifts in these populations. We observed qualitative shifts in cortical layering at P0, particularly with Ctip2-positive cells in layer V. The results identify a suite of genes and functional gene networks that can be used to further dissect the role of Vegf in regulating NSC differentiation and downstream consequences for NSC fate decisions.

Bone Marrow Mesenchymal Stem Cells Stimulate Proliferation and Neuronal Differentiation of Retinal Progenitor Cells

During retina development, retinal progenitor cell (RPC) proliferation and differentiation are regulated by complex inter- and intracellular interactions. Bone marrow mesenchymal stem cells (BMSCs) are reported to express a variety of cytokines and neurotrophic factors, which have powerful trophic and protective functions for neural tissue-derived cells. Here, we show that the expanded RPC cultures treated with BMSC-derived conditioned medium (CM) which was substantially enriched for bFGF and CNTF, expressed clearly increased levels of nuclear receptor TLX, an essential regulator of neural stem cell (NSC) self-renewal, as well as betacellulin (BTC), an EGF-like protein described as supporting NSC expansion. The BMSC CM- or bFGF-treated RPCs also displayed an obviously enhanced proliferation capability, while BMSC CM-derived bFGF knocked down by anti-bFGF, the effect of BMSC CM on enhancing RPC proliferation was partly reversed. Under differentiation conditions, treatment with BMSC CM or CNTF markedly favoured RPC differentiation towards retinal neurons, including Brn3a-positive retinal ganglion cells (RGCs) and rhodopsin-positive photoreceptors, and clearly diminished retinal glial cell differentiation. These findings demonstrate that BMSCs supported RPC proliferation and neuronal differentiation which may be partly mediated by BMSC CM-derived bFGF and CNTF, reveal potential limitations of RPC culture systems, and suggest a means for optimizing RPC cell fate determination in vitro.

Basic Fibroblast Growth Factor (bFGF) Facilitates Differentiation of Adult Dorsal Root Ganglia-Derived Neural Stem Cells Toward Schwann Cells by Binding to FGFR-1 Through MAPK/ERK Activation

Considerable research has been devoted to unraveling the regulation of neural stem cell (NSC) differentiation. The responses of NSCs to various differentiation-inducing stimuli, however, are still difficult to estimate. In this study, we aimed to search for a potent growth factor that was able to effectively induce differentiation of NSCs toward Schwann cells. NSCs were isolated from dorsal root ganglia (DRGs) of adult rats and identified by immunostaining. Three different growth factors were used to stimulate the differentiation of DRG-derived NSCs (DRG-NSCs). We found that among these three growth factors, bFGF was the strongest inducer for the glial differentiation of DRG-NSCs, and bFGF induced the generation of an increased number of Schwann cell-like cells as compared to nerve growth factor (NGF) and neuregulin1-β (NRG). These Schwann cell-like cells demonstrated the same characteristics as those of primary Schwann cells. Furthermore, we noted that bFGF-induced differentiation of DRG-NSCs toward Schwann cells might be mediated by binding to fibroblast growth factor receptor-1 (FGFR-1) through activation of MAPK/ERK signal pathway.

Fibroblast Growth Factor-2 Signaling in Neurogenesis and Neurodegeneration

Fibroblast growth factor-2 (FGF2), also known as basic FGF, is a multi-functional growth factor. One of the 22-member FGF family, it signals through receptor tyrosine kinases encoding FGFR1-4. FGF2 activates FGFRs in cooperation with heparin or heparin sulfate proteoglycan to induce its pleiotropic effects in different tissues and organs, which include potent angiogenic effects and important roles in the differentiation and function of the central nervous system (CNS). FGF2 is crucial to development of the CNS, which explains its importance in adult neurogenesis. During development, high levels of FGF2 are detected from neurulation onwards. Moreover, developmental expression of FGF2 and its receptors is temporally and spatially regulated, concurring with development of specific brain regions including the hippocampus and substantia nigra pars compacta. In adult neurogenesis, FGF2 has been implicated based on its expression and regulation of neural stem and progenitor cells in the neurogenic niches, the subventricular zone (SVZ) and the subgranular zone (SGZ) of the hippocampal dentate gyrus. FGFR1 signaling also modulates inflammatory signaling through the surface glycoprotein CD200, which regulates microglial activation. Because of its importance in adult neurogenesis and neuroinflammation, manipulation of FGF2/FGFR1 signaling has been a focus of therapeutic development for neurodegenerative disorders, such as Alzheimer's disease, multiple sclerosis, Parkinson's disease and traumatic brain injury. Novel strategies include intranasal administration of FGF2, administration of an NCAM-derived FGFR1 agonist, and chitosan-based nanoparticles for the delivery of FGF2 in pre-clinical animal models. In this review, we highlight current research towards therapeutic interventions targeting FGF2/FGFR1 in neurodegenerative disorders.

Stimulation of adult neural stem cells with a novel glycolipid biosurfactant

Glycolipids are amphipathic molecules which are highly expressed on cell membranes in skin and brain where they mediate several key cellular processes. Neural stem cells are defined as undifferentiated, proliferative, multipotential cells with extensive self-renewal and are responsive to brain injury. Di-rhamnolipid: α-L-rhamnopyranosyl-(1-2)α-L-rhamnopyranosyl-3-hydroxydecanoyl-3-hydroxydecanoic acid, also referred to as di-rhamnolipid BAC-3, is a glycolipid isolated from the bacteria Pseudomonas aeruginosa. In the previous studies, di-rhamnolipid enhanced dermal tissue healing and regeneration. The present study provides the first assessment of di-rhamnolipid, and glycolipid biosurfactants in general, on the nervous system. Treatment of neural stem cells isolated from the lateral ventricle of adult mice and cultured in defined media containing growth factors at 0.5 and 1 μg/ml of di-rhamnolipid increased the number of neurospheres (2.7- and 2.8-fold, respectively) compared to controls and this effect remained even after passaging in the absence of di-rhamnolipid. In addition, neural stem cells treated with di-rhamnolipid at 50 and 100 μg/ml in defined media supplemented with fetal calf serum and without growth factors exhibited increased cell viability, indicating an interaction between di-rhamnolipid and serum components in the regulation of neural stem cells and neuroprogenitors. Intracerebroventricular administration of di-rhamnolipid at 300 and 120 ng/day increased the number of neurospheres (1.3- and 1.63-fold, respectively) that could be derived from the anterior lateral ventricles of adult mice. These results indicate that di-rhamnolipid stimulates proliferation of neural stem cells and increases their endogenous pools which may have therapeutic potential in managing neurodegenerative or neuropsychiatric disorders and promoting nervous tissue regeneration following injury.

MicroRNA let-7d regulates the TLX/microRNA-9 cascade to control neural cell fate and neurogenesis

MicroRNAs have important functions in the nervous system through post-transcriptional regulation of neurogenesis genes. Here we show that microRNA let-7d, which has been implicated in cocaine addiction and other neurological disorders, targets the neural stem cell regulator TLX. Overexpression of let-7d in vivo reduced neural stem cell proliferation and promoted premature neuronal differentiation and migration, a phenotype similar to those induced by TLX knockdown or overexpression of its negatively-regulated target, microRNA-9. We found a let-7d binding sequence in the tlx 3′ UTR and demonstrated that let-7d reduced TLX expression levels in neural stem cells, which in turn, up-regulated miR-9 expression. Moreover, co-expression of let-7d and TLX lacking its 3′ UTR in vivo restored neural stem cell proliferation and reversed the premature neuronal differentiation and migration. Therefore, manipulating let-7d and its downstream targets could be a novel strategy to unravel neurogenic signaling pathways and identify potential interventions for relevant neurological disorders.

SoxB, cell cycle and neurogenesis

SoxB, cell cycle and neurogenesis

PPARγ regulates the mitochondrial dysfunction in human neural stem cells with tumor necrosis factor alpha

Peroxisome proliferator-activated receptor gamma (PPARγ) belongs to a family of ligand-activated transcription factors, and its ligands are known to control many physiological and pathological conditions. The hypothesis of our study was that the PPARγ agonist (rosiglitazone) could mediate tumor necrosis factor alpha (TNFα) related to the regulation of human neural stem cells (hNSCs), by which TNFα possibly fulfills important roles in neuronal impairment. The results show that PPARγ mediates the cell viability of hNSCs via the downregulation of the activity of caspase 3, indicating that this rescue effect of PPARγ could improve the reduced levels of two mitochondrial regulators, adenosine monophosphate-activated protein kinase (AMPK) and Sirtuin 1 (SIRT1) in the hNSCs with TNFα. The stimulation of mitochondrial function by PPARγ was associated with activation of the PPAR coactivator1 alpha (PGC1α) pathway by up-regulation of oxidative defense and mitochondrial systems. The above protective effects appeared to be exerted by a direct activation of the rosiglitazone, because it protected hNSCs from TNFα-evoked oxidative stress and mitochondrial deficiency. Here we show that the rosiglitazone protects hNSCs against Aβ-induced apoptosis and promotes cell survival. These findings extend our understanding of the central role of PPARγ in TNFα-related neuronal impairment, which probably increases risks of neurodegenerative diseases. The anti-inflammatory effects of PPARγ in the hNSCs with TNFα, and the involved mechanisms were also characterized.

Comparison of Spheroids Formed by Rat Glioma Stem Cells and Neural Stem Cells Reveals Differences in Glucose Metabolism and Promising Therapeutic Applications

Cancer stem cells (CSCs) are thought to be partially responsible for cancer resistance to current therapies and tumor recurrence. Dichloroacetate (DCA), a compound capable of shifting metabolism from glycolysis to glucose oxidation, via an inhibition of pyruvate dehydrogenase kinase was used. We show that DCA is able to shift the pyruvate metabolism in rat glioma CSCs but has no effect in rat neural stem cells. DCA forces CSCs into oxidative phosphorylation but does not trigger the production of reactive oxygen species and consecutive anti-cancer apoptosis. However, DCA, associated with etoposide or irradiation, induced a Bax-dependent apoptosis in CSCs in vitro and decreased their proliferation in vivo. The former phenomenon is related to DCA-induced Foxo3 and p53 expression, resulting in the overexpression of BH3-only proteins (Bad, Noxa, and Puma), which in turn facilitates Bax-dependent apoptosis. Our results demonstrate that a small drug available for clinical studies potentiates the induction of apoptosis in glioma CSCs.