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Schematic representation of neurogenesis and gliogenesis processes during development and in adulthood.
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A2B5 IgM recognizes c-series gangliosides with three sialic acids. The aim of this review was to focus on A2B5 expression in the central nervous system and gliomas. In brain development, A2B5+ cells are recorded in areas containing multipotent neural stem cells (NSC). In adults, A2B5+ cells persist in neurogenic areas and in white matter where it i...
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... the embryonic development of the vertebrate nervous system, neurons and glia (including astrocytes, oligodendrocytes and ependymal cells) derive from multipotent neural stem cells (NSCs) located in the neuroepithelium (Figure 2). These NSCs undergo symmetric division that expands the neuroepithelial surface area and therefore the pool of NSCs, although some can generate neurons. ...
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... the embryonic development of the vertebrate nervous system, neurons and glia (including astrocytes, oligodendrocytes and ependymal cells) derive from multipotent neural stem cells (NSCs) located in the neuroepithelium (Figure 2). These NSCs undergo symmetric division that expands the neuroepithelial surface area and therefore the pool of NSCs, although some can generate neurons. ...
Citations
... Gangliosides are glycosphingolipids composed of a ceramide lipid tail attached through glycosidic linkage to a glycan headgroup containing one or more sialic acid residues. According to the Svennerholm classification, gangliosides can be classified in four series (0-, a-, b-, and c-series) based on the number of sialic acid residues (from 0 to 3) linked to the inner galactose residue [14], the A2B5 antibody recognizing gangliosides of the c-series (for review [15]). ...
Glioblastoma (GBM) contains cancer stem cells (CSC) that are resistant to treatment. GBM CSC expresses glycolipids recognized by the A2B5 antibody. A2B5, induced by the enzyme ST8 alpha-N-acetyl-neuraminide alpha-2,8-sialyl transferase 3 (ST8Sia3), plays a crucial role in the proliferation, migration, clonogenicity and tumorigenesis of GBM CSC. Our aim was to characterize the resulting effects of neuraminidase that removes A2B5 in order to target GBM CSC. To this end, we set up a GBM organotypic slice model; quantified A2B5 expression by flow cytometry in U87-MG, U87-ST8Sia3 and GBM CSC lines, treated or not by neuraminidase; performed RNAseq and DNA methylation profiling; and analyzed the ganglioside expression by liquid chromatography–mass spectrometry in these cell lines, treated or not with neuraminidase. Results demonstrated that neuraminidase decreased A2B5 expression, tumor size and regrowth after surgical removal in the organotypic slice model but did not induce a distinct transcriptomic or epigenetic signature in GBM CSC lines. RNAseq analysis revealed that OLIG2, CHI3L1, TIMP3, TNFAIP2, and TNFAIP6 transcripts were significantly overexpressed in U87-ST8Sia3 compared to U87-MG. RT-qPCR confirmed these results and demonstrated that neuraminidase decreased gene expression in GBM CSC lines. Moreover, neuraminidase drastically reduced ganglioside expression in GBM CSC lines. Neuraminidase, by its pleiotropic action, is an attractive local treatment against GBM.
Glioblastoma is the most frequent and aggressive primary brain tumor in adults. Currently, no curative treatment is available. Despite first-line treatment composed by the association of surgery, radiotherapy, and chemotherapy, relapse remains inevitable in a median delay of 6 to 10 months. Improving patient management and developing new therapeutic strategies are therefore a critical medical need in neuro-oncology. Gangliosides are sialic acid-containing glycosphingolipids, the most abundant in the nervous system, representing attractive therapeutic targets. The ganglioside GD3 is highly expressed in neuroectoderm-derived tumors such as melanoma and neuroblastoma, but also in gliomas. Moreover, interesting results, including our own, have reported the involvement of GD3 in the stemness of glioblastoma cells. In this review, we will first describe the characteristics of the ganglioside GD3 and its enzyme, the GD3 synthase (GD3S), including their biosynthesis and metabolism. Then, we will detail their expression and role in gliomas. Finally, we will summarize the current knowledge regarding the therapeutic development opportunities against GD3 and GD3S.
Oligodendrocytes are the myelinating cells in the CNS and multiple sclerosis (MS) is a demyelinating disorder that is characterized by progressive loss of myelin. Although oligodendroglial progenitor cells (OPCs) should be differentiated into oligodendrocytes, for multiple reasons, OPCs fail to differentiate into oligodendrocytes in MS. Therefore, increasing the maturation of OPCs to oligodendrocytes may be of therapeutic benefit for MS. The β‐hydroxy β‐methylbutyrate (HMB) is a muscle‐building supplement in humans and this study underlines the importance of HMB in stimulating the maturation of OPCs to oligodendrocytes. HMB treatment upregulated the expression of different maturation markers including PLP, MBP, and MOG in cultured OPCs. Double‐label immunofluorescence followed by immunoblot analyses confirmed the upregulation of OPC maturation by HMB. While investigating mechanisms, we found that HMB increased the maturation of OPCs isolated from peroxisome proliferator‐activated receptor β −/− (PPARβ −/− ) mice, but not PPARα −/− mice. Similarly, GW6471 (an antagonist of PPARα), but not GSK0660 (an antagonist of PPARβ), inhibited HMB‐induced maturation of OPCs. GW9662, a specific inhibitor of PPARγ, also could not inhibit HMB‐mediated stimulation of OPC maturation. Furthermore, PPARα agonist GW7647, but neither PPARβ agonist GW0742 nor PPARγ agonist GW1929, alone increased the maturation of OPCs. Finally, HMB treatment of OPCs led to the recruitment of PPARα, but neither PPARβ nor PPARγ, to the PLP gene promoter. These results suggest that HMB stimulates the maturation of OPCs via PPARα and that HMB may have therapeutic prospects in remyelination.
Glioblastoma (GBM) recurrences are inevitable, and mainly originate from residual tumor cells and the presence of glioma stem cells (GSC) around the resection cavity borders. We previously showed that the local treatment of GBM with nanomedicine-based Lauroyl-gemcitabine lipid nanocapsules (GemC12-LNC) hydrogel delayed tumor onset in various preclinical models and can be used as a scaffold to deliver multiple drugs. However, it does not inhibit tumor relapse in the long-term. In this work, we aim at encapsulating an anti-GSC molecule in the GemC12-LNC hydrogel to eliminate both GBM cells and GSC. We performed a screening on GBM cell lines (GL261 and U-87 MG) and patient-derived GSC (GBM9) to select the anti-GSC molecule that could act synergically with GemC12. Based on our results, salinomycin (Sal) and curcumin (Cur) were selected for further development. Both GemC12-Sal-LNC and GemC12-Cur LNC showed similar size (55 nm), zeta potential (- 2 mV) and viscoelastic properties compared to the GemC12-LNC hydrogel. Encapsulation efficiency was above 95 %. Moreover, the GemC12-Sal-LNC hydrogel was stable for at least 6 months and released both drugs over 30 days in vitro. Both hydrogels inhibited the growth of GL261 and U-87 MG spheroids. Flow cytometry analysis showed that Sal reduced the GSC population in GL261 and U-87 MG cells. Our results show that the co-encapsulation of Sal in the GemC12-LNC hydrogel can reduce both GBM cells and GSC, and therefore might be promising to avoid the onset of GBM recurrences.
