Adult Human Glioblastomas Harbor Radial Glia-like Cells.
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ABSTRACT:
SUBMITTER: Wang R
PROVIDER: S-EPMC7014025 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Limited knowledge about human oligodendrogenesis prompted us to explore the lineage relationship between cortical radial glia (RG) cells and oligodendrocytes (OLs) in the human fetal forebrain. RG cells were isolated from cortical ventricular/subventricular zone and their progeny was followed in vitro. One portion of RG cells differentiated into cells of OL lineage identified by cell-type specific antibodies, including platelet-derived growth factor receptor-alpha (PDGFRalpha), NG2, O4, myelin basic protein, and myelin oligodendrocyte glycoprotein. Moreover, using Cre Lox fate mapping (brain lipid binding protein-Cre/Floxed-yellow fluorescent protein) we established a direct link between RG cells and OL progenitors. In vitro generation of RG-derived O4(+) OL progenitors was enhanced by addition of sonic hedgehog (SHH) and reduced by the SHH inhibitor, cyclopamine, suggesting the role of SHH signaling in this process. In summary, our in vitro experiments revealed that a portion of cortical RG cells isolated from human forebrain at the second trimester of gestation generates OL progenitors and this suggests a role of SHH in this process.
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Project description:Immature neurons migrate tangentially within the rostral migratory stream (RMS) to the adult olfactory bulb (OB), then radially to their final positions as granule and periglomerular neurons; the controls over this transition are not well understood. Using adult transgenic mice with the human GFAP promoter driving expression of enhanced GFP, we identified a population of radial glia-like cells that we term adult olfactory radial glia-like cells (AORGs). AORGs have large, round somas and simple, radially oriented processes. Confocal reconstructions indicate that AORGs variably express typical radial glial markers, only rarely express mouse GFAP, and do not express astroglial, oligodendroglial, neuronal, or tanycyte markers. Electron microscopy provides further supporting evidence that AORGs are not immature neurons. Developmental analyses indicate that AORGs are present as early as P1, and are generated through adulthood. Tracing studies show that AORGs are not born in the SVZa, suggesting that they are born either in the RMS or the OB. Migrating immature neurons from the adult SVZa are closely apposed to AORGs during radial migration in vivo and in vitro. Taken together, these data indicate a newly-identified population of radial glia-like cells in the adult OB that might function uniquely in neuronal radial migration during adult OB neurogenesis.
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Project description:Radial glia is a cell type traditionally associated with the developing nervous system, particularly with the formation of cortical layers in the mammalian brain. Nonetheless, some of these cells, or closely related types, called radial glia-like cells are found in adult central nervous system structures, functioning as neurogenic progenitors in normal homeostatic maintenance and in response to injury. The heterogeneity of radial glia-like cells is nowadays being probed with molecular tools, primarily by the expression of specific genes that define cell types. Similar markers have identified radial glia-like cells in the nervous system of non-vertebrate organisms. In this review, we focus on adult radial glia-like cells in neurogenic processes during homeostasis and in response to injury. We highlight our results using a non-vertebrate model system, the echinoderm Holothuria glaberrima where we have described a radial glia-like cell that plays a prominent role in the regeneration of the holothurian central nervous system.
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Project description:Neural stem cells with the characteristics of astrocytes persist in the subventricular zone (SVZ) of the juvenile and adult brain. These cells generate large numbers of new neurons that migrate through the rostral migratory stream to the olfactory bulb. The developmental origin of adult neural stem cells is not known. Here, we describe a lox-Cre-based technique to specifically and permanently label a restricted population of striatal radial glia in newborn mice. Within the first few days after labeling, these radial glial cells gave rise to neurons, oligodendrocytes, and astrocytes, including astrocytes in the SVZ. Remarkably, the rostral migratory stream contained labeled migratory neuroblasts at all ages examined, including 150-day-old mice. Labeling dividing cells with the S-phase marker BrdUrd showed that new neurons continue to be produced in the adult by precursors ultimately derived from radial glia. Furthermore, both radial glia in neonates and radial glia-derived cells in the adult lateral ventricular wall generated self-renewing, multipotent neurospheres. These results demonstrate that radial glial cells not only serve as progenitors for many neurons and glial cells soon after birth but also give rise to adult SVZ stem cells that continue to produce neurons throughout adult life. This study identifies and provides a method to genetically modify the lineage that links neonatal and adult neural stem cells.
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Project description:The oxygen (O2) concentration is a vital parameter for controlling the survival, proliferation, and differentiation of neural stem cells. A prenatal reduction of O2 levels (hypoxia) often leads to cognitive and behavioral defects, attributable to altered neural development. In this study, we analyzed the effects of O2 levels on human cortical progenitors, the radial glia cells (RGCs), during active neurogenesis, corresponding to the second trimester of gestation. Small changes in O2 levels profoundly affected RGC survival, proliferation, and differentiation. Physiological hypoxia (3% O2) promoted neurogenesis, whereas anoxia (<1% O2) and severe hypoxia (1% O2) arrested the differentiation of human RGCs, mainly by altering the generation of glutamatergic neurons. The in vitro activation of Wnt-?-catenin signaling rescued the proliferation and neuronal differentiation of RGCs subjected to anoxia. Pathologic hypoxia (?1% O2) also exerted negative effects on gliogenesis, by decreasing the number of O4+ preoligodendrocytes and increasing the number of reactive astrocytes derived from cortical RGCs. O2-dependent alterations in glutamatergic neurogenesis and oligodendrogenesis can lead to significant changes in cortical circuitry formation. A better understanding of the cellular effects caused by changes in O2 levels during human cortical development is essential to elucidating the etiology of numerous neurodevelopmental disorders.
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Project description:Radial glia (RG) are primarily embryonic neuroglial progenitors that express Brain Lipid Binding Protein (Blbp a.k.a. Fabp7) and Glial Fibrillary Acidic Protein (Gfap). We used these transcripts to demarcate the distribution of spinal cord radial glia (SCRG) and screen for SCRG gene expression in the Allen Spinal Cord Atlas (ASCA). We reveal that neonatal and adult SCRG are anchored in a non-ventricular niche at the spinal cord (SC) pial boundary, and express a "signature" subset of 122 genes, many of which are shared with "classic" neural stem cells (NSCs) of the subventricular zone (SVZ) and SC central canal (CC). A core expressed gene set shared between SCRG and progenitors of the SVZ and CC is particularly enriched in genes associated with human disease. Visualizing SCRG in a Fabp7-EGFP reporter mouse reveals an extensive population of SCRG that extend processes around the SC boundary and inwardly (through) the SC white matter (WM), whose abundance increases in a gradient from cervical to lumbar SC. Confocal analysis of multiple NSC-enriched proteins reveals that postnatal SCRG are a discrete and heterogeneous potential progenitor population that become activated by multiple SC lesions, and that CC progenitors are also more heterogeneous than previously appreciated. Gene ontology analysis highlights potentially unique regulatory pathways that may be further manipulated in SCRG to enhance repair in the context of injury and SC disease.
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Project description:The efficient production of human neocortical neurons from human embryonic stem cells (hESC) is the primary requirement for studying early stages of human cortical development. We used hESC to obtain radial glial cells (hESC-RG) and then compared them with RG cells isolated from human fetal forebrain. Fate of hESC-RG cells critically depends on intrinsic and extrinsic factors. The expression of Pax6 (intrinsic factor) has a similar neurogenic effect on hESC-RG differentiation as reported for human fetal RG cells. Factors from the microenvironment also play a significant role in determining hESC-RG cell fate. In contrast to control cultures, wherein hESC-RG generate mainly astroglia and far fewer neurons, in co-cultures with human fetal forebrain cells, the reverse was found to be true. This neurogenic effect was partly due to soluble factors from human fetal brain cultures. The detected shift towards neurogenesis has significance for developing future efficient neuro-differentiation protocols. Importantly, we established that hESC-RG cells are similar in many respects to human fetal RG cells, including their proliferative capacity, neurogenic potential, and ability to generate various cortical neuronal sub-types. Unlike fetal RG cells, the hESC-RG cells are readily available and can be standardized, features that have considerable practical advantages in research and clinics.
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Project description:In the adult dentate gyrus, radial glia-like cells represent putative stem cells generating neurons and glial cells. Here, we combined patch-clamp recordings, biocytin filling, immunohistochemistry, single-cell transcript analysis, and mouse transgenics to test for connexin expression and gap junctional coupling of radial glia-like cells and its impact on neurogenesis. Radial glia-like cells were identified in mice expressing EGFP under control of the nestin and gfap promoters. We show that a majority of Radial glia-like cells are coupled and express Cx43. Neuronal precursors were not coupled. Mice lacking Cx30 and Cx43 in GFAP-positive cells displayed almost complete inhibition of proliferation and a significant decline in numbers of radial glia-like cells and granule neurons. Inducible virus-mediated ablation of connexins in the adult hippocampus also reduced neurogenesis. These findings strongly suggest the requirement of connexin expression by radial glia-like cells for intact neurogenesis in the adult brain and point to possible communication pathways of these cells.
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Project description:Human gliogenesis remains poorly understood, and derivation of astrocytes from human pluripotent stem cells (hPSCs) is inefficient and cumbersome. Here, we report controlled glial differentiation from hPSCs that bypasses neurogenesis, which otherwise precedes astrogliogenesis during brain development and in vitro differentiation. hPSCs were first differentiated into radial glial cells (RGCs) resembling resident RGCs of the fetal telencephalon, and modulation of specific cell signaling pathways resulted in direct and stepwise induction of key astroglial markers (NFIA, NFIB, SOX9, CD44, S100B, glial fibrillary acidic protein [GFAP]). Transcriptomic and genome-wide epigenetic mapping and single-cell analysis confirmed RGC-to-astrocyte differentiation, obviating neurogenesis and the gliogenic switch. Detailed molecular and cellular characterization experiments uncovered new mechanisms and markers for human RGCs and astrocytes. In summary, establishment of a glia-exclusive neural lineage progression model serves as a unique serum-free platform of manufacturing large numbers of RGCs and astrocytes for neuroscience, disease modeling (e.g., Alexander disease), and regenerative medicine.
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Project description:Radial glia, the neural stem cells of the neocortex, are located in two niches: the ventricular zone and outer subventricular zone. Although outer subventricular zone radial glia may generate the majority of human cortical neurons, their molecular features remain elusive. By analyzing gene expression across single cells, we find that outer radial glia preferentially express genes related to extracellular matrix formation, migration, and stemness, including TNC, PTPRZ1, FAM107A, HOPX, and LIFR. Using dynamic imaging, immunostaining, and clonal analysis, we relate these molecular features to distinctive behaviors of outer radial glia, demonstrate the necessity of STAT3 signaling for their cell cycle progression, and establish their extensive proliferative potential. These results suggest that outer radial glia directly support the subventricular niche through local production of growth factors, potentiation of growth factor signals by extracellular matrix proteins, and activation of self-renewal pathways, thereby enabling the developmental and evolutionary expansion of the human neocortex.
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