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Fate determination of adult human glial progenitor cells

ABSTRACT: Glial progenitor cells comprise the most abundant population of progenitor cells in the adult human brain. They are responsible for CNS remyelination, and likely contribute to the astrogliotic response to brain injury and degeneration as well. Adult human GPCs are biased to differentiate as oligodendrocytes and elaborate new myelin, and yet they retain multilineage plasticity, and can give rise to neurons as well as astrocytes and oligodendrocytes once removed from the adult parenchymal environment. GPCs retain strong mechanisms for cell-autonomous self-renewal, and yet both their phenotype and fate may be dictated by their microenvironment. Using the transcriptional profiles of acutely isolated GPCs, we have begun to understand the operative ligand-receptor interactions involved in these processes, and have identified several key signaling pathways by which adult human GPCs may be reliably instructed to either oligodendrocytic or astrocytic fate. In addition, we have noted significant differences between the expressed genes and dominant signaling pathways of fetal and adult human GPCs, as well as between rodent and human GPCs. The latter data in particular call into question therapeutic strategies predicated solely upon data obtained using rodents, while perhaps highlighting the extent to which evolution has been attended by the phylogenetic modification of glial phenotype and function. Human adult brain dissociates were sorted for one of three markers, either GLT1 (astrocyte, n =3), CD11b (microglia, n=4) or A2B5 (glial progenitor cell, n=7). In addition to positively selected, the negative fraction and unsorted dissociates were collected as matched controls for each sort.

ORGANISM(S): Homo sapiens

SUBMITTER: Fraser Sim

PROVIDER: E-GEOD-36634 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Fate determination of adult human glial progenitor cells

Project description:Glial progenitor cells comprise the most abundant population of progenitor cells in the adult human brain. They are responsible for CNS remyelination, and likely contribute to the astrogliotic response to brain injury and degeneration as well. Adult human GPCs are biased to differentiate as oligodendrocytes and elaborate new myelin, and yet they retain multilineage plasticity, and can give rise to neurons as well as astrocytes and oligodendrocytes once removed from the adult parenchymal environment. GPCs retain strong mechanisms for cell-autonomous self-renewal, and yet both their phenotype and fate may be dictated by their microenvironment. Using the transcriptional profiles of acutely isolated GPCs, we have begun to understand the operative ligand-receptor interactions involved in these processes, and have identified several key signaling pathways by which adult human GPCs may be reliably instructed to either oligodendrocytic or astrocytic fate. In addition, we have noted significant differences between the expressed genes and dominant signaling pathways of fetal and adult human GPCs, as well as between rodent and human GPCs. The latter data in particular call into question therapeutic strategies predicated solely upon data obtained using rodents, while perhaps highlighting the extent to which evolution has been attended by the phylogenetic modification of glial phenotype and function.

2012-11-01 | GSE36634 | GEO

Human iPSC glial mouse chimeras reveal glial contributions to schizophrenia

Project description:Genetic studies have suggested a role for glial pathology in the genesis of schizophrenia (SCZ). To assess the nature of SCZ-associated human glial dysfunction in vivo, we established human glial chimeric mice using glial progenitor cells (GPCs) produced from induced pluripotential cells (hiPSCs), derived from patients with juvenile-onset schizophrenia or healthy controls. To this end, hiPSC GPCs were implanted neonatally into either immunodeficient myelin wild-type mice, in which donor GPCs remained as progenitors or became astrocytes, or into myelin-deficient shiverer mice, in which the GPCs also gave rise to oligodendrocytes. When implanted into shiverers, the SCZ-derived GPCs exhibited less expansion in the white matter than did control GPCs, instead migrating prematurely into the cortex. The SCZ GPC-transplanted shiverers were consequently hypomyelinated relative to control GPC-engrafted mice. When established instead in myelin wild-type hosts, the SCZ hiPSC glial chimeras manifested markedly delayed and diminished astrocytic differentiation, which was associated with diminished prepulse inhibition and an aberrant behavioral phenotype across multiple modalities. Accordingly, RNA-seq revealed significant differences in both glial differentiation-associated and synaptic gene expression by SCZ GPCs. These data suggest a potent contribution of cell-autonomous glial dysfunction to the development of schizophrenia, and provide a model for the in vivo assessment of human glial pathology in this disorder.

2017-07-20 | GSE86906 | GEO

Human Adult Glial Progenitors Are Transcriptionally Distinct from Their Fetal Counterparts [scRNA-seq]

Project description:Glial progenitor cells (GPCs), the primary source of oligodendrocytes and astrocytes in the human CNS, emerge during the 2nd trimester of human development and subsequently colonize the brain, where a pool remains throughout adulthood. While fetal GPCs are highly migratory and proliferative, there is evidence that their capacities diminish throughout aging or as a result of demyelination-induced exhaustion, thus compromising their ability to mobilize, remyelinate, and self-renew. To investigate this mechanism, we first utilized bulk and scRNA-Sequencing to characterize the human fetal GPC pool and leveraged these data to elucidate transcriptional discrepancies in adult human GPCs. This revealed age-induced transcriptional shifts towards loss of proliferative competency and the potential onset of senescence. Further, we inferred adult networks of direct repressive transcription factor activity that may drive functional decline during GPC aging. Finally, we coupled these data with miRNA profiling of both populations to establish both upstream and parallel arms of repression that may stifle the functional aptitude of aged GPCs. These identified upstream regulators may be ideal therapeutic targets toward rejuvenating GPCs crippled by mitotic exhaustion or aging.

2024-01-29 | GSE165995 | GEO

Human Adult Glial Progenitors Are Transcriptionally Distinct from Their Fetal Counterparts [bulk RNA-seq]

2023-08-28 | GSE165994 | GEO

Differential gene expression by A2B5-defined Human glioma-initiating progenitor cells at all stages of gliomagenesis

Project description:Glial progenitor cells (GPCs) of the adult human white matter, which express gangliosides recognized by monoclonal antibody A2B5, are a potential source of glial tumors of the brain. We used A2B5-based sorting to extract progenitor-like cells from a range of human glial tumors, that included low-grade glioma, oligodendroglioma, oligo-astrocytomas, anaplastic astrocytoma, and glioblastoma multiforme. The A2B5+ tumor cells proved tumorigenic upon orthotopic xenograft, and the tumors generated reflected the phenotypes of those from which they derived. Expression profiling revealed that A2B5+ tumor progenitors expressed a cohort of genes by which they could be distinguished from A2B5+ GPCs isolated from normal adult white matter. Most of the genes differentially expressed by glioma-derived A2B5+ cells varied as a function of tumor stage; however, a small number were invariably expressed at all stages of gliomagenesis. These glioma progenitor-associated genes included CD24, SIX1 and EYA1, which were up-regulated at all stages of gliomagenesis, and MTUS1 and SPOCK3, which were down-regulated at all stages of tumor progression. qPCR and immunolabeling confirmed the differential expression of these genes in primary gliomas, while pathway analysis permitted their segregation into differentially active signaling pathways. By comparing the expression patterns of glial tumor progenitors to their identically-isolated normal homologues, we have identified a discrete set of oncogenic pathways by which glial tumorigenesis may be both better understood, and more efficiently targeted. Samples originating from patients with matched disease and/or pathology were considered as replicates either on the basis of exact tumor phenotype, tumor grade, or tumor vs. normal tissue samples.

2013-05-16 | E-GEOD-29796 | biostudies-arrayexpress

CD140a+ human glial progenitor cells

Project description:Glial progenitor cells (GPCs) pervade the human brain. These cells express gangliosides recognized by MAb A2B5, and some but not all can generate oligodendrocytes. Since some A2B5+ GPCs express PDGFa receptor (PDGFRa), which is critical to oligodendrocyte development, we asked if PDGFRa-directed sorting might isolate oligodendrocyte-competent progenitors. We used FACS to sort PDGFRa+ cells from the second trimester fetal human forebrain, based on expression of the PDGFRa epitope CD140a. CD140a+ cells could be maintained as mitotic progenitors that could be instructed to either oligodendrocyte or astrocyte phenotype. Transplanted CD140a+ cells robustly myelinated the hypomyelinated shiverer mouse brain. Microarray confirmed that CD140a+ cells differentially expressed PDGFRA, NG2, OLIG1/2, NKX2.2 and SOX2. Some expressed CD9, thereby defining a CD140a+/CD9+ fraction of oligodendrocyte-biased progenitors. CD140a+ cells differentially expressed genes of the PTN-PTPRZ1, wnt, notch and BMP pathways, suggesting the interaction of self-renewal and fate-restricting pathways in these cells, while identifying targets for their mobilization and instruction. 10 samples, 5 CD140a+, and 5 CD140a- sorted samples for individual fetal human brain

2011-09-30 | E-GEOD-29368 | biostudies-arrayexpress

Transcriptional Differences between Normal and Glioma-Derived Glial Progenitor Cells Identify a Core Set of Dysregulated Genes.

2013-05-16 | GSE29796 | GEO

CD140a+ human oligodendrocyte progenitor cells

2011-10-01 | GSE29368 | GEO

Young human glial progenitor cells outcompete and replace older and diseased human cells when transplanted into adult human glial chimeric mice

Project description:Human glial progenitor cells (hGPCs) are highly migratory, and glial replacement has the potential to treat those neurological disorders in which astrocytic and oligodendrocytic pathology are contributory. Yet it remains unknown whether allografted human glia can out compete diseased cells to achieve therapeutic replacement in the adult human brain.To that end, we engrafted healthy wild-type (WT) hGPCs into the striata of adult mice that had been earlier chimerized neonatally with mutant HTT-expressing hGPCs generated from Huntington disease (HD)-derived human embryonic stemcells. The WT hGPCs effectively out competed and ultimately eliminated their HD counterparts, repopulating the host striata with healthy humanglia. Single-cell transcriptomics revealed that WT hGPCs actively assumed a dominant competitor phenotype upon interaction with their resident HD counter parts.The outcomes of clonal competition depended primarily upon the age difference between competing clones, in that adult-transplanted WT GPCs effectively out competed their isogenic WT counter parts that had been transplanted neonatally, and which were thus necessarily older.These data suggest that both aged and diseased human glia may be broadly replaced in the adult brain by younger and healthier human glial progenitor cells.

2023-04-04 | GSE206322 | GEO

hESC-based human glial chimeric mice reveal glial differentiation defects in Huntington disease

Project description:Huntington’s disease (HD) is characterized by hypomyelination as well as by neuronal loss. To assess the basis for white matter involution in HD, we generated bipotential glial progenitor cells (GPCs) from human embryonic stem cells (hESCs), derived from either huntingtin (mHTT)-mutant embryos or normal controls, and performed RNA sequence analysis to assess mHTT-dependent changes in gene expression. In hGPCs derived from 3 distinct mHTT-expressing hESC lines, a set of transcription factors associated with glial differentiation and myelin synthesis was sharply down-regulated, relative to normal hESC GPCs. In particular, NKX2.2, OLIG2, SOX10 and MYRF were all suppressed, with the consequent diminution of myelinogenesis-associated transcription. Accordingly, when mHTT-expressing hGPCs were transplanted into hypomyelinated shiverer mice, the resultant mHTT glial chimeras were hypomyelinated. The mHTT hGPCs also manifested impaired astrocytic differentiation, and developed abnormal fiber domain architecture. These data suggest that white matter involution in HD is a product of a cell-autonomous mHTT-dependent suppression of both astrocytic and oligodendrocytic differentiation by affected GPCs.

2018-11-10 | GSE105041 | GEO

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