Human Adult Glial Progenitors Express Distinct miRNA Profiles Compared to their Fetal Counterparts
Ontology highlight
ABSTRACT:
ORGANISM(S): synthetic construct Homo sapiens
PROVIDER: GSE255589 | GEO | 2024/02/12
REPOSITORIES: GEO
Similar Datasets
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
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.
2023-08-28 | GSE165994 | GEO
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
Project description:With advancing age, senescent cells accumulate as they are not efficiently cleared by the immune system anymore. Via a senescence-associated secretory phenotype, chronic senescent cells alter the microenvironment, creating an unfavorable milieu for neurogenesis and neurorepair. Using an innovative and rapid aging model, the African turquoise killifish, we have previously demonstrated a dramatic decline in neurogenic potential of non-glial progenitors with age. Even after traumatic brain injury, progenitor proliferation and neuron production was very low in aged killifish in comparison to young adult killifish, and overall neurorepair was incomplete. In the present study, we validated if the senolytic cocktail dasatinib and quercetin (D+Q) could reboot the neurogenic output by clearing chronic senescent cells from the aged killifish brain to re-create the necessary supportive environment. Our results confirm that the aged killifish telencephalon holds a very high senescent cell burden, which we could diminish by short-term systemic D+Q treatment. As a consequence of D+Q administration, proliferation of non-glial progenitors increased and more new neurons were generated and migrated into the parenchyma after injury. Injury-induced inflammation and glial scarring, a phenomenon only seen in aged killifish, remained unaltered. Senolytic treatment with D+Q might thus hold promise for improving brain function in aged populations, and is especially interesting for reviving the neurogenic potential of an already aged central nervous system.
2023-07-20 | PXD036437 | Pride
Project description:Huntington’s disease (HD) and juvenile-onset schizophrenia (SCZ) have long been regarded as distinct disorders. However, both manifest cell-intrinsic abnormalities in glial differentiation, with resultant astrocytic dysfunction and hypomyelination. To assess whether a common mechanism might underlie the similar glial pathology of these otherwise disparate conditions, we utilized comparative correlation network approaches to analyze RNA-seq data from human glial progenitor cells (hGPCs) produced from disease-derived pluripotent stem cells. We identified gene sets preserved between HD and SCZ hGPCs yet distinct from normal controls, that included 174 highly-connected genes in the shared disease-associated network, focused on genes involved in synaptic signaling. These synaptic genes were largely suppressed in both SCZ and HD hGPCs, and gene regulatory network analysis identified a core set of upstream regulators of this network, of which OLIG2 and TCF7L2 were prominent. Among their downstream targets, ADGRL3, a modulator of glutamatergic synapses, was notably suppressed in both SCZ and HD hGPCs. ChIP-seq confirmed that OLIG2 and TCF7L2 each bound to the regulatory region of ADGRL3, whose expression was then rescued by lentiviral overexpression of these transcription factors. These data suggest that the disease-associated suppression of OLIG2 and TCF7L2-dependent transcription of glutamate signaling regulators may impair glial receptivity to neuronal glutamate. The consequent loss of activity-dependent mobilization of hGPCs may yield deficient oligodendrocyte production, and hence the hypomyelination noted in these disorders, as well as the disrupted astrocytic differentiation and attendant synaptic dysfunction associated with each. Together, these data highlight the importance of convergent glial molecular pathology in both the pathogenesis and phenotypic similarities of two otherwise unrelated disorders, HD and SCZ.
2024-05-08 | GSE188558 | GEO
Project description:Huntington’s disease (HD) and juvenile-onset schizophrenia (SCZ) have long been regarded as distinct disorders. However, both manifest cell-intrinsic abnormalities in glial differentiation, with resultant astrocytic dysfunction and hypomyelination. To assess whether a common mechanism might underlie the similar glial pathology of these otherwise disparate conditions, we utilized comparative correlation network approaches to analyze RNA-seq data from human glial progenitor cells (hGPCs) produced from disease-derived pluripotent stem cells. We identified gene sets preserved between HD and SCZ hGPCs yet distinct from normal controls, that included 174 highly-connected genes in the shared disease-associated network, focused on genes involved in synaptic signaling. These synaptic genes were largely suppressed in both SCZ and HD hGPCs, and gene regulatory network analysis identified a core set of upstream regulators of this network, of which OLIG2 and TCF7L2 were prominent. Among their downstream targets, ADGRL3, a modulator of glutamatergic synapses, was notably suppressed in both SCZ and HD hGPCs. ChIP-seq confirmed that OLIG2 and TCF7L2 each bound to the regulatory region of ADGRL3, whose expression was then rescued by lentiviral overexpression of these transcription factors. These data suggest that the disease-associated suppression of OLIG2 and TCF7L2-dependent transcription of glutamate signaling regulators may impair glial receptivity to neuronal glutamate. The consequent loss of activity-dependent mobilization of hGPCs may yield deficient oligodendrocyte production, and hence the hypomyelination noted in these disorders, as well as the disrupted astrocytic differentiation and attendant synaptic dysfunction associated with each. Together, these data highlight the importance of convergent glial molecular pathology in both the pathogenesis and phenotypic similarities of two otherwise unrelated disorders, HD and SCZ.
2024-05-08 | GSE188561 | GEO
Project description:Huntington’s disease (HD) and juvenile-onset schizophrenia (SCZ) have long been regarded as distinct disorders. However, both manifest cell-intrinsic abnormalities in glial differentiation, with resultant astrocytic dysfunction and hypomyelination. To assess whether a common mechanism might underlie the similar glial pathology of these otherwise disparate conditions, we utilized comparative correlation network approaches to analyze RNA-seq data from human glial progenitor cells (hGPCs) produced from disease-derived pluripotent stem cells. We identified gene sets preserved between HD and SCZ hGPCs yet distinct from normal controls, that included 174 highly-connected genes in the shared disease-associated network, focused on genes involved in synaptic signaling. These synaptic genes were largely suppressed in both SCZ and HD hGPCs, and gene regulatory network analysis identified a core set of upstream regulators of this network, of which OLIG2 and TCF7L2 were prominent. Among their downstream targets, ADGRL3, a modulator of glutamatergic synapses, was notably suppressed in both SCZ and HD hGPCs. ChIP-seq confirmed that OLIG2 and TCF7L2 each bound to the regulatory region of ADGRL3, whose expression was then rescued by lentiviral overexpression of these transcription factors. These data suggest that the disease-associated suppression of OLIG2 and TCF7L2-dependent transcription of glutamate signaling regulators may impair glial receptivity to neuronal glutamate. The consequent loss of activity-dependent mobilization of hGPCs may yield deficient oligodendrocyte production, and hence the hypomyelination noted in these disorders, as well as the disrupted astrocytic differentiation and attendant synaptic dysfunction associated with each. Together, these data highlight the importance of convergent glial molecular pathology in both the pathogenesis and phenotypic similarities of two otherwise unrelated disorders, HD and SCZ.
2024-05-08 | GSE188559 | GEO
Project description:In differentiated cells, aging is associated with hypermethylation of DNA regions enriched in repressive histone posttranslational modifications. However, the chromatin marks associated with changes in DNA methylation in adult stem cells during lifetime are still largely unknown. Here, DNA methylation profiling of mesenchymal stem cells obtained from individuals aged 2 to 92 identified 18735 hypermethylated and 45407 hypomethylated CpG sites associated with aging. As in differentiated cells, hypermethylated sequences were enriched in chromatin repressive marks. Most importantly, hypomethylated CpG sites were strongly enriched in the active chromatin mark H3K4me1 in stem and differentiated cells, suggesting this is a cell type-independent chromatin signature of DNA hypomethylation during aging. Analysis of scedasticity showed that interindividual variability of DNA methylation increased during aging in MSCs and differentiated cells, providing a new avenue for the identification of DNA methylation changes over time. DNA methylation profiling of genetically identical individuals showed that both the tendency of DNA methylation changes and scedasticity depended on non-genetic as well as genetic factors. Our results indicate that the dynamics of DNA methylation during aging depend on a complex mixture of factors that include the DNA sequence, cell type and chromatin context involved, and that, depending on the locus, the changes can be modulated by genetic and/or external factors. Total DNA isolated by standard procedures from human adult mesenchymal stem cells (MSCs) obtained from 34 individuals aged 2 to 92
2014-09-25 | E-GEOD-52112 | biostudies-arrayexpress
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
Project description:In differentiated cells, aging is associated with hypermethylation of DNA regions enriched in repressive histone posttranslational modifications. However, the chromatin marks associated with changes in DNA methylation in adult stem cells during lifetime are still largely unknown. Here, DNA methylation profiling of mesenchymal stem cells obtained from individuals aged 2 to 92 identified 18735 hypermethylated and 45407 hypomethylated CpG sites associated with aging. As in differentiated cells, hypermethylated sequences were enriched in chromatin repressive marks. Most importantly, hypomethylated CpG sites were strongly enriched in the active chromatin mark H3K4me1 in stem and differentiated cells, suggesting this is a cell type-independent chromatin signature of DNA hypomethylation during aging. Analysis of scedasticity showed that interindividual variability of DNA methylation increased during aging in MSCs and differentiated cells, providing a new avenue for the identification of DNA methylation changes over time. DNA methylation profiling of genetically identical individuals showed that both the tendency of DNA methylation changes and scedasticity depended on non-genetic as well as genetic factors. Our results indicate that the dynamics of DNA methylation during aging depend on a complex mixture of factors that include the DNA sequence, cell type and chromatin context involved, and that, depending on the locus, the changes can be modulated by genetic and/or external factors. Total DNA isolated by standard procedures from peripheral blood of 24 samples obtained from 12 pairs of MZ twins aged 21 to 66.
2014-09-25 | E-GEOD-52113 | biostudies-arrayexpress