HESC-based human glial chimeric mice reveal glial differentiation defects in Huntington disease
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA414457 | ENA |
REPOSITORIES: ENA
Similar Datasets
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: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:Gene expression profile comparison from fibroblasts of Huntington individuals and normal ones We used microarrays to detail the global gene expression of fibroblasts from Huntington patients
2013-03-28 | GSE45516 | GEO
Project description:Cell-intrinsic glial pathology is conserved across human and murine models of Huntington Disease
| PRJNA645187 | ENA
Project description:Gene expression profile comparison from fibroblasts of Huntington individuals and normal ones We used microarrays to detail the global gene expression of fibroblasts from Huntington patients Comparison between six Huntington human fibroblasts and three normal controls. All individuals were aged and sex matched. In fact they are all males with the subsequent ages: 28, 48, 57 for the controls and 38, 63, 57, 47, 38, 37 for the HD patients. The average age is comparable.
2013-03-28 | E-GEOD-45516 | biostudies-arrayexpress
Project description:Whole proteome profiling and quantification was performed on an isogenic Huntington disease (IsoHD) human embryonic stem cell (hESC) allelic panel. The IsoHD hESCs harbour 30, 45, 65 and 81 CAG repeats in the first exon of HTT. Whole proteome quantification was also performed on neural progenitor cells derived from the IsoHD hESC panel.
2019-02-14 | PXD006585 | JPOST Repository
Project description:Striato nigral circuit is composed of medium spiny neuronal projections that were mainly sent from striatum to midbrain substantial nigra (SN), which is essential for regulating motor behaviors. Dysfunction of striato-nigral circuitry may cause a series of motor disabilities which are associated with neurodegenerative disorders, such as Huntington disease (HD). Although the etiology of HD is known as abnormally expanded CAG repeats of the huntingtin gene (HTT), treatment of HD remains tremendous challenges. One possible reason is lack of effective HD model which resembles striato nigral circuitry deficits for the pharmacology studies. Here we first differentiate striatum-like organoids from human pluripotent stem cells, containing functional medium spiny neurons (MSN). We then generated 3D striato nigral circuitoids by assembling striatum-like organoids with midbrain substantial nigra like organoids. With AVV hSYN GFP viral tracing, the extensive MSN projections from striatum to SN are established, which form synaptic connection with dopaminergic neurons and showed the electronic field potentials by labeling striatum like organoids with optogenetic virus. Furthermore, this striato nigral circuitoids exhibited improved calcium activity than individual striatal organoids. Importantly, we further demonstrated the reciprocal projection defects of the HD iPSC derived circuitoids, which could be reversed with the treatment of brain derived nerve factors. Altogether, the striato nigral circuitoids could be used for identifying MSN projection defects, which would be applied as a potential drug test platform for HD.
2024-05-06 | GSE251684 | GEO
Project description:Detailed comparison of human pluripotent stem cells, to determine how hESC and iPSC differ in their protein expression profiles. The data was acquired in a TMT 10-plex SPS-MS3. 4 replicates of hESC compared to 4 replicates of HipSci human iPSCs.
2021-11-03 | PXD014502 | Pride
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
Project description:Huntington disease is a severe neurological disorder caused by an abnormal polyglutamine expansion in the N-terminal of the huntingtin protein. Here we show that breast tumours appear earlier when mutant huntingtin is expressed in an activated polyomavirus middle T antigen (PyVT) mouse breast cancer model as compared to the control mice expressing wild-type huntingtin. Tumours bearing mutant huntingtin have a modified gene expression pattern revealing increases in the IGF-1/Akt signalling, epithelial-mesenchymal transition and metastatic properties. Indeed, polyQ-huntingtin expressing tumours show hyper-activation of Akt pathway. Also, when mutant huntingtin is expressed, cancer cells in culture change morphology and the levels of cell adhesion and mesenchymal markers are affected in primary tumour or corresponding derived cells. As a consequence, PyVT induced lung metastasis is higher in Huntington disease mice than in the control mice. Finally, analysis of cases of Huntington disease patients developing breast cancer may suggest an increased aggressiveness of breast cancer when compared to the control population. 8 Total samples were analyzed: 4 x MMTV-PyVT/HdhQ7/Q7 breast tumours; 4 x MMTV-PyVT/HdhQ111/Q111 breast tumours;
2014-04-14 | E-GEOD-28685 | biostudies-arrayexpress