Morphological diversification and functional maturation of human astrocytes in glia-enriched cortical organoids transplanted in the mouse brain
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ABSTRACT:
PROVIDER: PRJNA769136 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
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| SRR16227151.fastq.gz | Fastqsanger.gz | |||
| SRR16227152.fastq.gz | Fastqsanger.gz | |||
| SRR16227153.fastq.gz | Fastqsanger.gz | |||
| SRR16227154.fastq.gz | Fastqsanger.gz | |||
| SRR22044200.fastq.gz | Fastqsanger.gz |
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Project description:Astrocytes, the most abundant glial cell type in the brain, are underrepresented in traditional cortical organoid models due to the delayed onset of cortical gliogenesis. Here we introduce a new glia-enriched cortical organoid model that exhibits accelerated astrogliogenesis. We demonstrated that induction of a gliogenic switch in a subset of progenitors enabled the rapid derivation of astroglial cells, which account for 25-31% of the cell population within 8-10 weeks of differentiation. Intracerebral transplantation of these organoids reliably generated a diverse repertoire of cortical neurons and anatomical subclasses of human astrocytes. Spatial transcriptome profiling identified layer-specific expression patterns among distinct subclasses of astrocytes within organoid transplants. Using an in vivo acute neuroinflammation model, we identified a subpopulation of astrocytes that rapidly activates pro-inflammatory pathways upon cytokine stimulation. Additionally, we demonstrated that CD38 signaling has a crucial role in mediating metabolic and mitochondrial stress in reactive astrocytes. This model provides a robust platform for investigating human astrocyte function.
| S-EPMC11349933 | biostudies-literature
Project description:Astrocytes, the most abundant glial cell type in the brain, are underrepresented in traditional cortical organoid models due to the delayed onset of cortical gliogenesis. Here, we introduce a novel glia-enriched cortical organoid model that exhibits accelerated astrogliogenesis. We demonstrated that induction of a gliogenic switch in a subset of progenitors enabled rapid derivation of astroglial cells, which account for 25-31% of the cell population within eight to ten weeks of differentiation. Intracerebral transplantation of these organoids reliably generated a diverse repertoire of cortical neurons and anatomical subclasses of human astrocytes. Spatial transcriptome profiling identified layer-specific expression patterns among distinct subclasses of astrocytes within the organoid transplants. Using an in vivo acute neuroinflammation model, we identified a subpopulation of astrocytes that rapidly activates proinflammatory pathways upon cytokine stimulation. Additionally, we demonstrated that CD38 signaling plays a crucial role in mediating metabolic and mitochondrial stress in reactive astrocytes. This model provides a robust platform for investigating human astrocyte function.
2024-01-16 | GSE185472 | GEO
Project description:To identify the gene expression profile of enteric glia and assess the transcriptional similarity between enteric and extraenteric glia, we performed RNA sequencing analysis on PLP1-expressing cells in the mouse intestine. This analysis shows that enteric glia are transcriptionally unique and distinct from other cell types in the nervous system. Enteric glia express many genes characteristic of the myelinating glia, Schwann cells and oli- godendrocytes, although there is no evidence of myelination in the murine ENS. Total RNA expression profiles of PLP1 expressing enteric glial cells (GFP+) and non-glial cells (GFP-negative) were obtained from the ileum and colon of juvenile PLP1-eGFP transgenic mice.
2015-09-01 | E-GEOD-72560 | biostudies-arrayexpress
Project description:Neural cell type diversity arises from both spatial and temporal patterning of neural stem cells. Although spatial patterning mechanisms have been extensively studied, temporal patterning mechanisms remain relatively unexplored. In this study, we addressed generation of diverse neural cell types through lineage progression of mouse cortical radial glia. The time series scRNA-seq and snATAC-seq of mouse cortical development revealed that radial glia temporally transitioned from neurogenesis to gliogenesis. During gliogenic stages, various cell types were generated simultaneously along multidirectional lineage trajectories. We established comprehensive molecular maps for cortical lineage commitment and cellular diversification. The transcriptome and epigenome of cortical radial glia exhibit temporal dynamics, as revealed by scRNA-seq and snATAC-seq. Lhx2, a transcription factor with temporal dynamic chromatin binding activities, was identified as a key regulator of the neurogenesis-to-gliogenesis transition. It maintains neurogenic competence by establishing the active epigenetic state of its target genes.
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Project description:Subretinal transplantation of human retinal organoid-derived cells can potentially restore vision lost in photoreceptor dystrophies. Prior studies analyzed the maturation, integration, and function of transplanted organoid cells in the subretinal region, but detailed molecular analysis of transplanted photoreceptor and of cells that migrate to other retinal layers has not been conducted. Here, we characterized migratory and non-migratory organoid-derived cells following subretinal transplantation into a dystrophic host. Retinal organoids derived from Crx-tdTomato+ H9 human embryonic stem cells (hESC) (aged D134) were transplanted into immunodeficient Rd1/NS mice. Graft-derived cells using single-cell RNA sequencing and histological analysis were analyzed 4.5 months later. Age-matched human retinal organoids maintained in vitro served as controls. Graft-derived cells migrated to all retinal layers, and underwent long-distance tangential migration. Transcriptomic analysis of transplanted cells identified two cell types not found in cultured controls – PAX2-positive retinal astrocytes, and ARX/NKX2-2/HOXC8-positive brain/spinal cord-like neural precursors. Some migrating cells were proliferative, but overall less proliferation was observed in the transplants than the cultured organoids. Transplanted rod and cone photoreceptors remained in the subretinal space, and were more mature than age-matched photoreceptors in cultured organoids. This study shows that extrinsic signals present in the degenerative subretinal space promote maturation of photoreceptors in transplanted retinal organoids, while also inducing formation of migratory cell populations that are not normally derived from retinal progenitors, either in cultured organoids or in vivo. This has important implications for the design and safety of cell-based therapies for treating photoreceptor dystrophies.
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2022-12-05 | GSE215336 | GEO
Project description:Proteins exhibit dynamics in their expression level in response to intracellular and extracellular signals. Regulation of protein turnover allows cells to rapidly and efficiently remodel their proteomes. It is known that proteins can show very different turnover rates in different tissue of the same organism, but little is known about protein turnover rates in different brain cell types. We used a dynamic SILAC approach to determine protein half-lives in primary hippocampal cultures (containing a mixture of neurons and glia cells) as well as in neuron-enriched and glia-enriched cultures. We determined the protein half-lives for over 5100 proteins and found half-lives ranging from <1 to > 20 days with a median half-life of 5.4 days in mixed cultures. Membrane proteins as a group were shorter-lived and mitochondrial proteins, surprisingly, were longer-lived. Proteins in glia possessed significantly shorter half-lives than the same proteins in neurons. The presence of glia sped up or slowed down the half-lives of neuronal proteins. Our results demonstrate that both the cell-type of origin as well as the nature of the extracellular environment have potent influences on protein turnover.
2018-06-05 | PXD008596 | Pride
Project description:BackgroundIncreasing evidence for a direct contribution of astrocytes to neuroinflammatory and neurodegenerative processes causing Alzheimer's disease comes from molecular and functional studies in rodent models. However, these models may not fully recapitulate human disease as human and rodent astrocytes differ considerably in morphology, functionality, and gene expression.ResultsTo address these challenges, we established an approach to study human astrocytes within the mouse brain by transplanting human induced pluripotent stem cell (hiPSC)-derived astrocyte progenitors into neonatal brains. Xenografted hiPSC-derived astrocyte progenitors differentiated into astrocytes that integrated functionally within the mouse host brain and matured in a cell-autonomous way retaining human-specific morphologies, unique features, and physiological properties. In Alzheimer´s chimeric brains, transplanted hiPSC-derived astrocytes responded to the presence of amyloid plaques undergoing morphological changes that seemed independent of the APOE allelic background.ConclusionsIn sum, we describe here a promising approach that consist of transplanting patient-derived and genetically modified astrocytes into the mouse brain to study human astrocyte pathophysiology in the context of Alzheimer´s disease.
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Project description:These data serve as a reference transcriptomic profile for adult mouse retinal Muller glia. Retinas were dissociated into single cell suspensions and sorted into two fractions: a Muller glia-enriched fraction on the basis of Muller glia-specific tdTomato expression and a second fraction containing the remaining retinal cells that were tdTomato-negative. Both fractions were sequenced.
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Project description:Non-mammalian vertebrates have a robust ability to regenerate injured retinal neurons from Müller glia cells (MG) that activate the proneural factor Achaete-scute homolog 1 (Ascl1/Mash1) and de-differentiate into progenitors cells. In contrast, mammalian MG have a limited regenerative response and fail to upregulate Ascl1 after injury. To test whether Ascl1 could restore a neurogenic potential to mammalian MG, we over-expressed Ascl1 in dissociated mouse MG cultures and intact retinal explants. Ascl1-infected MG upregulate retinal progenitor-specific genes, while downregulating glial genes. Furthermore, Ascl1 remodeled the chromatin at its targets from a repressive to active configuration. MG-derived progenitors differentiated into cells that exhibited neuronal morphologies, expressed retinal subtype-specific neuronal markers, and displayed neuron-like physiological responses. These results indicate that a single transcription factor, Ascl1, can produce a neurogenic state in mature Muller glia. Expresssion profiling was used to determine the genes that were changed after Ascl1 infection of P12 cultured Müller glia compared with those present in P0 progenitors and P7-P21 Müller glia Retinas were dissociated and FAC-sorted from Hes5-GFP mice at P0, P7, P10, P14 or P21 and submitted for profiling. WT Retinas were dissociated at P12, grown for 1 week in culture, and infected with lentiviruses expressing Ascl1 or GFP for four days. Total RNA was extracted and submitted for profiling.
2013-04-06 | E-GEOD-45835 | biostudies-arrayexpress