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Morphological diversification and functional maturation of human astrocytes in glia-enriched cortical organoids transplanted in the mouse brain

ABSTRACT: Morphological diversification and functional maturation of human astrocytes in glia-enriched cortical organoids transplanted in the mouse brain

PROVIDER: PRJNA769136 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	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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Morphological diversification and functional maturation of human astrocytes in glia-enriched cortical organoid transplanted in mouse brain.

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

Morphological diversification and functional maturation of human astrocytes in glia-enriched cortical organoids transplanted in the mouse brain

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

Molecular Signatures and Lineage Diversification of Neurogenic and Gliogenic Radial Glia in the Gyrencephalic Ferret Cortex

Project description:Molecular Signatures and Lineage Diversification of Neurogenic and Gliogenic Radial Glia in the Gyrencephalic Ferret Cortex

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A Hedgehog-Induced Homeodomain Cascade Couples Progenitor Identity to Neuronal Diversification

Project description:How progenitor identity instructs neuronal diversification remains unclear. We uncover a homeodomain transcription factor (HDTF) cascade that links the identity of a single lamina progenitor type to the diversification of all five lamina neuron subtypes in the Drosophila visual system. Hedgehog signaling induces a pan-class HDTF—expressed across all subtypes of a neuronal class, here all lamina neurons—in progenitors, promoting cell-cycle exit. This progenitor-derived pan-class HDTF is inherited by newborn lamina neurons, where it activates subtype-specific, differentially expressed (DE) HDTFs and acts combinatorially with these DE-HDTFs to specify distinct neuronal subtypes. Loss of DE-HDTFs induces predictable, subtype-specific fate conversions—morphological and functional—reducing neuronal diversity. Strikingly, we find mouse retinal neurons express analogous pan-class and DE-HDTFs, indicating an evolutionarily conserved strategy. With HDTFs broadly expressed, our findings define a progenitor-to-newborn HDTF cascade that provides a generalizable mechanism by which progenitor identity drives neuronal diversification from a limited progenitor pool.

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Enteric glia express proteolipid protein 1 and are a transcriptionally unique population of glia in the mammalian nervous system

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.

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Project description:Human exceptional cognition stems from evolutionarily derived cortical adaptations that drive expansive neurogenesis. Deciphering these mechanisms is crucial for understanding mammalian cortical evolution. In this study, we employ the ferret model to comprehensively map molecular profiles and lineage dynamics of cortical radial glia (RGs). By applying scRNA-Seq to ferret and human cortices, we identify conserved regulatory programs underlying cortical neurogenesis and gliogenesis in mammals. Through integrated scRNA-Seq, BrdU pulse-chase labeling, and immunohistochemical approaches, we demonstrate that, similar to their human counterparts, ferret cortical outer radial glia (oRGs), exhibit enhanced ERK and PKA signaling. ERK and PKA act in a mutually reinforcing manner to boost oRG self-renewal and neurogenesis, while inhibiting gliogenesis and prolonging the neurogenic period. Furthermore, we identify regional specialization within cortical gliogenic RGs: YAP/TAZ activation drives ventricular zone truncated radial glia (tRGs) toward ependymal fate in medial cortex, whereas SHH signaling instructs lateral cortical tRGs to generate tripotential intermediate progenitor cells, which serve as a shared source of astrocytes, oligodendrocytes, and olfactory bulb interneurons. Our data support a model in which mammalian cortical neurogenesis, gliogenesis, and evolutionary expansion are co-regulated through an integrated signaling network involving ERK, PKA, YAP/TAZ, and SHH. These findings provide key insights into the molecular and cellular mechanisms driving cortical development and evolution.

2025-08-07 | GSE304846 | GEO

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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.

2023-05-10 | GSE197847 | GEO

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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:Cerebellar glia are affected in SCA1. We used single nuclei RNA sequencing (snRNA-seq) to analyze the gene expression changes in glia in response to neuronal dysfunction in SCA1.

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