Gene expression changes associated with Alexander disease (AxD)
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE116327 | GEO | 2018/08/01
REPOSITORIES: GEO
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Project description:Alexander disease (AxD) is a rare, severe neurodegenerative disorder caused by mutations in the glial fibrillary acidic protein (GFAP). While the exact disease mechanism remains unknown, existing studies suggest that the mutant GFAP influences many cellular processes, including cytoskeleton stability, mechanosensing, cell energetics, and proteasome function. While most studies have primarily focused on GFAP-expressing astrocytes, this protein is also expressed by radial glia and neural progenitor cells, prompting questions about the impact of GFAP mutations on central nervous system (CNS) development. In this study, we present an intriguing observation of an impaired differentiation of astrocytes and neurons in co-cultures of astrocytes and neurons, as well as in brain organoids, both generated from patient-derived induced pluripotent stem (iPS) cells with a GFAP (R239C) mutation. Leveraging single-cell RNA sequencing (scRNA-seq), we identified distinct cell populations and transcriptomic changes between the GFAP mutant cells and an isogenic corrected control. These findings are supported with immunocytochemistry and proteomics. In co-cultures, the AxD mutation resulted in an increased abundance of immature cells, while in organoids, we observed an altered cell differentiation and reduced abundance of astrocytes. Additionally, gene expression analysis associated the AxD mutation with increased stress susceptibility, cytoskeletal abnormalities, and altered extracellular matrix and cell-cell communication patterns. Overall, our results suggest the possibility of a faulty differentiation in human iPS cell-derived models of AxD, opening new avenues for AxD research.
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Project description:Growing evidence implicates the importance of glia, particularly astrocytes, in neurological and psychiatric diseases. Here, we describe a rapid and robust method for the differentiation of highly pure populations of astrocytes from human induced pluripotent stem cells (hiPSCs), via a neural progenitor cell (NPC) intermediate. Using this method, we generated hiPSC-derived astrocyte populations (hiPSC-astrocytes) from 42 NPC lines (derived from 30 individuals) with an average of ~90% S100β-positive cells. Transcriptomic analysis demonstrated that the hiPSC-astrocytes are highly similar to primary human fetal astrocytes and characteristic of a non-reactive state. hiPSC-astrocytes respond to inflammatory stimulants, display phagocytic capacity and enhance microglial phagocytosis. hiPSC-astrocytes also possess spontaneous calcium transient activity. Our novel protocol is a reproducible, straightforward (single media) and rapid (<30 days) method to generate homogenous populations of hiPSC-astrocytes that can be used for neuron-astrocyte and microglia-astrocyte co-cultures for the study of neuropsychiatric disorders.
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Project description:Co-cultures of neurons and astrocytes derived from human iPS cells carrying a GFAP (R239C) mutation - an identified cause of Alexander disease (AxD) - were analyzed with single-cell RNA sequencing to assess cell population composition, differential gene expression, and cell-cell interaction differences in AxD co-cultures compared to controls. Oxygen-glucose deprivation (OGD) challenge was applied to identify differences in stress response. Our results suggested differentiation impairment especially in AxD astrocytes, represented by an enriched population of less differentiated cells and downregulation of mature astrocyte genes in AxD astrocytes-containing co-cultures. Furthermore, AxD co-cultures showed increased stress response represented by upregulation of metallothioneins and increased susceptibility to the OGD challenge.
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Project description:Alexander disease is a neurodegenerative diseases caused by mutations of GFAP, an astrocyte-specific gene. We used single cell RNA sequencing (scRNA-seq) to analyze the diversity of astrocytes.
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Project description:Schizophrenia is a complex and severe neuropsychiatric disorder, with a wide range of debilitating symptoms. Several aspects of its multifactorial complexity are still unknown, and some are accepted to be an early developmental deficiency with a more specifically neurodevelopmental origin. ??Molecular and functional abnormalities in astrocytes play a role in the etiology and pathogenesis of schizophrenia. In this study, human induced pluripotent stem cells (hiPSC)-derived astrocytes from schizophrenia patients were investigated regarding their proteome, inflammatory responses, and their secretome effect on vascularization. Proteomic analysis revealed alterations in proteins related to immune function and vascularization. Taken together, our results suggest that schizophrenia astrocytes are immunologically dysfunctional which might affect vascularization through secreted factors.
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Project description:Gene expression changes associated with Alexander disease (AxD)
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Project description:Whereas highly penetrant variants have proven well-suited to human induced pluripotent stem cell (hiPSC)-based models, the power of hiPSC-based studies to resolve the much smaller effects of common variants within the size of cohorts that can be realistically assembled remains uncertain. In developing a large case/control schizophrenia (SZ) hiPSC-derived cohort of neural progenitor cells and neurons, we identified and accounted for a variety of technical and biological sources of variation. Reducing the stochastic effects of the differentiation process by correcting for cell type composition boosted the SZ signal in hiPSC-based models and increased the concordance with post mortem datasets. Because this concordance was strongest in hiPSC-neurons, it suggests that this cell type may better model genetic risk for SZ. We predict a growing convergence between hiPSC and post mortem studies as both approaches expand to larger cohort sizes. For studies of complex genetic disorders, to maximize the power of hiPSC cohorts currently feasible, in most cases and whenever possible, we recommend expanding the number of individuals even at the expense of the number of replicate hiPSC clones.
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Project description:Previous studies have implicated several brain cell types in schizophrenia, but the genetic impact of astrocytes is unknown. Considering their high complexity in humans, astrocytes are likely key determinants of neurodevelopmental diseases. Human induced pluripotent stem cell (hiPSC) -derived astrocytes differentiated from five monozygotic twin pairs discordant for schizophrenia and five healthy subjects were studied for alterations related to high genetic risk and clinical manifestation of SCZ in astrocyte transcriptomics.
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