Insights for disease modeling from single cell transcriptomics of iPSC-derived neurons and astrocytes across differentiation time and co-culture
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ABSTRACT:
PROVIDER: PRJNA1081888 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR28154000_1.fastq.gz | Fastqsanger.gz | |||
| SRR28154000_2.fastq.gz | Fastqsanger.gz | |||
| SRR28154001_1.fastq.gz | Fastqsanger.gz | |||
| SRR28154001_2.fastq.gz | Fastqsanger.gz | |||
| SRR28154002_1.fastq.gz | Fastqsanger.gz |
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Project description:Trans-differentiation of human induced pluripotent stem cells into neurons (hiPSC-N) via Ngn2-induction has become an efficient system to quickly generate neurons for disease modeling and in vitro assay development, a significant step up from previously used neoplastic and other cell lines. Recent single-cell interrogation of Ngn2-induced neurons however, has revealed some similarities to unexpected neuronal lineages. Similarly, a straightforward method to generate hiPSC derived astrocytes (hiPSC-A) for the study of neuropsychiatric disorders has also been described. Here we examine the homogeneity and similarity of hiPSC-N and hiPSC-A to their in vivo counterparts, the impact of different lengths of time post Ngn2 induction on hiPSC-N (15 or 21 days) and of hiPSC-N / hiPSC-A co-culture. We explore how often genes differentially expressed between conditions relate to genetic risk for neuropsychiatric disease. Leveraging the wealth of existing public single-cell RNA-seq (scRNA-seq) data in Ngn2-induced neurons and in vivo data from the developing brain, we provide perspectives on the lineage origins and maturation of hiPSC-N and hiPSC-A. Both show heterogeneity and share similarity with multiple in vivo cell fates, and both cell types more precisely approximate their in vivo counterparts when co-cultured. hiPSC-A show more heterogeneity and similarities to other non-neural cell types, especially when cultured in isolation. Gene expression data from the hiPSC-N show excess of genes linked to schizophrenia (SZ) and autism spectrum disorders (ASD) as has been previously shown for neural stem cells and neurons. These overrepresentations of disease genes are strongest in our system at early times (day 15) in Ngn2-induction/maturation of neurons, which together with our observation of similarities with in vivo neurons earlier in development suggest they may be a better model for neurodevelopmental disorders. We have assembled this new scRNA-seq data along with the public data explored here as an integrated biologist-friendly web-resource for researchers seeking to understand this system more deeply: https://nemoanalytics.org/p?l=DasEtAl2022 .
2024-03-04 | GSE260498 | GEO
Project description:BackgroundTrans-differentiation of human-induced pluripotent stem cells into neurons via Ngn2-induction (hiPSC-N) has become an efficient system to quickly generate neurons a likely significant advance for disease modeling and in vitro assay development. Recent single-cell interrogation of Ngn2-induced neurons, however, has revealed some similarities to unexpected neuronal lineages. Similarly, a straightforward method to generate hiPSC-derived astrocytes (hiPSC-A) for the study of neuropsychiatric disorders has also been described.ResultsHere, we examine the homogeneity and similarity of hiPSC-N and hiPSC-A to their in vivo counterparts, the impact of different lengths of time post Ngn2 induction on hiPSC-N (15 or 21 days), and the impact of hiPSC-N/hiPSC-A co-culture. Leveraging the wealth of existing public single-cell RNA-seq (scRNA-seq) data in Ngn2-induced neurons and in vivo data from the developing brain, we provide perspectives on the lineage origins and maturation of hiPSC-N and hiPSC-A. While induction protocols in different labs produce consistent cell type profiles, both hiPSC-N and hiPSC-A show significant heterogeneity and similarity to multiple in vivo cell fates, and both more precisely approximate their in vivo counterparts when co-cultured. Gene expression data from the hiPSC-N show enrichment of genes linked to schizophrenia (SZ) and autism spectrum disorders (ASD) as has been previously shown for neural stem cells and neurons. These overrepresentations of disease genes are strongest in our system at early times (day 15) in Ngn2-induction/maturation of neurons, when we also observe the greatest similarity to early in vivo excitatory neurons. We have assembled this new scRNA-seq data along with the public data explored here as an integrated biologist-friendly web-resource for researchers seeking to understand this system more deeply: https://nemoanalytics.org/p?l=DasEtAlNGN2&g=NES .ConclusionsWhile overall we support the use of the investigated cellular models for the study of neuropsychiatric disease, we also identify important limitations. We hope that this work will contribute to understanding and optimizing cellular modeling for complex brain disorders.
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Project description:RNA-Seq experiment to detect transcriptional differences in iPSC derived astrocytes between 3 primate species, humans, chimpanzees and macaques. The goal of the experiment is to characterise genome-wide evolutionary changes in transcriptional and regulatory systems across the primate lineage in astrocytes
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Project description:Reprogramming somatic cells to induced pluripotent stem cells (iPSCs) sets their identity back to an embryonic age. This presents a fundamental hurdle for modeling late-onset disorders using iPSC-derived cells. We therefore developed a strategy to induce age-like features in multiple iPSC-derived lineages and tested its impact on modeling Parkinson’s disease (PD). We first describe markers that predict fibroblast donor age and observed the loss of these age-related markers following iPSC induction and re-differentiation into fibroblasts. Remarkably, age-related markers were readily induced in iPSC-derived fibroblasts or neurons following exposure to progerin including dopamine neuron-specific phenotypes such as neuromelanin accumulation. Induced aging in PD-iPSC-derived dopamine neurons revealed disease phenotypes requiring both aging and genetic susceptibility such as frank dendrite degeneration, progressive loss of tyrosine-hydroxylase expression and enlarged mitochondria or Lewy body-precursor inclusions. Our study presents a strategy for inducing age-related cellular properties and enables the modeling of late-onset disease features. Induced pluripotent stem cell-derived midbrain dopamine neurons from a young and old donor overexpressing either GFP or Progerin.
2014-01-23 | E-GEOD-52431 | biostudies-arrayexpress
Project description:We generated a stable healthy and diseased (with ALS-linked FUS-R521H mutation) iPSC line containing the coding sequence of SOX9 under a Tet-on promotor in the safe harbor AAVS1 locus via recombinase-mediated cassette exchange. This allows the induction of SOX9 expression after doxycycline addition and generates in this way PSC-derived astrocytes. RNASeq is performed on these healthy and diseased iSOX9-astrocytes at an early and late timepoint. In addition, we included commercially available PSC-derived astrocytes (called "iCell") and fetal human primary astrocytes (called "fHA").
2021-05-10 | GSE162892 | GEO
Project description:RNA sequencing on iPSC-derived iSOX9-astrocytes
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Project description:We performed RNA-seq on human iPSC derived astrocytes and iPSC derived astrocyte derived extracellular vesicles.
2024-04-24 | GSE229016 | GEO
Project description:Single-cell RNA-seq: We used single-cell RNAseq to investigate the maturation of astrocytes within human cortical spheroids Bulk RNA-seq: Bulk sequencing from astrocytes and neurons purified (via immunopanning) from iPSC-derived coritical spheroids at varying in vitro differentiation states
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Project description:Astrocytes interact closely with neurons and facilitate neuronal maturation and function by providing trophic support, regulating the extracellular environment, and engaging in a variety of inter-cellular signalling mechanisms. We have described the generation of human astrocytes and neurons from a common cortical progenitor pool, thereby recapitulating aspects of in vivo development. Firstly, we show that the iPSC-derived astrocytes exhibit many of the key molecular and functional hallmarks predicted of astrocytes. Secondly, we provide functional and transcriptomic analyses of the astrocytes’ capacity to interact with neurons both through rapid regulation of ongoing synaptic transmission as well as exerting pro-maturational effects on the synaptic networks. Transcriptional analysis included the comparison of the present RNA-seq of iPSC-derived astrocytes to other iPSC-derived astrocyte datasets as well as fetal and adult human astrocytes. We investigated differences in gene expression between our maturation-enhancing iPSC-astrocytes and iPSC-astrocytes previously shown to be unable to promote synaptic network maturation. By integrating transcriptomic data, functional genomic annotations and protein-protein interaction resources we support that astrocytic extracellular signalling is important for the ability of astrocytes to mediate functional neuronal maturation. This work provides a foundation for future investigations into astrocyte-neuron interactions in human health and disease.
2020-04-30 | GSE149598 | GEO
Project description:Reprogramming somatic cells to induced pluripotent stem cells (iPSCs) sets their identity back to an embryonic age. This presents a fundamental hurdle for modeling late-onset disorders using iPSC-derived cells. We therefore developed a strategy to induce age-like features in multiple iPSC-derived lineages and tested its impact on modeling Parkinson’s disease (PD). We first describe markers that predict fibroblast donor age and observed the loss of these age-related markers following iPSC induction and re-differentiation into fibroblasts. Remarkably, age-related markers were readily induced in iPSC-derived fibroblasts or neurons following exposure to progerin including dopamine neuron-specific phenotypes such as neuromelanin accumulation. Induced aging in PD-iPSC-derived dopamine neurons revealed disease phenotypes requiring both aging and genetic susceptibility such as frank dendrite degeneration, progressive loss of tyrosine-hydroxylase expression and enlarged mitochondria or Lewy body-precursor inclusions. Our study presents a strategy for inducing age-related cellular properties and enables the modeling of late-onset disease features.
2014-01-23 | GSE52431 | GEO