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Neuron. 2017 Aug 16;95(4):779-790.e6. doi: 10.1016/j.neuron.2017.07.035.

Human Astrocyte Maturation Captured in 3D Cerebral Cortical Spheroids Derived from Pluripotent Stem Cells.

Author information

1
Department of Neurobiology, Stanford University School of Medicine, Stanford, CA 94305, USA.
2
Departments of Bioengineering and Applied Physics, Stanford University and Chan Zuckerberg Biohub, Stanford, CA 94305, USA.
3
Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA.
4
Department of Neurology and Neurological Science, Stanford University School of Medicine, Stanford, CA 94305, USA.
5
Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: spasca@stanford.du.

Abstract

There is significant need to develop physiologically relevant models for investigating human astrocytes in health and disease. Here, we present an approach for generating astrocyte lineage cells in a three-dimensional (3D) cytoarchitecture using human cerebral cortical spheroids (hCSs) derived from pluripotent stem cells. We acutely purified astrocyte-lineage cells from hCSs at varying stages up to 20 months in vitro using immunopanning and cell sorting and performed high-depth bulk and single-cell RNA sequencing to directly compare them to purified primary human brain cells. We found that hCS-derived glia closely resemble primary human fetal astrocytes and that, over time in vitro, they transition from a predominantly fetal to an increasingly mature astrocyte state. Transcriptional changes in astrocytes are accompanied by alterations in phagocytic capacity and effects on neuronal calcium signaling. These findings suggest that hCS-derived astrocytes closely resemble primary human astrocytes and can be used for studying development and modeling disease.

KEYWORDS:

RNA-seq; astrocyte; cerebral cortex; hCS; human; iPSC; maturation; organoids; spheroids; transcriptome

PMID:
28817799
PMCID:
PMC5890820
DOI:
10.1016/j.neuron.2017.07.035
[Indexed for MEDLINE]
Free PMC Article

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