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Stem Cell Reports. 2017 Jun 6;8(6):1727-1742. doi: 10.1016/j.stemcr.2017.05.017.

A Highly Efficient Human Pluripotent Stem Cell Microglia Model Displays a Neuronal-Co-culture-Specific Expression Profile and Inflammatory Response.

Author information

1
Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK.
2
Kennedy Institute of Rheumatology, University of Oxford, Roosevelt Drive, Headington, Oxford OX3 7FY, UK.
3
Department of Pharmacology, University of Oxford, Oxford OX1 3QT, UK.
4
Division of BioMedical Sciences, Faculty of Medicine, Memorial University of Newfoundland, St. John's, NL A1B 3V6, Canada.
5
Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford OX3 7JX, UK.
6
Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK.
7
School of Biosciences, College of Biomedical and Life Sciences, Cardiff University, Cardiff CF10 3AT, UK.
8
Montreal Neurological Institute, McGill University, Montreal, QC H3A 2B4, Canada.
9
Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford OX1 3QX, UK; Oxford Parkinson's Disease Centre, University of Oxford, South Parks Road, Oxford OX1 3QX, UK.
10
Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK; Oxford Parkinson's Disease Centre, University of Oxford, South Parks Road, Oxford OX1 3QX, UK. Electronic address: sally.cowley@path.ox.ac.uk.

Abstract

Microglia are increasingly implicated in brain pathology, particularly neurodegenerative disease, with many genes implicated in Alzheimer's, Parkinson's, and motor neuron disease expressed in microglia. There is, therefore, a need for authentic, efficient in vitro models to study human microglial pathological mechanisms. Microglia originate from the yolk sac as MYB-independent macrophages, migrating into the developing brain to complete differentiation. Here, we recapitulate microglial ontogeny by highly efficient differentiation of embryonic MYB-independent iPSC-derived macrophages then co-culture them with iPSC-derived cortical neurons. Co-cultures retain neuronal maturity and functionality for many weeks. Co-culture microglia express key microglia-specific markers and neurodegenerative disease-relevant genes, develop highly dynamic ramifications, and are phagocytic. Upon activation they become more ameboid, releasing multiple microglia-relevant cytokines. Importantly, co-culture microglia downregulate pathogen-response pathways, upregulate homeostatic function pathways, and promote a more anti-inflammatory and pro-remodeling cytokine response than corresponding monocultures, demonstrating that co-cultures are preferable for modeling authentic microglial physiology.

KEYWORDS:

Alzheimer's disease; Parkinson's disease; cortical neurons; human; iPSC; induced pluripotent stem cell; macrophage; microglia; neurodegeneration; neuroinflammation

PMID:
28591653
PMCID:
PMC5470330
DOI:
10.1016/j.stemcr.2017.05.017
[Indexed for MEDLINE]
Free PMC Article

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