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A highly efficient human pluripotent stem cell microglia model displays a neuronal-co-culture-specific expression profile and inflammatory response

Haenseler, Walther, Sansom, Stephen N., Buchrieser, Julian, Newey, Sarah E., Moore, Craig S., Nicholls, Francesca J., Chintawar, Satyan, Schnell, Christian, Antel, Jack P., Allen, Nicholas Denby, Cader, M. Zameel, Wade-Martins, Richard, James, William S. and Cowley, Sally A. 2017. A highly efficient human pluripotent stem cell microglia model displays a neuronal-co-culture-specific expression profile and inflammatory response. Stem Cell Reports 8 (6) , pp. 1727-1742. 10.1016/j.stemcr.2017.05.017

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
Uncontrolled Keywords: human; induced pluripotent stem cell; iPSC; macrophage; microglia; cortical neurons; neuroinflammation; neurodegeneration; Alzheimer's disease; Parkinson's disease
Publisher: Elsevier
ISSN: 2213-6711
Funders: MRC
Date of First Compliant Deposit: 26 June 2017
Date of Acceptance: 15 May 2017
Last Modified: 27 Jun 2017 09:19
URI: http://orca.cf.ac.uk/id/eprint/101735

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