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

• Published in: Stem cell reports Vol. 8; no. 6; pp. 1727 - 1742
• Main Authors: 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 D., Cader, M. Zameel, Wade-Martins, Richard, James, William S., Cowley, Sally A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 06.06.2017; Elsevier
• Subjects: Alzheimer's disease; Cells, Cultured; Coculture Techniques; cortical neurons; Cytokines - metabolism; Down-Regulation; fms-Like Tyrosine Kinase 3 - metabolism; human; Humans; induced pluripotent stem cell; iPSC; macrophage; Macrophages - cytology; Macrophages - metabolism; microglia; Microglia - cytology; Microglia - metabolism; Models, Biological; neurodegeneration; Neurodegenerative Diseases - metabolism; Neurodegenerative Diseases - pathology; neuroinflammation; Neurons - cytology; Neurons - metabolism; Parkinson's disease; Phagocytosis; Pluripotent Stem Cells - cytology; Pluripotent Stem Cells - metabolism; Proto-Oncogene Proteins c-myb - genetics; Proto-Oncogene Proteins c-myb - metabolism; Transcriptome; cortical neurons; Parkinson's disease; induced pluripotent stem cell; neuroinflammation; iPSC; neurodegeneration; macrophage; human; microglia; Alzheimer's disease
• ISSN: 2213-6711; 2213-6711
• DOI: 10.1016/j.stemcr.2017.05.017

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. [Display omitted] •iPSC microglia co-culture model with iPSC cortical neurons•Expression of microglia markers in co-culture•Co-culture promotes microglial ramification and motility•Co-culture-specific cytokine release profiles Microglia are implicated in neurodegenerative disease, and authentic human in vitro models are needed. The iPSC microglia model described here recapitulates microglia ontogeny by differentiating MYB-independent embryonic iPSC macrophages, then co-culturing them with iPSC cortical neurons. Co-culture microglia express microglia-specific markers and neurodegenerative disease genes, upregulate homeostatic pathways, develop dynamic ramifications, are phagocytic, and produce a cytokine profile that is co-culture specific.