Journal
STEM CELL REPORTS
Volume 8, Issue 6, Pages 1727-1742Publisher
CELL PRESS
DOI: 10.1016/j.stemcr.2017.05.017
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Funding
- Wellcome Trust [WTISSF121302, 090532/Z/09/Z]
- Oxford Martin School [LC0910-004]
- MRC [MC_EX_MR/N50192X/1, MR/N013255/1, MC_PC_16034]
- Swiss National Foundation Early Postdoc Mobility [148607]
- ARUK Oxford pilot grant
- Kennedy Institute of Rheumatology Trust
- Royal Society Dorothy Hodgkin Fellowship
- Medical Research Council
- Heatley Merck Sharpe and Dohme studentship
- seventh Framework Program, RepairHD
- Innovative Medicines Initiative Joint Undertaking from the European Union's Seventh Framework Program (FP7) [115439]
- EFPIA companies'
- MRC Hub grant [G090074791070]
- Monument Trust Discovery Award from Parkinson's UK [2581970, SC037554]
- National Institute for Health Research (NIHR) Oxford Biomedical Research Center based at Oxford University Hospitals NHS Trust and University of Oxford
- NIHR Comprehensive Local Research Network
- MRC [MR/L023784/2, MR/L023784/1, MR/M024962/1, MR/N013255/1, MC_PC_16034, MC_EX_MR/N50192X/1] Funding Source: UKRI
- Medical Research Council [MC_PC_16034, MR/L023784/1, MR/L023784/2, MR/N013255/1, MC_EX_MR/N50192X/1, MR/M024962/1] Funding Source: researchfish
- Parkinson's UK [J-0901] Funding Source: researchfish
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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.
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