A Highly Efficient Human Pluripotent Stem Cell Microglia Model Displays a Neuronal-Co-culture-Specific Expression Profile and Inflammatory Response
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 mic...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2017-06-01
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| Series: | Stem Cell Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213671117302242 |
| _version_ | 1828857583367094272 |
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| author | Walther Haenseler Stephen N. Sansom Julian Buchrieser Sarah E. Newey Craig S. Moore Francesca J. Nicholls Satyan Chintawar Christian Schnell Jack P. Antel Nicholas D. Allen M. Zameel Cader Richard Wade-Martins William S. James Sally A. Cowley |
| author_facet | Walther Haenseler Stephen N. Sansom Julian Buchrieser Sarah E. Newey Craig S. Moore Francesca J. Nicholls Satyan Chintawar Christian Schnell Jack P. Antel Nicholas D. Allen M. Zameel Cader Richard Wade-Martins William S. James Sally A. Cowley |
| author_sort | Walther Haenseler |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-13T01:39:33Z |
| format | Article |
| id | doaj.art-edac014090934a7e8219864d7c951707 |
| institution | Directory Open Access Journal |
| issn | 2213-6711 |
| language | English |
| last_indexed | 2024-12-13T01:39:33Z |
| publishDate | 2017-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Stem Cell Reports |
| spelling | doaj.art-edac014090934a7e8219864d7c9517072022-12-22T00:03:48ZengElsevierStem Cell Reports2213-67112017-06-01861727174210.1016/j.stemcr.2017.05.017A Highly Efficient Human Pluripotent Stem Cell Microglia Model Displays a Neuronal-Co-culture-Specific Expression Profile and Inflammatory ResponseWalther Haenseler0Stephen N. Sansom1Julian Buchrieser2Sarah E. Newey3Craig S. Moore4Francesca J. Nicholls5Satyan Chintawar6Christian Schnell7Jack P. Antel8Nicholas D. Allen9M. Zameel Cader10Richard Wade-Martins11William S. James12Sally A. Cowley13Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UKKennedy Institute of Rheumatology, University of Oxford, Roosevelt Drive, Headington, Oxford OX3 7FY, UKSir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UKDepartment of Pharmacology, University of Oxford, Oxford OX1 3QT, UKDivision of BioMedical Sciences, Faculty of Medicine, Memorial University of Newfoundland, St. John's, NL A1B 3V6, CanadaDepartment of Psychiatry, University of Oxford, Warneford Hospital, Oxford OX3 7JX, UKWeatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UKSchool of Biosciences, College of Biomedical and Life Sciences, Cardiff University, Cardiff CF10 3AT, UKMontreal Neurological Institute, McGill University, Montreal, QC H3A 2B4, CanadaSchool of Biosciences, College of Biomedical and Life Sciences, Cardiff University, Cardiff CF10 3AT, UKWeatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UKDepartment of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford OX1 3QX, UKSir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UKSir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UKMicroglia 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.http://www.sciencedirect.com/science/article/pii/S2213671117302242humaninduced pluripotent stem celliPSCmacrophagemicrogliacortical neuronsneuroinflammationneurodegenerationAlzheimer's diseaseParkinson's disease |
| spellingShingle | Walther Haenseler Stephen N. Sansom Julian Buchrieser Sarah E. Newey Craig S. Moore Francesca J. Nicholls Satyan Chintawar Christian Schnell Jack P. Antel Nicholas D. Allen M. Zameel Cader Richard Wade-Martins William S. James Sally A. Cowley A Highly Efficient Human Pluripotent Stem Cell Microglia Model Displays a Neuronal-Co-culture-Specific Expression Profile and Inflammatory Response Stem Cell Reports human induced pluripotent stem cell iPSC macrophage microglia cortical neurons neuroinflammation neurodegeneration Alzheimer's disease Parkinson's disease |
| title | A Highly Efficient Human Pluripotent Stem Cell Microglia Model Displays a Neuronal-Co-culture-Specific Expression Profile and Inflammatory Response |
| title_full | A Highly Efficient Human Pluripotent Stem Cell Microglia Model Displays a Neuronal-Co-culture-Specific Expression Profile and Inflammatory Response |
| title_fullStr | A Highly Efficient Human Pluripotent Stem Cell Microglia Model Displays a Neuronal-Co-culture-Specific Expression Profile and Inflammatory Response |
| title_full_unstemmed | A Highly Efficient Human Pluripotent Stem Cell Microglia Model Displays a Neuronal-Co-culture-Specific Expression Profile and Inflammatory Response |
| title_short | A Highly Efficient Human Pluripotent Stem Cell Microglia Model Displays a Neuronal-Co-culture-Specific Expression Profile and Inflammatory Response |
| title_sort | highly efficient human pluripotent stem cell microglia model displays a neuronal co culture specific expression profile and inflammatory response |
| topic | human induced pluripotent stem cell iPSC macrophage microglia cortical neurons neuroinflammation neurodegeneration Alzheimer's disease Parkinson's disease |
| url | http://www.sciencedirect.com/science/article/pii/S2213671117302242 |
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