Rapid and deterministic generation of microglia from human pluripotent stem cells - an in vitro platform for disease progression in neurodegeneration and neuroinflammation
Final Report Abstract
Microglia are the resident macrophages of the central nervous system. They play an important role in the development and resolution of many diseases of the brain. Until recently, the study of human microglia was limited to sparse cell material that had to be isolated from post-mortem brain tissue or neurosurgical specimen. We have established a new method for highly efficient production of pure and large amounts of microglia from human pluripotent stem cells (hPSCs). The microglia were characterised in detail using transcriptomic, proteomic, and functional analyses, which collectively show that our hPSC- derived microglia closely resemble primary human microglia in vitro. Coculture models with hPSC- derived cortical neurons or cortical organoids enabled the study of microglia in model systems with different layers of complexity. This versatile technology of hPSC-derived microglia will improve in vitro models of the human brain and neurological disease. The platform will also facilitate biomedical research, including compound screening, drug discovery, and transplantation studies. Furthermore, we have established a human tauopathy model consisting of MAPT-mutant hiPSC- derived glutamatergic cortical neurons with and without coculture with hiPSC-derived microglia. We were able to identify different MAPT-genotype-dependent neuronal phenotypes as well as a secondary, dystrophic microglia phenotype. These findings provide evidence for mutationdependent, differential pathophysiological effects on the immune response in the hereditary tauopathies.
Publications
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Rapid and efficient generation of microglia from human pluripotent stem cells: a versatile human in vitro platform to model the role of microglia in neurological diseases. Publikation: Glia. 2019 Jul:67 Suppl 1:E3-E766. XIV European Meeting on Glial Cells in Health and Disease 2019, Porto, Portugal
Speicher A.M., Kovac S., Gonzalez-Cano L., Gola L., Wiendl H., Meuth S.G., Schöler H.R. & Pawlowski M.
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German Stem Cell Network (GSCN) 8th Annual Conference 2020 – Virtual. Programming human pluripotent stem cells into microglia – a novel in vitro model of neuroinflammation and neurodegneration
Pawlowski, M.
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Programming human pluripotent stem cells into microglia – a new model to study CNS disease. Publikation: Glia. 2021 Jul:69 Suppl 1:E3-E611. XV European Meeting on Glial Cells in Health and Disease 2021 – Virtual
Speicher A.M., Korn L., Gonzalez-Cano L., Heming M., Thomas C., Kuhlmann T., Meyer zu Hörste G., Kovac S., Wiendl H., Meuth S.G., Schöler H. & Pawlowski M.
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Deterministic programming of human pluripotent stem cells into microglia facilitates studying their role in health and disease. Proceedings of the National Academy of Sciences, 119(43).
Speicher, Anna M.; Korn, Lisanne; Csatári, Júlia; Gonzalez-Cano, Laura; Heming, Michael; Thomas, Christian; Schroeter, Christina B.; Schafflick, David; Li, Xiaolin; Gola, Lukas; Engler, Alexander; Kaehne, Thilo; Vallier, Ludovic; Meuth, Sven G.; Meyer, zu Hörste Gerd; Kovac, Stjepana; Wiendl, Heinz; Schöler, Hans R. & Pawlowski, Matthias
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International conference poster [International Society for Stem Cell Research (ISSCR) Annual Meeting 2019 – Los Angeles, USA]: Rapid and deterministic forward programming of human pluripotent stem cells into microglia to model their role in neurological diseases
Pawlowski M., Kovac S., Gonzalez-Cano L., Gola L., Wiendl H., Meuth S., Schoeler H. & Speicher A.
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MAPT genotype-dependent mitochondrial aberration and ROS production trigger dysfunction and death in cortical neurons of patients with hereditary FTLD. Redox Biology, 59, 102597.
Korn, Lisanne; Speicher, Anna M.; Schroeter, Christina B.; Gola, Lukas; Kaehne, Thilo; Engler, Alexander; Disse, Paul; Fernández-Orth, Juncal; Csatári, Júlia; Naumann, Michael; Seebohm, Guiscard; Meuth, Sven G.; Schöler, Hans R.; Wiendl, Heinz; Kovac, Stjepana & Pawlowski, Matthias
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Forward programming human pluripotent stem cells into microglia. Trends in Cell Biology, 34(12), 1007-1017.
Csatári, Júlia; Wiendl, Heinz & Pawlowski, Matthias
