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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
Proceedings of the National Academy of Sciences - PNAS, 10/2022, Letnik: 119, Številka: 43Journal Article
Microglia, the resident immune cells of the central nervous system (CNS), are derived from yolk-sac macrophages that populate the developing CNS during early embryonic development. Once established, the microglia population is self-maintained throughout life by local proliferation. As a scalable source of microglia-like cells (MGLs), we here present a forward programming protocol for their generation from human pluripotent stem cells (hPSCs). The transient overexpression of PU.1 and C/EBPβ in hPSCs led to a homogenous population of mature microglia within 16 d. MGLs met microglia characteristics on a morphological, transcriptional, and functional level. MGLs facilitated the investigation of a human tauopathy model in cortical neuron-microglia cocultures, revealing a secondary dystrophic microglia phenotype. Single-cell RNA sequencing of microglia integrated into hPSC-derived cortical brain organoids demonstrated a shift of microglia signatures toward a more-developmental in vivo-like phenotype, inducing intercellular interactions promoting neurogenesis and arborization. Taken together, our microglia forward programming platform represents a tool for both reductionist studies in monocultures and complex coculture systems, including 3D brain organoids for the study of cellular interactions in healthy or diseased environments.
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in: SICRIS
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