Deterministic programming of human pluripotent stem cells into microglia facilitates studying their role in health and disease

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 sou...

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Published in:Proceedings of the National Academy of Sciences - PNAS 2022-10, Vol.119 (43), p.e2123476119-e2123476119
Main Authors: 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
Format: Article
Language:English
Subjects:
Biological Sciences
Brain
Cell Differentiation - genetics
Cell proliferation
Central Nervous System
Embryogenesis
Embryonic growth stage
Gene sequencing
Humans
Immune system
Macrophages
Microglia
Monoculture
Neurodegenerative diseases
Neurogenesis
Neurons
Organoids
Phenotypes
Physical characteristics
Pluripotency
Pluripotent Stem Cells
Programming
PU.1 protein
Stem cells
Tau protein
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Summary: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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.2123476119