Cell reports · 2026
Topoisomerase I inhibition yields a CD74high/MHChigh human microglial subtype with enhanced Aβ uptake.
СтатьяНазвание и аннотация: Перевод в очереди
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Haage Verena, Tuddenham John F, Comandante-Lou Natacha, Bautista Alex R, Monzel Anna S, Garcia Frankie G, Chiu Rebecca, Fujita Masashi, Bhattarai Prabesh, White Charles C, Patel Ronak, Buonfiglioli Alice, Idiarte Juan, Herman Mathieu, Rinderspacher Alison, Mela Angeliki, Zhao Wenting, Argenziano Michael G, Furnari Julia L, Banu Matei A, Landry Donald W, Bruce Jeffrey N, Canoll Peter, Zhang Ya, Nuriel Tal, Sproul Andrew A, de Witte Lotje D, Sims Peter A, Menon Vilas, Kizil Caghan, Picard Martin, De Jager Philip L
Аннотация
While efforts to identify microglial subtypes have recently accelerated, the relation of transcriptomically defined states to cellular function has been largely limited to in silico annotations. Here, we characterize two topoisomerase I inhibitors that polarize human microglia toward a distinct state characterized by increased antigen presentation gene expression. Using HMC3 cells, iPSC-derived microglia, and cerebral organoids, we show that Camptothecin induces a CD74high/MHChigh microglia-like cell subtype specialized in amyloid beta phagocytosis and reduced IL-6, IL-8, and MCP-1 secretion in response to TNF-α stimulation. Moreover, Camptothecin suppresses amyloid toxicity and restores microglia to their homeostatic morphology in a zebrafish amyloid proteinopathy model. We also identify Topotecan, a Food and Drug Administration (FDA)-approved Camptothecin analog, as a driver of the CD74high/MHChigh signature. This report provides a reproducible approach to recapitulate a human microglial state in vitro, enabling its functional characterization and providing a foundation for rational modulation of human microglia in vivo.