期刊
NATURE NEUROSCIENCE
卷 25, 期 9, 页码 1149-+出版社
NATURE PORTFOLIO
DOI: 10.1038/s41593-022-01131-4
关键词
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资金
- NIH [DP2 GM119139, U01 MH115747, U54 NS100717, R01 AG051390, F30 AG066418, F30 AG062043]
- Center for Alzheimer's and Related Dementias (CARD) of the National Institutes of Health (NIH) [ZO1 AG000534-02]
- Intramural Research Program of the National Institutes of Neurological Disorders and Stroke
- NSF Graduate Research Fellowship
- Tau Consortium Investigator Awards (Rainwater Charitable Foundation)
- Chan Zuckerberg Initiative Ben Barres Early Career Acceleration Award
- Chan Zuckerberg Biohub Investigator Award
- Kampmann Lab, UCSF
- Data Tecnica International, LLC
- Center for Alzheimer's and Related Dementias, National Institutes of Health
This study presents a screening platform to systematically elucidate the functional consequences of genetic perturbations in human induced pluripotent stem cell-derived microglia. The researchers identified genes controlling microglia survival, activation, and phagocytosis, as well as disease-associated genes. They also determined regulators of disease-relevant microglial states using single-cell RNA sequencing. The platform has the potential for therapeutic targeting and functional characterization of microglia.
Microglia are emerging as key drivers of neurological diseases. However, we lack a systematic understanding of the underlying mechanisms. Here, we present a screening platform to systematically elucidate functional consequences of genetic perturbations in human induced pluripotent stem cell-derived microglia. We developed an efficient 8-day protocol for the generation of microglia-like cells based on the inducible expression of six transcription factors. We established inducible CRISPR interference and activation in this system and conducted three screens targeting the 'druggable genome'. These screens uncovered genes controlling microglia survival, activation and phagocytosis, including neurodegeneration-associated genes. A screen with single-cell RNA sequencing as the readout revealed that these microglia adopt a spectrum of states mirroring those observed in human brains and identified regulators of these states. A disease-associated state characterized by osteopontin (SPP1) expression was selectively depleted by colony-stimulating factor-1 (CSF1R) inhibition. Thus, our platform can systematically uncover regulators of microglial states, enabling their functional characterization and therapeutic targeting. Drager et al. establish a rapid, scalable platform for iPSC-derived microglia. CRISPRi/a screens uncover roles of disease-associated genes in phagocytosis, and regulators of disease-relevant microglial states that can be targeted pharmacologically.
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