A CRISPRi/a platform in human iPSC-derived microglia uncovers regulators of disease states
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...
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| Veröffentlicht in: | Nature neuroscience 2022-09, Vol.25 (9), p.1149-1162 |
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| creator | Dräger, Nina M. Sattler, Sydney M. Huang, Cindy Tzu-Ling Teter, Olivia M. Leng, Kun Hashemi, Sayed Hadi Hong, Jason Aviles, Giovanni Clelland, Claire D. Zhan, Lihong Udeochu, Joe C. Kodama, Lay Singleton, Andrew B. Nalls, Mike A. Ichida, Justin Ward, Michael E. Faghri, Faraz Gan, Li Kampmann, Martin |
| description | 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.
Dräger 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. |
| doi_str_mv | 10.1038/s41593-022-01131-4 |
| format | Article |
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Dräger 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.</description><identifier>ISSN: 1097-6256</identifier><identifier>EISSN: 1546-1726</identifier><identifier>DOI: 10.1038/s41593-022-01131-4</identifier><identifier>PMID: 35953545</identifier><language>eng</language><publisher>New York: Nature Publishing Group US</publisher><subject>631/1647/2163 ; 631/208/191 ; 631/378/2596/1953 ; 631/532/1360 ; Animal Genetics and Genomics ; Behavioral Sciences ; Biological Techniques ; Biomedical and Life Sciences ; Biomedicine ; Brain - metabolism ; Clustered Regularly Interspaced Short Palindromic Repeats - genetics ; Colony-stimulating factor ; CRISPR ; Disease ; Gene sequencing ; Genes ; Genomes ; Humans ; Induced Pluripotent Stem Cells - metabolism ; Macrophage colony-stimulating factor ; Microglia ; Microglia - metabolism ; Neurobiology ; Neurodegeneration ; Neurological diseases ; Neurosciences ; Osteopontin ; Perturbation ; Phagocytosis ; Phagocytosis - genetics ; Pluripotency ; Stem cells ; Therapeutic targets ; Transcription activation ; Transcription factors</subject><ispartof>Nature neuroscience, 2022-09, Vol.25 (9), p.1149-1162</ispartof><rights>The Author(s) 2022</rights><rights>2022. The Author(s).</rights><rights>The Author(s) 2022. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). 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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.
Dräger et al. establish a rapid, scalable platform for iPSC-derived microglia. 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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.
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| fulltext | fulltext |
| identifier | ISSN: 1097-6256 |
| ispartof | Nature neuroscience, 2022-09, Vol.25 (9), p.1149-1162 |
| issn | 1097-6256 1546-1726 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_9448678 |
| source | MEDLINE; Nature Journals Online; SpringerLink Journals - AutoHoldings |
| subjects | 631/1647/2163 631/208/191 631/378/2596/1953 631/532/1360 Animal Genetics and Genomics Behavioral Sciences Biological Techniques Biomedical and Life Sciences Biomedicine Brain - metabolism Clustered Regularly Interspaced Short Palindromic Repeats - genetics Colony-stimulating factor CRISPR Disease Gene sequencing Genes Genomes Humans Induced Pluripotent Stem Cells - metabolism Macrophage colony-stimulating factor Microglia Microglia - metabolism Neurobiology Neurodegeneration Neurological diseases Neurosciences Osteopontin Perturbation Phagocytosis Phagocytosis - genetics Pluripotency Stem cells Therapeutic targets Transcription activation Transcription factors |
| title | A CRISPRi/a platform in human iPSC-derived microglia uncovers regulators of disease states |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-18T09%3A00%3A12IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=A%20CRISPRi/a%20platform%20in%20human%20iPSC-derived%20microglia%20uncovers%20regulators%20of%20disease%20states&rft.jtitle=Nature%20neuroscience&rft.au=Dr%C3%A4ger,%20Nina%20M.&rft.date=2022-09-01&rft.volume=25&rft.issue=9&rft.spage=1149&rft.epage=1162&rft.pages=1149-1162&rft.issn=1097-6256&rft.eissn=1546-1726&rft_id=info:doi/10.1038/s41593-022-01131-4&rft_dat=%3Cproquest_pubme%3E2710039535%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2710039535&rft_id=info:pmid/35953545&rfr_iscdi=true |