A cross-disease resource of living human microglia identifies disease-enriched subsets and tool compounds recapitulating microglial states

IF 21.2 1区 医学 Q1 NEUROSCIENCES
John F. Tuddenham, Mariko Taga, Verena Haage, Victoria S. Marshe, Tina Roostaei, Charles White, Annie J. Lee, Masashi Fujita, Anthony Khairallah, Ya Zhang, Gilad Green, Bradley Hyman, Matthew Frosch, Sarah Hopp, Thomas G. Beach, Geidy E. Serrano, John Corboy, Naomi Habib, Hans-Ulrich Klein, Rajesh Kumar Soni, Andrew F. Teich, Richard A. Hickman, Roy N. Alcalay, Neil Shneider, Julie Schneider, Peter A. Sims, David A. Bennett, Marta Olah, Vilas Menon, Philip L. De Jager
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Abstract

Human microglia play a pivotal role in neurological diseases, but we still have an incomplete understanding of microglial heterogeneity, which limits the development of targeted therapies directly modulating their state or function. Here, we use single-cell RNA sequencing to profile 215,680 live human microglia from 74 donors across diverse neurological diseases and CNS regions. We observe a central divide between oxidative and heterocyclic metabolism and identify microglial subsets associated with antigen presentation, motility and proliferation. Specific subsets are enriched in susceptibility genes for neurodegenerative diseases or the disease-associated microglial signature. We validate subtypes in situ with an RNAscope–immunofluorescence pipeline and high-dimensional MERFISH. We also leverage our dataset as a classification resource, finding that induced pluripotent stem cell model systems capture substantial in vivo heterogeneity. Finally, we identify and validate compounds that recapitulate certain subtypes in vitro, including camptothecin, which downregulates the signature of disease-enriched subtypes and upregulates a signature previously associated with Alzheimer’s disease. Profiling >200,000 live human microglia from 74 donors across neurological diseases reveals 12 subtypes of microglia that were validated in situ. Camptothecin is also identified as a compound reducing disease-enriched microglial subsets.

Abstract Image

Abstract Image

活体人类小胶质细胞跨疾病资源可识别疾病富集亚群和重现小胶质细胞状态的工具化合物
人类小胶质细胞在神经系统疾病中起着举足轻重的作用,但我们对小胶质细胞异质性的了解仍不全面,这限制了直接调节其状态或功能的靶向疗法的开发。在这里,我们利用单细胞 RNA 测序对来自 74 名供体的 215,680 个活体人类小胶质细胞进行了分析,这些小胶质细胞来自不同的神经系统疾病和中枢神经系统区域。我们观察到氧化代谢和杂环代谢之间的中心分化,并确定了与抗原呈递、运动和增殖相关的小胶质细胞亚群。特定的亚群富含神经退行性疾病的易感基因或疾病相关的小胶质细胞特征。我们利用 RNAscope-unmunofluorescence 管道和高维 MERFISH 对亚型进行了原位验证。我们还利用我们的数据集作为分类资源,发现诱导多能干细胞模型系统捕获了大量体内异质性。最后,我们确定并验证了能在体外再现某些亚型的化合物,包括喜树碱,它能下调疾病丰富亚型的特征,并上调以前与阿尔茨海默病相关的特征。
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来源期刊
Nature neuroscience
Nature neuroscience 医学-神经科学
CiteScore
38.60
自引率
1.20%
发文量
212
审稿时长
1 months
期刊介绍: Nature Neuroscience, a multidisciplinary journal, publishes papers of the utmost quality and significance across all realms of neuroscience. The editors welcome contributions spanning molecular, cellular, systems, and cognitive neuroscience, along with psychophysics, computational modeling, and nervous system disorders. While no area is off-limits, studies offering fundamental insights into nervous system function receive priority. The journal offers high visibility to both readers and authors, fostering interdisciplinary communication and accessibility to a broad audience. It maintains high standards of copy editing and production, rigorous peer review, rapid publication, and operates independently from academic societies and other vested interests. In addition to primary research, Nature Neuroscience features news and views, reviews, editorials, commentaries, perspectives, book reviews, and correspondence, aiming to serve as the voice of the global neuroscience community.
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