美国哥伦比亚大学Philip L. De Jager及其团队发现，人类活体小胶质细胞跨疾病资源可作为识别疾病富集亚群和重现小胶质细胞状态的工具。这一研究成果于2024年10月15日发表在国际学术期刊《自然-神经科学》上。

据悉，人类小胶质细胞在神经系统疾病中发挥举足轻重的作用，但对小胶质细胞异质性的了解仍不全面，这限制了研发直接调控其状态或功能的靶向疗法。

研究人员利用单细胞RNA测序对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患有不同神经系统疾病的个体和中枢神经系统区域。研究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。

特定亚群富含神经退行性疾病的易感基因或与疾病相关的小胶质细胞特征。研究人员利用RNA scope-unmunofluorescence工具和高维MERFISH对细胞亚型进行了原位验证。

研究还将该数据集作为分类资源，利用诱导多能干细胞模型系统捕获了大量体内的异质性亚群。

最后，研究人员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。

附：英文原文

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

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

Issue&Volume: 2024-10-15

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.

DOI: 10.1038/s41593-024-01764-7

Source: https://www.nature.com/articles/s41593-024-01764-7