美国华盛顿大学医学院Qingyun Li团队近期取得重要工作进展，他们研究开发了一种可诱导遗传工具，可用来追踪和操纵特定小胶质细胞状态并揭示它们的可塑性和在再髓鞘化中的作用。相关研究成果2024年5月30日在线发表于《免疫》杂志上。

据介绍，最近的单细胞RNA测序研究揭示了小胶质细胞在发育和疾病中的不同状态。其中包括白质发育中的增殖区相关小胶质细胞（PAM）和在各种神经退行性疾病中普遍存在的疾病相关小胶质瘤（DAM）。PAM和DAM具有相似的核心基因特征。然而，这些小胶质细胞状态的动态性和可塑性程度及其功能意义仍然不清楚，部分原因是缺乏特定的工具。

研究人员开发了一种可诱导的Cre驱动系统，Clec7a-CreER^T2，靶向脑实质中的PAM和DAM。利用这一工具，研究人员对发育过程中和几种疾病模型中的标记细胞进行了分析，揭示了PAM和DAM基因表达的趋同和环境依赖性差异。通过长期跟踪，研究人员展示了小胶质细胞状态的可塑性。最后，通过耗尽脱髓鞘中的DAM，研究人员揭示了它们在疾病恢复中的作用。

总之，这一研究提供了一种多功能的遗传工具，来表征中枢神经系统发育和疾病中的小胶质细胞状态。

附：英文原文

Title: An inducible genetic tool to track and manipulate specific microglial states reveals their plasticity and roles in remyelination

Author: Kia M. Barclay, Nora Abduljawad, Zuolin Cheng, Min Woo Kim, Lu Zhou, Jin Yang, Justin Rustenhoven, Jose A. Mazzitelli, Leon C.D. Smyth, Dvita Kapadia, Simone Brioschi, Wandy Beatty, JinChao Hou, Naresha Saligrama, Marco Colonna, Guoqiang Yu, Jonathan Kipnis, Qingyun Li

Issue&Volume: 2024-05-30

Abstract: Recent single-cell RNA sequencing studies have revealed distinct microglial states in development and disease. These include proliferative-region-associated microglia (PAMs) in developing white matter and disease-associated microglia (DAMs) prevalent in various neurodegenerative conditions. PAMs and DAMs share a similar core gene signature. However, the extent of the dynamism and plasticity of these microglial states, as well as their functional significance, remains elusive, partly due to the lack of specific tools. Here, we generated an inducible Cre driver line, Clec7a-CreERT2, that targets PAMs and DAMs in the brain parenchyma. Utilizing this tool, we profiled labeled cells during development and in several disease models, uncovering convergence and context-dependent differences in PAM and DAM gene expression. Through long-term tracking, we demonstrated microglial state plasticity. Lastly, we specifically depleted DAMs in demyelination, revealing their roles in disease recovery. Together, we provide a versatile genetic tool to characterize microglial states in CNS development and disease.

DOI: 10.1016/j.immuni.2024.05.005

Source: https://www.cell.com/immunity/fulltext/S1074-7613(24)00258-9