小柯机器人

美国加州大学Martin Kampmann团队的最新研究在人iPSC来源的星形胶质细胞中，通过CRISPRi筛选揭示了调控不同炎症反应状态的调节因子。相关论文于2022年10月27日发表在《自然-神经科学》杂志上。

在这项研究中，研究人员研发了在人诱导的多能干细胞衍生星形胶质细胞中，利用CRISPR干扰筛选与单细胞转录组学偶联相结合的方法，以系统地检测细胞因子诱导炎症星形胶质细胞的反应性。研究人员发现自分泌-旁分泌IL-6和经典NF-κB激活下游干扰素信号，传导驱动了两种不同的炎症反应特征，一种由STAT3激活，另一种被STAT3抑制。这些特征与在其他实验环境中观察到的特征重叠，包括小鼠模型，并且它们的标记物在阿尔茨海默病和缺氧缺血性脑病患者的脑中上调。

此外，研究人员使用神经炎症小鼠模型验证了这些特征标志物在体内受到STAT3的调节。这些结果和该研究研发的平台有利于治疗方法的开发，以选择性地调节炎症星形胶质细胞的反应性特征。

研究人员表示，星形胶质细胞通过特定内环境中的细胞特征和输出，对中枢神经系统的损害做出响应反应，但缺乏对潜在分子机制的系统理解。

附：英文原文

Title: CRISPRi screens in human iPSC-derived astrocytes elucidate regulators of distinct inflammatory reactive states

Author: Leng, Kun, Rose, Indigo V. L., Kim, Hyosung, Xia, Wenlong, Romero-Fernandez, Wilber, Rooney, Brendan, Koontz, Mark, Li, Emmy, Ao, Yan, Wang, Shinong, Krawczyk, Mitchell, TCW, Julia, Goate, Alison, Zhang, Ye, Ullian, Erik M., Sofroniew, Michael V., Fancy, Stephen P. J., Schrag, Matthew S., Lippmann, Ethan S., Kampmann, Martin

Issue&Volume: 2022-10-27

Abstract: Astrocytes become reactive in response to insults to the central nervous system by adopting context-specific cellular signatures and outputs, but a systematic understanding of the underlying molecular mechanisms is lacking. In this study, we developed CRISPR interference screening in human induced pluripotent stem cell-derived astrocytes coupled to single-cell transcriptomics to systematically interrogate cytokine-induced inflammatory astrocyte reactivity. We found that autocrine–paracrine IL-6 and interferon signaling downstream of canonical NF-κB activation drove two distinct inflammatory reactive signatures, one promoted by STAT3 and the other inhibited by STAT3. These signatures overlapped with those observed in other experimental contexts, including mouse models, and their markers were upregulated in human brains in Alzheimer’s disease and hypoxic-ischemic encephalopathy. Furthermore, we validated that markers of these signatures were regulated by STAT3 in vivo using a mouse model of neuroinflammation. These results and the platform that we established have the potential to guide the development of therapeutics to selectively modulate different aspects of inflammatory astrocyte reactivity.

DOI: 10.1038/s41593-022-01180-9

Source: https://www.nature.com/articles/s41593-022-01180-9

Nature Neuroscience：《自然—神经科学》，创刊于1998年。隶属于施普林格·自然出版集团，最新IF：28.771
官方网址：https://www.nature.com/neuro/
投稿链接：https://mts-nn.nature.com/cgi-bin/main.plex