Functional analysis of CX3CR1 in human induced pluripotent stem (iPS) cell‐derived microglia‐like cells,European Journal of Neuroscience

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Functional analysis of CX3CR1 in human induced pluripotent stem (iPS) cell‐derived microglia‐like cells
European Journal of Neuroscience ( IF 2.7 ) Pub Date : 2020-06-24 , DOI: 10.1111/ejn.14879
Nobuhito Murai _{1,

2} , Maisam Mitalipova ₁ , Rudolf Jaenisch _{1,

3}

Affiliation

Microglia are the primary immune cells of the central nervous system and crucial to proper development and maintenance of the brain. Microglia have been recognized to be associated with neurodegenerative diseases and neuroinflammatory disorders. CX3C chemokine receptor 1 (CX3CR1), which is specifically expressed in microglia, regulates microglia homeostatic functions such as microglial activation and is downregulated in aged brain and disease‐associated microglia in rodents, yet its role in human microglia is not fully understood. In this study, we investigated the function of CX3CR1 in human microglia using human induced pluripotent stem (iPS) cell‐derived microglia‐like cells. Human iPS cell‐derived microglia‐like cells expressed microglial markers and showed an activated state and phagocytic activity. Using CRISPR/Cas9 genome editing, we deleted CX3CR1 in human iPS cells and found increased inflammatory responses and phagocytic activity in mutant as compared to wild‐type microglia‐like cells. In addition, the CX3C chemokine ligand 1 (CX3CL1, a ligand for CX3CR1) significantly decreased the upregulation of IL‐6 by lipopolysaccharide stimulation in human iPS cell‐derived microglia‐like cells. These results suggest that CX3CR1 in human microglia may contribute to microglial homeostasis by regulating inflammatory response and phagocytosis.

中文翻译：

CX3CR1在人诱导多能干（iPS）细胞源性小胶质细胞中的功能分析

小胶质细胞是中枢神经系统的主要免疫细胞，对大脑的正常发育和维持至关重要。小胶质细胞已被认为与神经退行性疾病和神经炎性疾病有关。CX3C趋化因子受体1（CX3CR1）在小胶质细胞中特异性表达，可调节小胶质细胞的稳态功能，例如小胶质细胞的活化，并在啮齿动物的老年大脑和与疾病相关的小胶质细胞中被下调，但其在人小胶质细胞中的作用尚不完全清楚。在这项研究中，我们使用人诱导的多能干（iPS）细胞来源的小胶质样细胞研究了CX3CR1在人小胶质细胞中的功能。来自人iPS细胞的小胶质细胞样细胞表达小胶质细胞标记物，并显示活化状态和吞噬活性。使用CRISPR / Cas9基因组编辑，我们删除了人iPS细胞中的CX3CR1，发现与野生型小胶质细胞相比，突变体中的炎症反应和吞噬活性增强。此外，CX3C趋化因子配体1（CX3CL1，CX3CR1的配体）显着降低了脂多糖刺激人iPS细胞衍生的小胶质细胞中IL-6的上调。这些结果表明，人类小胶质细胞中的CX3CR1可能通过调节炎症反应和吞噬作用来促进小胶质细胞稳态。CX3CR1的配体）显着降低了脂多糖刺激人iPS细胞来源的小胶质细胞样细胞中IL-6的上调。这些结果表明，人类小胶质细胞中的CX3CR1可能通过调节炎症反应和吞噬作用来促进小胶质细胞稳态。CX3CR1的配体）显着降低了脂多糖刺激人iPS细胞来源的小胶质细胞样细胞中IL-6的上调。这些结果表明，人类小胶质细胞中的CX3CR1可能通过调节炎症反应和吞噬作用来促进小胶质细胞稳态。

更新日期：2020-06-24

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