细胞因子处理的人类胰岛的单细胞 RNAseq 分析:细胞压力与细胞因子反应能力受损的关系

IF 5.1 Q2 CELL BIOLOGY Function (Oxford, England) Pub Date : 2024-07-11 DOI:10.1093/function/zqae015
Jennifer S Stancill, Moujtaba Y Kasmani, Weiguo Cui, John A Corbett
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引用次数: 0

摘要

胰岛β细胞是唯一能够分泌胰岛素的细胞类型,对胰岛β细胞的存活至关重要。虽然人们认为它们容易受到白细胞介素-1β(IL-1β)和γ干扰素(IFN-γ)等炎症细胞因子的损害,但我们最近发现细胞因子信号在啮齿动物β细胞中的生理作用包括刺激抗病毒和抗微生物基因表达以及抑制病毒复制。在本研究中,我们利用单细胞 RNA 测序技术研究了细胞因子刺激下人类胰岛基因表达的变化。令人惊讶的是,与我们之前在小鼠体内观察到的结果相比,人类胰岛细胞对细胞因子暴露的整体反应明显减弱。对细胞因子有反应的一小部分人胰岛细胞表现出IL-1β刺激的抗病毒鸟苷酸结合蛋白的表达增加,就像在小鼠中一样。大多数人的胰岛细胞对细胞因子没有反应,这种缺乏反应与核糖体蛋白编码基因的高表达有关。我们进一步将 RPL5 的表达水平与应激反应基因相关联,当 RPL5 高水平表达时,可预测所有内分泌细胞对细胞因子的反应失败。我们推测,供体的死因和分离方法可能会导致胰岛制备过程中的应激反应。我们的研究结果表明,人类胰岛中应激反应的激活限制了细胞因子刺激基因的表达,因此我们呼吁在评估那些未评估应激相关基因表达就检测人类胰岛中细胞因子刺激基因表达的研究时要谨慎。
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Single Cell RNAseq Analysis of Cytokine-Treated Human Islets: Association of Cellular Stress with Impaired Cytokine Responsiveness.

Pancreatic β-cells are essential for survival, being the only cell type capable of insulin secretion. While they are believed to be vulnerable to damage by inflammatory cytokines such as interleukin-1 beta (IL-1β) and interferon-gamma, we have recently identified physiological roles for cytokine signaling in rodent β-cells that include the stimulation of antiviral and antimicrobial gene expression and the inhibition of viral replication. In this study, we examine cytokine-stimulated changes in gene expression in human islets using single-cell RNA sequencing. Surprisingly, the global responses of human islets to cytokine exposure were remarkably blunted compared to our previous observations in the mouse. The small population of human islet cells that were cytokine responsive exhibited increased expression of IL-1β-stimulated antiviral guanylate-binding proteins, just like in the mouse. Most human islet cells were not responsive to cytokines, and this lack of responsiveness was associated with high expression of genes encoding ribosomal proteins. We further correlated the expression levels of RPL5 with stress response genes, and when expressed at high levels, RPL5 is predictive of failure to respond to cytokines in all endocrine cells. We postulate that donor causes of death and isolation methodologies may contribute to stress of the islet preparation. Our findings indicate that activation of stress responses in human islets limits cytokine-stimulated gene expression, and we urge caution in the evaluation of studies that have examined cytokine-stimulated gene expression in human islets without evaluation of stress-related gene expression.

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