IFN-γ- stat1介导的CD8+ t细胞-神经干细胞串扰控制脊髓损伤后星形胶质细胞的发生。

IF 5 3区 医学 Q2 IMMUNOLOGY
Jingyu Wang, Lintao Xu, Deqing Peng, Yongjian Zhu, Zhaowen Gu, Ying Yao, Heyangzi Li, Xi Cao, Chun-Yan Fu, Mingzhi Zheng, Xinghui Song, Yueming Ding, Yueliang Shen, Jinjie Zhong, Ying-Ying Chen, Jue Hu, Lin-Lin Wang
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引用次数: 2

摘要

背景:脊髓损伤(SCI)导致了几乎所有患者的长期残疾。一种涉及内源性神经干细胞(NSCs)募集的新兴治疗策略已经被开发出来。然而,成人脊髓内源性NSCs在创伤后主要分化为星形胶质细胞,形成胶质瘢痕,这是脊髓损伤再生失败的主要原因。因此,了解哪些因素驱动脊髓损伤后内源性NSCs的激活和分化对于开发治疗药物至关重要。方法:采用流式细胞术和免疫荧光(IF)染色法分析脊髓损伤后CD8+ T细胞的浸润、状态和位置。运动行为分析采用Basso Mouse Scale (BMS)评分法和rotarod法。NSCs与CD8+ T细胞共培养。EdU法检测增殖细胞。Western blotting分析STAT1、p-STAT1、p27的表达水平。采用ChIP-seq和ChIP-qRT-PCR检测STAT1下游基因。采用neestin - creert2::Ai9转基因小鼠进行体内脊髓损伤后Nestin+ NSCs的遗传谱系追踪。结果:损伤脊髓中活化的CD8+ T细胞持续增加。行为学分析表明,抗cd8抗体的使用促进了运动功能的恢复。然后,我们在体外发现CD8+ T细胞通过IFN-γ-STAT1途径抑制NSCs的增殖,促进NSCs向星形胶质细胞的分化。ChIP-seq和ChIP-qRT-PCR分析显示STAT1可以直接结合星形胶质细胞标记基因GFAP和Aldh1l1的启动子。Nestin+ NSCs的遗传谱系追踪表明,大多数NSCs在脊髓损伤后分化为星形胶质细胞。消耗CD8+ T细胞减少了NSCs向星形胶质细胞的分化,反而促进了NSCs向少突胶质细胞的分化。结论:综上所述,CD8+ T细胞通过IFN-γ-STAT1-GFAP/ aldhl11轴抑制NSCs的增殖,促进NSCs向星形胶质细胞的分化。我们的研究发现,INF-γ是CD8+ t细胞- nsc串扰的关键介质,也是脊髓损伤治疗干预的潜在节点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

IFN-γ-STAT1-mediated CD8<sup>+</sup> T-cell-neural stem cell cross talk controls astrogliogenesis after spinal cord injury.

IFN-γ-STAT1-mediated CD8<sup>+</sup> T-cell-neural stem cell cross talk controls astrogliogenesis after spinal cord injury.

IFN-γ-STAT1-mediated CD8<sup>+</sup> T-cell-neural stem cell cross talk controls astrogliogenesis after spinal cord injury.

IFN-γ-STAT1-mediated CD8+ T-cell-neural stem cell cross talk controls astrogliogenesis after spinal cord injury.

Background: Spinal cord injury (SCI) causes nearly all patients to suffer from protracted disabilities. An emerging therapeutic strategy involving the recruitment of endogenous neural stem cells (NSCs) has been developed. However, endogenous NSCs in the adult spinal cord differentiate into mostly astrocytes after traumatic injury, forming glial scars, which is a major cause of regeneration failure in SCI. Thus, understanding which factors drive the activation and differentiation of endogenous NSCs after SCI is critical for developing therapeutic drugs.

Methods: The infiltration, state, and location of CD8+ T cells in spinal cord after traumatic injury were analyzed by flow cytometry and immunofluorescence (IF) staining. The Basso Mouse Scale (BMS) scores and rotarod testing were used for motor behavioral analysis. NSCs were co-cultured with CD8+ T cells. EdU assay was used to detect proliferative cells. Western blotting was used to analyze the expression levels of STAT1, p-STAT1, and p27. ChIP-seq and ChIP-qRT-PCR analyses were used to detect the downstream of STAT1. Nestin-CreERT2::Ai9 transgenic mice were used to genetic lineage tracing of Nestin+ NSCs after SCI in vivo.

Results: A prolonged increase of activated CD8+ T cells occurs in the injured spinal cords. The behavioral analysis demonstrated that the administration of an anti-CD8 antibody promotes the recovery of locomotor function. Then, we discovered that CD8+ T cells suppressed the proliferation of NSCs and promoted the differentiation of NSCs into astrocytes by the IFN-γ-STAT1 pathway in vitro. ChIP-seq and ChIP-qRT-PCR analysis revealed that STAT1 could directly bind to the promoters of astrocyte marker genes GFAP and Aldh1l1. Genetic lineage tracing of Nestin+ NSCs demonstrated that most NSCs differentiated into astrocytes following SCI. Depleting CD8+ T cells reduced the differentiation of NSCs into astrocytes and instead promoted the differentiation of NSCs into oligodendrocytes.

Conclusion: In conclusion, CD8+ T cells suppressed the proliferation of NSCs and promoted the differentiation of NSCs into astrocytes by the IFN-γ-STAT1-GFAP/Aldhl1l axis. Our study identifies INF-γ as a critical mediator of CD8+ T-cell-NSC cross talk and a potential node for therapeutic intervention in SCI.

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来源期刊
CiteScore
11.10
自引率
1.20%
发文量
45
审稿时长
11 weeks
期刊介绍: Inflammation and Regeneration is the official journal of the Japanese Society of Inflammation and Regeneration (JSIR). This journal provides an open access forum which covers a wide range of scientific topics in the basic and clinical researches on inflammation and regenerative medicine. It also covers investigations of infectious diseases, including COVID-19 and other emerging infectious diseases, which involve the inflammatory responses. Inflammation and Regeneration publishes papers in the following categories: research article, note, rapid communication, case report, review and clinical drug evaluation.
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