IFN-γ-STAT1-mediated CD8(+) 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.
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DOI：
10.1186/s41232-023-00263-9
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发表时间：
2023-02-13
影响因子：
8.1
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中科院分区：
文献类型：
--
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脊髓损伤（SCI）导致几乎所有患者遭受长期残疾。一个新兴的治疗策略，涉及招募内源性神经干细胞（NSC）已经开发出来。然而，成年脊髓中的内源性神经干细胞在创伤性损伤后主要分化为星形胶质细胞，形成胶质瘢痕，这是SCI再生失败的主要原因。因此，了解哪些因素驱动SCI后内源性神经干细胞的激活和分化对于开发治疗药物至关重要。应用流式细胞术和免疫荧光染色技术分析脊髓创伤后CD 8 + T细胞的浸润、状态和定位。Basso小鼠量表（BMS）评分和旋转棒测试用于运动行为分析。将NSC与⑶ 8 + T细胞共培养。EdU法检测增殖细胞。Western blotting分析STAT 1、p-STAT 1和p27的表达水平。使用ChIP-seq和ChIP-qRT-PCR分析来检测STAT 1的下游。采用Nestin-CreERT 2：：Ai 9转基因小鼠对脊髓损伤后Nestin+ NSCs进行体内遗传谱系追踪。在受损的脊髓中，活化的CD 8 + T细胞的延长增加。行为分析表明，施用抗CD 8抗体促进运动功能的恢复。在体外实验中，我们发现CD 8 + T细胞通过IFN-γ-STAT 1途径抑制神经干细胞的增殖并促进神经干细胞向星形胶质细胞分化。ChIP-seq和ChIP-qRT-PCR分析显示STAT 1可直接与星形胶质细胞标志基因GFAP和Aldh 1 l1的启动子结合。Nestin+ NSCs的遗传谱系追踪表明，大多数NSCs在SCI后分化为星形胶质细胞。耗尽CD 8 + T细胞减少了NSC向星形胶质细胞的分化，反而促进了NSC向少突胶质细胞的分化。结论：CD 8 + T细胞通过IFN-γ-STAT 1-GFAP/Aldh 111轴抑制NSCs增殖，促进NSCs向星形胶质细胞分化。我们的研究确定INF-γ是CD 8 + T细胞-NSC串扰的关键介质，也是SCI治疗干预的潜在节点。在线版本包含补充材料，可通过10.1186/s41232-023-00263-9获得。
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. 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. 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. 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. The online version contains supplementary material available at 10.1186/s41232-023-00263-9.
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影响因子：
25
作者：
Glasgow, Stacey M.;Zhu, Wenyi;Stolt, C. Claus;Huang, Teng-Wei;Chen, Fuyi;LoTurco, Joseph J.;Neul, Jeffrey L.;Wegner, Michael;Mohila, Carrie;Deneen, Benjamin
通讯作者：
Deneen, Benjamin
影响因子：
4.6
作者：
Fan, GP;Martinowich, K;Sun, YE
通讯作者：
Sun, YE
DOI：
10.1016/j.apmr.2004.03.015
发表时间：
2004-11-01
影响因子：
4.3
作者：
Kirshblum, S;Millis, S;Tulsky, D
通讯作者：
Tulsky, D
影响因子：
23.9
作者：
Ceto, Steven;Sekiguchi, Kohei J.;Tuszynski, Mark H.
通讯作者：
Tuszynski, Mark H.
影响因子：
56.9
作者：
Sabelstrom, Hanna;Stenudd, Moa;Frisen, Jonas
通讯作者：
Frisen, Jonas