Deletion or Inhibition of Astrocytic Transglutaminase 2 Promotes Functional Recovery after Spinal Cord Injury.
Deletion or Inhibition of Astrocytic Transglutaminase 2 Promotes Functional Recovery after Spinal Cord Injury.
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DOI：
10.3390/cells10112942
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发表时间：
2021-10-29
期刊：
影响因子：
6
通讯作者：
Pröschel C
中科院分区：
文献类型：
--
作者：
Elahi A;Emerson J;Rudlong J;Keillor JW;Salois G;Visca A;Girardi P;Johnson GVW;Pröschel C
中枢神经系统损伤后，星形胶质细胞变得“反应性”并表现出促再生或有害的特性。然而，导致星形胶质细胞采用任一表型的分子机制尚不清楚。转谷氨酰胺酶 2 (TG2) 在调节星形胶质细胞对损伤的反应中发挥着关键作用。在这里，我们在脊髓挫伤（SCI）模型中使用了星形胶质细胞中 TG2 被特异性删除的小鼠（Gfap-Cre+/- TG2fl/fl，此处称为 TG2-A-cKO）。从星形胶质细胞中删除 TG2 可导致 SCI 后运动功能显着改善。 TG2-A-cKO 小鼠中 GFAP 和 NG2 免疫反应性以及 SOX9 阳性细胞数量显着减少。损伤后 3 天，对 TG2-A-cKO 和对照小鼠的脊髓进行 RNA 测序分析，发现了 37 个差异表达基因，所有这些基因在 TG2-A-cKO 小鼠中均有所增加。通路分析揭示了脂肪酸代谢、脂质储存和能量通路的普遍存在，这些通路在神经元-星形胶质细胞代谢耦合中发挥着重要作用。令人兴奋的是，用选择性 TG2 抑制剂 VA4 治疗野生型小鼠可显着改善 SCI 后的功能恢复，类似于使用遗传模型观察到的结果。这些发现表明 TG2 抑制剂可作为治疗 SCI 和其他中枢神经系统损伤的新策略。
Following CNS injury, astrocytes become “reactive” and exhibit pro-regenerative or harmful properties. However, the molecular mechanisms that cause astrocytes to adopt either phenotype are not well understood. Transglutaminase 2 (TG2) plays a key role in regulating the response of astrocytes to insults. Here, we used mice in which TG2 was specifically deleted in astrocytes (Gfap-Cre+/− TG2fl/fl, referred to here as TG2-A-cKO) in a spinal cord contusion injury (SCI) model. Deletion of TG2 from astrocytes resulted in a significant improvement in motor function following SCI. GFAP and NG2 immunoreactivity, as well as number of SOX9 positive cells, were significantly reduced in TG2-A-cKO mice. RNA-seq analysis of spinal cords from TG2-A-cKO and control mice 3 days post-injury identified thirty-seven differentially expressed genes, all of which were increased in TG2-A-cKO mice. Pathway analysis revealed a prevalence for fatty acid metabolism, lipid storage and energy pathways, which play essential roles in neuron–astrocyte metabolic coupling. Excitingly, treatment of wild type mice with the selective TG2 inhibitor VA4 significantly improved functional recovery after SCI, similar to what was observed using the genetic model. These findings indicate the use of TG2 inhibitors as a novel strategy for the treatment of SCI and other CNS injuries.
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影响因子：
29
作者：
Liu L;MacKenzie KR;Putluri N;Maletić-Savatić M;Bellen HJ
通讯作者：
Bellen HJ
影响因子：
14.9
作者：
Kuleshov MV;Jones MR;Rouillard AD;Fernandez NF;Duan Q;Wang Z;Koplev S;Jenkins SL;Jagodnik KM;Lachmann A;McDermott MG;Monteiro CD;Gundersen GW;Ma'ayan A
通讯作者：
Ma'ayan A
影响因子：
11.2
作者：
Fisher ML;Kerr C;Adhikary G;Grun D;Xu W;Keillor JW;Eckert RL
通讯作者：
Eckert RL
DOI：
10.1016/j.bbamcr.2011.09.012
发表时间：
2012-02
期刊：
Biochimica et biophysica acta
影响因子：
--
作者：
Gundemir S;Colak G;Tucholski J;Johnson GV
通讯作者：
Johnson GV
影响因子：
15.9
作者：
Gundemir, Soner;Monteagudo, Alina;Johnson, Gail V. W.
通讯作者：
Johnson, Gail V. W.