Glial scar survives until the chronic phase by recruiting scar-forming astrocytes after spinal cord injury
Glial scar survives until the chronic phase by recruiting scar-forming astrocytes after spinal cord injury
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脊髓损伤后，神经胶质疤痕通过招募形成疤痕的星形胶质细胞而存活至慢性期
DOI：
10.1016/j.expneurol.2022.114264
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发表时间：
2023
影响因子：
5.3
通讯作者：
Nak
中科院分区：
文献类型：
--
作者：
Tamaru Tetsuya;Kobayakawa Kazu;Saiwai Hirokazu;Konno Daijiro;Kijima Ken;Yoshizaki Shingo;Hata Kazuhiro;Iura Hirotaka;Ono Gentaro;Haruta Yohei;Kitade Kazuki;Iida Kei-Ichiro;Kawaguchi Ken-Ichi;Matsumoto Yoshihiro;Kubota Kensuke;Maeda Takeshi;Okada Seiji;Nak
脊髓损伤（SCI）引起反应性星形胶质细胞增生，星形胶质细胞的连续表型变化，其中幼稚星形胶质细胞（NAs）转化为反应性星形胶质细胞（RAs），随后成为瘢痕形成星形胶质细胞（SAs），导致损伤部位周围的胶质瘢痕形成，从而限制轴突再生和运动/感觉功能恢复。在急性期抑制RA向SA的转化可减弱反应性星形胶质细胞增生并促进再生。然而，SA一旦形成是否可以恢复为RA或SA尚不清楚。我们进行了选择性分离的星形胶质细胞从胶质细胞瘢痕在不同的时间点的基因表达分析，发现sox 9，一个重要的转录因子的胶质细胞分化，在慢性期星形胶质细胞（CA）的表达显着增加相比，SA在亚急性期。此外，CA显示硫酸软骨素蛋白聚糖（CSPG）相关基因的表达显着低于SA。这些结果表明，随着时间的推移，SA根据损伤脊髓的周围环境改变其表型。尽管整合素-N-钙粘蛋白途径对胶质瘢痕形成至关重要，但胶原-I-生长的瘢痕形成星形胶质细胞（Col-I-SA）在耗尽整合素或N-钙粘蛋白的作用后并未改变其表型。此外，我们发现Col-I-SA移植到幼稚脊髓中通过维持整合素-N-钙粘蛋白通路相关基因的高表达和CSPG相关基因的低表达再次形成胶质瘢痕。有趣的是，移植的Col-I-SAs将NAs转化为SA，并且抗β1-整合素抗体阻断了SA的募集，同时减少了慢性期胶质瘢痕的体积。我们的研究结果表明，虽然胶质瘢痕的特征随着SCI后的时间而变化，但SA具有形成和维持胶质瘢痕的细胞自主功能，突出了中枢神经系统损伤后胶质瘢痕持续存在的基本机制，直到慢性期，这可能是治疗目标。
Spinal cord injury (SCI) causes reactive astrogliosis, the sequential phenotypic change of astrocytes in which naïve astrocytes (NAs) transform into reactive astrocytes (RAs) and subsequently become scar-forming astrocytes (SAs), resulting in glial scar formation around the lesion site and thereby limiting axonal regeneration and motor/sensory functional recovery. Inhibiting the transformation of RAs into SAs in the acute phase attenuates the reactive astrogliosis and promotes regeneration. However, whether or not SAs once formed can revert to RAs or SAs is unclear. We performed selective isolation of astrocytes from glial scars at different time points for a gene expression analysis and found that the expression ofSox9, an important transcriptional factor for glial cell differentiation, was significantly increased in chronic phase astrocytes (CAs) compared to SAs in the sub-acute phase. Furthermore, CAs showed a significantly lower expression of chondroitin sulfate proteoglycan (CSPG)-related genes than SAs. These results indicated that SAs changed their phenotypes according to the surrounding environment of the injured spinal cord over time. Even though the integrin-N-cadherin pathway is critical for glial scar formation, collagen-I-grown scar-forming astrocytes (Col-I-SAs) did not change their phenotype after depleting the effect of integrin or N-cadherin. In addition, we found that Col-I-SAs transplanted into a naïve spinal cord formed glial scar again by maintaining a high expression of genes involved in the integrin-N-cadherin pathway and a low expression of CSPG-related genes. Interestingly, the transplanted Col-I-SAs changed NAs into SAs, and anti-β1-integrin antibody blocked the recruitment of SAs while reducing the volume of glial scar in the chronic phase. Our findings indicate that while the characteristics of glial scars change over time after SCI, SAs have a cell-autonomous function to form and maintain a glial scar, highlighting the basic mechanism underlying the persistence of glial scars after central nervous system injury until the chronic phase, which may be a therapeutic target.