Distinct Spatio-Temporal Extracellular Matrix Accumulation within Demyelinated Spinal Cord Lesions in Theiler's Murine Encephalomyelitis
Distinct Spatio-Temporal Extracellular Matrix Accumulation within Demyelinated Spinal Cord Lesions in Theiler's Murine Encephalomyelitis
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DOI：
10.1111/j.1750-3639.2011.00518.x
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发表时间：
2012-03-01
期刊：
影响因子：
6.4
通讯作者：
Baumgaertner, Wolfgang
中科院分区：
文献类型：
--
作者：
Haist, Verena;Ulrich, Reiner;Baumgaertner, Wolfgang
细胞外基质（ECM）的积累和神经胶质疤痕的形成被认为是中枢神经系统（CNS）损伤和多发性硬化症再生失败的重要因素。泰勒氏鼠脑脊髓炎 (TME) 作为多发性硬化症模型，用于评估脱髓鞘条件下 ECM 改变的时空过程。微阵列分析显示，ECM 分子、其生物合成途径和促纤维化因子的基因表达仅轻度上调，而基质重塑酶的上调更为突出。免疫组织化学显示，脱髓鞘 TME 病变内硫酸软骨素蛋白聚糖、糖蛋白和胶原蛋白逐渐积累，与星形胶质细胞增生的发展并行。感染后 28 天 (dpi) 开始沉积 IV 型胶原蛋白、层粘连蛋白、基底膜聚糖和腱生蛋白-C，I 型胶原蛋白、核心蛋白聚糖、巢蛋白和神经聚糖从 56 dpi 开始累积，纤连蛋白从 98 dpi 开始累积。基底膜（BM）分子IV型胶原蛋白、巢蛋白、纤连蛋白、层粘连蛋白和基底膜蛋白聚糖表现出血管周围和实质沉积，而非BM成分胶原蛋白I、核心蛋白聚糖、神经蛋白聚糖和腱蛋白-C仅在脱髓鞘区域以非血管模式积累。相反，TME 期间磷酸聚糖表达逐渐减少。聚集蛋白聚糖和短蛋白聚糖的免疫反应性保持不变。基质积累与星形胶质细胞增生的时空关联表明 ECM 沉积物主要起源于星形胶质细胞，这反过来可能导致 TME 的髓鞘再生失败。
The accumulation of extracellular matrix (ECM) and glial scar formation are considered important factors for the failure of regeneration in central nervous system (CNS) injury and multiple sclerosis. Theiler's murine encephalomyelitis (TME) as a model of multiple sclerosis served to evaluate the spatio-temporal course of ECM alterations in demyelinating conditions. Microarray analysis revealed only mildly upregulated gene expression of ECM molecules, their biosynthesis pathways and pro-fibrotic factors, while upregulation of matrix remodeling enzymes was more prominent. Immunohistochemistry demonstrated progressive accumulation of chondroitin sulfate proteoglycans, glycoproteins and collagens within demyelinated TME lesions, paralleling the development of astrogliosis. Deposition of collagen IV, laminin, perlecan and tenascin-C started 28 days postinfection (dpi), collagen I, decorin, entactin and neurocan accumulated from 56 dpi on, and fibronectin from 98 dpi on. The basement membrane (BM) molecules collagen IV, entactin, fibronectin, laminin and perlecan showed perivascular and parenchymal deposition, while the non-BM components collagen I, decorin, neurocan and tenascin-C only accumulated in a nonvascular pattern in demyelinated areas. Contrary, phosphacan expression progressively decreased during TME. The immunoreactivity of aggrecan and brevican remained unchanged. The spatio-temporal association of matrix accumulation with astrogliosis suggests a mainly astrocytic origin of ECM deposits, which in turn may contribute to remyelination failure in TME.