Astrogliosis during acute and chronic cuprizone demyelination and implications for remyelination.
Astrogliosis during acute and chronic cuprizone demyelination and implications for remyelination.
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DOI：
10.1042/an20120062
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发表时间：
2012-10-30
期刊：
影响因子：
4.7
通讯作者：
Armstrong RC
中科院分区：
文献类型：
--
作者：
Hibbits N;Yoshino J;Le TQ;Armstrong RC
在多发性硬化症中，小胶质细胞/巨噬细胞激活和星形胶质细胞反应性是影响髓鞘再生的病变环境的重要组成部分。目前的研究描述了这些神经胶质细胞群与铜宗脱髓鞘胼胝体中候选调节分子表达的关系。重要的是，检查急性或慢性铜宗脱髓鞘后的恢复期，以分别比较有效髓鞘再生和有限髓鞘再生的情况。早期脱髓鞘后小胶质细胞活化减弱。相比之下，星形胶质细胞的反应性在整个脱髓鞘过程以及急性或慢性脱髓鞘后的 6 周恢复期内持续存在。这种星形胶质细胞反应的特点是 (a) 早期增殖，(b) GFAP（胶质纤维酸性蛋白）、Vim（波形蛋白）、Fn1（纤连蛋白）和 CSPG（硫酸软骨素蛋白聚糖）表达增加，以及（c）形成密集的过程网络。在急性脱髓鞘之后的强髓鞘再生和慢性脱髓鞘之后的部分髓鞘再生过程中，轴突平面中伸长的神经胶质突起持续存在于整个病变区域。然而，长期铜宗治疗的长期星形胶质细胞反应性不会进展为屏障形成，即星形胶质细胞突起致密压实以隔离病变区域。病变环境中的多种候选生长因子和炎症信号在急性铜宗脱髓鞘和恢复时间过程中与 GFAP 具有很强的相关性，但在慢性铜宗脱髓鞘和恢复过程中存在更大的分歧。然而，在铜宗模型的恢复过程中，差异性神经胶质疤痕形成似乎并不是造成差异性髓鞘再生的原因。该脱髓鞘模型中的星形胶质细胞表型和病变特征为确定慢性多发性硬化症病变中非髓鞘再生性硬化的触发因素提供了信息。
In multiple sclerosis, microglia/macrophage activation and astrocyte reactivity are important components of the lesion environment that can impact remyelination. The current study characterizes these glial populations relative to expression of candidate regulatory molecules in cuprizone demyelinated corpus callosum. Importantly, periods of recovery after acute or chronic cuprizone demyelination are examined to compare conditions of efficient versus limited remyelination, respectively. Microglial activation attenuates after early demyelination. In contrast, astrocyte reactivity persists throughout demyelination and a 6-week recovery period following either acute or chronic demyelination. This astrocyte reaction is characterized by (a) early proliferation, (b) increased expression of GFAP (glial fibrillary acidic protein), Vim (vimentin), Fn1 (fibronectin) and CSPGs (chondroitin sulphate proteoglycans) and (c) elaboration of a dense network of processes. Glial processes elongated in the axonal plane persist throughout lesion areas during both the robust remyelination that follows acute demyelination and the partial remyelination that follows chronic demyelination. However, prolonged astrocyte reactivity with chronic cuprizone treatment does not progress to barrier formation, i.e. dense compaction of astrocyte processes to wall off the lesion area. Multiple candidate growth factors and inflammatory signals in the lesion environment show strong correlations with GFAP across the acute cuprizone demyelination and recovery time course, yet there is more divergence across the progression of chronic cuprizone demyelination and recovery. However, differential glial scar formation does not appear to be responsible for differential remyelination during recovery in the cuprizone model. The astrocyte phenotype and lesion characteristics in this demyelination model inform studies to identify triggers of non-remyelinating sclerosis in chronic multiple sclerosis lesions.