星形胶质细胞活化在脊髓损伤修复中的作用及其调控
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摘要
脊髓损伤后再生修复极为困难，可能导致不可逆的感觉丧失和终生截瘫。这一方面原因是由于CNS中神经元的内在再生能力差造成的，但损伤后形成不利于再生的抑制性微环境也是造成这一结果的另一个重要原因。星形胶质细胞活化，伴随着分子表达谱与形态上的变化，是中枢神经系统损伤和疾病普遍存在而又未被深入了解的一个病理学特征。近来的研究显示，星形胶质细胞活化能够依赖特异的分子信号通路产生利弊两方面的效应。因此，活化星形胶质细胞被认为是一个潜在的、能够有效促进CNS损伤后组织保护和功能修复的干预靶点。本研究就星形胶质细胞活化在脊髓损伤修复中的作用及其机制进行一些探索。研究结果表明：（1）胶质疤痕内活化的星形胶质细胞可通过分泌TNF-α作用于寡突前体细胞上的TNFR1受体，抑制OPCs的分化成熟并促进其凋亡；（2）丙酮酸衍生物——丙酮酸乙酯可以抑制星形胶质细胞活化并减轻神经炎症反应，从而抑制胶质疤痕形成，促进神经再生和功能恢复；（3）两面针碱可以通过抑制星形胶质细胞活化，增加脊髓损伤后的白质残余并促进损伤后的功能修复。这些研究结果将有利于我们深入了解星形胶质细胞活化的机制，寻找有效调控星形胶质细胞活化的手段，为脊髓损伤治疗提供新的思路。
Spinal cord injury often results in loss of sensation and paralysis that are irreversible. This is in part because CNS neurons have a poor intrinsic capacity for growth, but also because injured axons encounter a series of inhibitory microenvironment that are non-permissive for growth. Reactive astrogliosis, whereby astrocytes undergo varying molecular and morphological changes, is a ubiquitous but poorly understood hallmark of all central nervous system pathologies. Recent studies provide compelling evidence that reactive astrogliosis can exert both beneficial and detrimental effects in a context-dependent manner determined by specific molecular signaling cascades.Thus, astrogliosis is an appealing target for therapeutic interventions aimed at promoting nervous tissue preservation and functional repair. In the present study, we explore the effects of reactive astrogliosis after CNS damage especially SCI and the underlying mechanisms. Our studies indicated that:(1) TNF-α produced by reactive astrocytes in glial scar inhibits the maturation of OPCs via TNFR1;(2) Ethyl pyruvate, a pyruvate derivative, inhibits the activation astrocytes and the formation of glial scar, which contributes to axon regeneration and functional recovery after SCI;(3) nitidine treatment could attenuate reactive astrogliosis and increase spinal tissue sparing and improved functional recovery. These results will be beneficial for us to understand the mechanisms of reactive astrogliosis and as a significant cue to open new avenues for treating SCI.
Spinal cord injury often results in loss of sensation and paralysis that are irreversible. This is in part because CNS neurons have a poor intrinsic capacity for growth, but also because injured axons encounter a series of inhibitory microenvironment that are non-permissive for growth. Reactive astrogliosis, whereby astrocytes undergo varying molecular and morphological changes, is a ubiquitous but poorly understood hallmark of all central nervous system pathologies. Recent studies provide compelling evidence that reactive astrogliosis can exert both beneficial and detrimental effects in a context-dependent manner determined by specific molecular signaling cascades.Thus, astrogliosis is an appealing target for therapeutic interventions aimed at promoting nervous tissue preservation and functional repair. In the present study, we explore the effects of reactive astrogliosis after CNS damage especially SCI and the underlying mechanisms. Our studies indicated that:(1) TNF-α produced by reactive astrocytes in glial scar inhibits the maturation of OPCs via TNFR1;(2) Ethyl pyruvate, a pyruvate derivative, inhibits the activation astrocytes and the formation of glial scar, which contributes to axon regeneration and functional recovery after SCI;(3) nitidine treatment could attenuate reactive astrogliosis and increase spinal tissue sparing and improved functional recovery. These results will be beneficial for us to understand the mechanisms of reactive astrogliosis and as a significant cue to open new avenues for treating SCI.
引文
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