Spinal cord injury and MicroRNA: in vitro prefabrication of tissue-engineered spinal cord and repair of spinal cord injury

doi:10.3969/j.issn.2095-4344.2015.02.020

Abstract

Abstract:

BACKGROUND: In the whole world, spinal cord injuries caused by trauma lead to more than 180 000 people presenting with permanent impairment annually. A large number of experiments have confirmed in recent years, under physiological conditions, microRNA has specific expression and plays an important role in the nervous system.
OBJECTIVE: To discuss the changes in microRNA expression induced by injuries as well as the pathophysiological significance in spinal cord injury, and to explore the development potential of microRNA in tissue-engineered and clinical repair of spinal cord injury.
METHODS: A computer-based search of PubMed and Chinese Journal Database was performed for related articles published from January 2000 to December 2014 using the keywords of “SCI, microRNA, transcriptional control, clinical research progress” in English and Chinese. Finally, 38 articles were included for result analysis.
RESULTS AND CONCLUSION: Mechanical injury initially triggers a series of complex secondary damages, including nervous, vascular and immune systems, which can influence the severity of spinal cord injury to a great extent. Secondary damage to the spinal cord is mainly attributed to the activation and deactivation of some specific genes associated with cellular and biochemical mechanisms, such as cysteine aspartate specific protease (caspase) gene family, apoptosis related protein Fas and its ligand Fasl system, P53 gene, apoptosis related gene Bcl-2 family. Recent studies have proved that the functional activation of microRNA expression is the key to spinal cord injury. With the development of biological information engineering, studies and controlling technologies associated with microRNA expression have been gradually dominated, some clinical application based on microRNA technology has entered the clinical trial stage. It is believed that with the continuous development of technology and decrease of cost, permanent dysfunction due to spinal cord injury can be regulated and repaired through the microRNA technology at gene level in the future.

中国组织工程研究杂志出版内容重点：组织构建；骨细胞；软骨细胞；细胞培养；成纤维细胞；血管内皮细胞；骨质疏松；组织工程

全文链接：

Key words: Tissue Engineering, Spinal Cord Injuries, Transcription Factors, Review

CLC Number:

R318

Li Mi, Yao Meng. Spinal cord injury and MicroRNA: in vitro prefabrication of tissue-engineered spinal cord and repair of spinal cord injury[J]. Chinese Journal of Tissue Engineering Research, 2015, 19(2): 267-272.

Figures/Tables 1

2 文献证据综合提炼 2.1 纳入资料基本概况纳入的文献包括脊髓损伤病理生理性概述性文章10篇[1-10]，脊髓损伤后基因表达的改变类文章4篇[11-14]，miRNA参与基因表达调控类文章17篇[15-31]。以此为依据对miRNA应用于未来脊髓损伤治疗的设想和展望的归纳和总结7篇[32-38]。 2.2 纳入资料的研究结果特征 2.2.1 脊髓损伤的病理生理概述所谓脊髓损伤是指由于脊髓创伤或疾病引起的脊髓损害，伤者损伤后面临的功能缺陷很大程度上取决于其产生的生理应答反应。虽然大多数的脊髓损伤是由创伤引起的，这种打击的原因多为交通事故或暴力因素引起的机械损伤，但仍有部分脊髓损伤的患者是由于非创伤性因素所致，如椎间盘退变和肿瘤等原因。脊髓损伤初期至其后几个月内引发一些列复杂的病理生理学反应机制过程，从而影响神经、血管和免疫系统。脊髓损伤参与细胞大多源于脊髓，仍有部分细胞依靠循环系统运至损伤区域[6-6]。创伤性脊髓损伤中，机械性创伤可导致脊髓的挤压、拉伸、撕裂或横断损伤。多数脊髓损伤损伤形式为挤压-挫裂型损伤，破裂的脊柱组织对脊髓产生瞬时或持久的挤压伤。挤压挫裂伤一旦达到结构阈值，即可引起一系列局部及全身细胞的生理生化反应，此过程为脊髓损伤的主要原因。局部损伤包括轴突断裂，神经元、神经胶质细胞和血管内皮细胞膜破裂甚至坏死。因细胞膜破裂产生的离子转移与释放，引起损伤区域尚存活的神经元细胞产生动作电位。由此产生的离子浓度达到中毒状态，引起周围的神经元坏死。兴奋性中毒引发的动作电位的导致神经递质释放与积累，会进一步加重神经元和神经胶质细胞的坏死[7]。表皮血管痉挛和血栓形成所造成缺氧，缺血，加速了神经细胞坏死。在机体层面，原发损伤引起一过性高血压之后随之而来长期低灌注压状态进一步加重脊髓缺氧。缺氧连同神经细胞内外离子的转移，引起损伤平面以下脊髓功能短暂性缺失，我们称之为脊髓休克[8]。机械损伤后最初几分钟至数月为脊髓二次损伤的主要时期。此阶段损伤区主要破坏为血管变性，生物化学功能紊乱及细胞应答反应介导的炎性反应和细胞坏死，其中主要致炎因子如一氧化氮、白细胞介素1β、肿瘤坏死因子α、活性氧簇(reactive oxygen species，ROS)、细胞黏附分子(cell adhesion molecules，CAMs)[9]等。脊髓损伤病理生理学过程中免疫细胞的应答反应起到了关键作用，中性粒细胞的数量在损伤24 h后达到顶峰。中性粒细胞释放的信号蛋白引起巨噬细胞的聚集并在1周内达到顶峰且存在数月之久，进而导致表型细胞形态和功能上的变化[10]。T淋巴细胞为脊髓损伤后细胞介导的应答反应，其在损伤1周后进入损伤区域，但其在损伤区域的作用目前仍不明确。脊髓损伤数月至1年后，脊髓损伤转归为慢性过程。细胞坏死、瘢痕化、神经胶质细胞增生以及局部组织变化所形成的胶质瘢痕累及损伤区及临近节段。功能离子通道内髓磷脂的丢失及变性引起神经元和轴突网状系统的变化进而导致慢性神经源性疼痛或痉挛。 2.2.2 脊髓损伤后基因表达的改变大多数细胞的功能、应答反应及表型变化依赖于大量转录机制的激活或抑制。通过微阵列分析观察研究不同脊髓损伤模型的菌落或物种发现了基因表达的改变。这些基因表达的改变引起一系列表达的改变：①转录和应激反应，损伤24 h内引起大量凝集因子聚集如核因子κB(bnuclear factor kappa B，NF-κB)、热休克蛋白70(heat shock protein 70，HSP-70)、人干扰素调节因子1(interferon regulatory factors，IRF-1) 等。其中核因子κB和人干扰素调节因子1为细胞凋亡、再生及促炎症反应过程中的重要的转录激活因子。②炎症反应，脊髓损伤后初期，大量促炎症基因表达于损伤后14天恢复正常水平，其中主要的炎症介质为COX-2，白细胞介素1β、白细胞介素6和肿瘤坏死因子α等，其主要作用为调节免疫应答和细胞增值[11]。③神经元相关基因，大量塑形与再生相关蛋白(如Rab13，cAMP，Coronin 1b等)参与Na，K，Ca离子通道蛋白的的编码从而影响神经递质传递的兴奋偶联[12]。④细胞周期和细胞坏死，细胞周期基因的表达在损伤24 h后开始上调，如c-myc，pcdna，gadd45a及细胞周期蛋白等，"

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