成体神经干细胞及其在神经修复中的应用

神经干细胞是一类具有多分化潜能的未分化细胞。在适宜的环境下可分化为神经元、神经胶质细胞和少突胶质细胞。神经干细胞的无限增殖性和多分化性使其成为细胞移植的良好供体。近年来,成年脑组织内也发现了具有多分化潜能的神经干细胞,成体神经干细胞的发现改变了以往中枢神经系统不可再生的理论,随着对成体神经干细胞研究的深入,通过诱导自体神经干细胞的体内增殖修复损伤的神经元,通过分离自体神经干细胞体外扩增后移植治疗等实验的探索为神经源性疾病的替代性治疗提供了新的思路。     

成体神经干细胞及其在神经修复中的应用

神经干细胞是一类具有多分化潜能的未分化细胞。在适宜的环境下可分化为神经元、神经胶质细胞和少突胶质细胞。神经干细胞的无限增殖性和多分化性使其成为细胞移植的良好供体。近年来，成年脑组织内也发现了具有多分化潜能的神经干细胞。成体神经干细胞的发现改变了以往中枢神经系统不可再生的理论，随着对成体神经干细胞研究的深入，通过诱导自体神经干细胞的体内增殖修复损伤的神经元，通过分离自体神经干细胞体外扩增后移植治疗等实验的探索为神经源性疾病的替代性治疗提供了新的思路。     

磁共振在体研究成体神经发生的进展

近年来,成体脑内神经发生的研究越来越受到关注。MR已成为在体研究成体神经发生的重要技术之一。本文针对MR在体研究成体神经发生的进展进行综述。     

神经干细胞与脑梗死康复

近年来的研究证实,成年中枢神经系统内广泛分布着神经干细胞(NSC),海马齿状回颗粒下层和侧脑室下区是成体大脑内源性NSC存在的主要脑区。NSC正常情况下处于静息状态,当大脑受到损伤或出现某些病理性变化时会被激活,分化为成熟的神经细胞,修复受损的神经功能。可以通过某些手段(如康复训练、丰富环境、局部应用外源性神经生长因子)激活自身干细胞或移植干细胞(包括NSC移植和非NSC移植)治疗脑梗死。     

中药诱导脑成体神经干细胞的增殖分化

神经干细胞是具有自我更新和多向分化潜能的一类细胞,其增殖分化与生长因子、细胞因子、环境信号等因素密切相关。近年来,成年脑组织内也发现了具有多向分化潜能的神经干细胞,成体神经干细胞的发现改变了以往中枢系统不可再生的理论。中药能够有效地诱导成体神经干细胞的增殖分化,为神经再生治疗策略开辟了崭新的研究方向,并在治疗缺血性脑损伤中显示出巨大潜能。     

环磷酸腺苷反应原件相关蛋白对抑郁症脑部区域特异性的研究进展

环磷酸腺苷(cAMP)反应原件相关蛋白(CREB)是转录因子蛋白家族成员,在所有脑细胞内表达。CREB定位在细胞核,能够将发生在细胞膜上的刺激信号转换成细胞核内基因表达的改变,在刺激－转录偶联中发挥重要作用。CREB通过调控基因表达来调节各种神经蛋白的表达,最终影响单个神经元或整个神经循环的功能,是多种抗抑郁药物发挥治疗作用的靶点。研究表明大脑不同区域内的CREB对抑郁症的影响不同。笔者综述CREB调节基因转录的分子机制,重点阐述CREB在抑郁症发生、发展过程中作用的多样性,从而探讨CREB对该疾病潜在的治疗价值。     

成体神经干细胞与微环境

背景：成体神经干细胞广泛分布于中枢神经系统,它存在于特殊的微环境中,有自我更新和分化能力,可作为内源性干细胞来源来修复受损的神经组织.目的：归纳总结神经干细胞与微环境的研究与进展.方法：由第一作者检索PubMed（1989至2012年）数据库与中国期刊全文数据库（CNKI：2001至2012年）,检索词分别为“神经干细胞;微环境;调控”和“neural stem cel s;microenviroment;regulation”.结果与结论：阅读文题和进行筛选,选择具有原创性,论点论据可靠且分析全面、密切相关的文章,排除重复性研究与以及质量较差文章,共检索到379篇英文文章,131篇中文文章,按纳入及排除标准筛选后,共纳入64篇文章.微环境中的各种组成成分如血管及内皮细胞、星形胶质细胞、室管膜细胞、细胞外基质与神经干细胞关系密切,在成体神经干细胞的生存、增殖、分化调控中均发挥重要作用.同时,成体神经干细胞的分化受基因调控.成体神经干细胞与微环境两者之间的研究将为神经组织的修复带来新的方向.     

WNT信号传导途径与肿瘤

WNT途径是传递生长刺激信号的通路 ,对动物的生长发育是必需的 ,而其活化却在结肠癌、黑素瘤等越来越多的肿瘤和癌细胞中被发现。WNT途径活化后可影响基因表达而促进细胞增殖 ,在动物胚胎发育过程中是必需的 ,但在成年动物细胞中则会导致肿瘤的发生和生长。因此 ,对WNT途径的传导及调控的研究可增进人们对胚胎发育机制和肿瘤的发生、发展机制的认识。本文就WNT途径的信号传导和调控及其与肿瘤的关系作一概述     

成体神经干细胞研究的最新进展

目的:成体哺乳动物脑中存在神经干细胞,将其分离出来长期培养具有多能性,探讨成体神经干细胞最新的研究现状。资料来源:应用计算机检索PubMed数据库2000-01/2004-01期间的相关文章,检索词为“adultneuralstemcells”和“mammal”,限定文章语言种类为English。资料选择:对资料进行初审,选择关于哺乳动物中枢神经系统成体神经干细胞部位、来源、分化及转化方面的相关文献,纳入标准:①动物实验。②神经干细胞。排除标准:①综述文献。②重复的同一研究。资料提炼:共收集到25篇关于哺乳动物成体神经干细胞的文章,入选20篇,因为这些文章能包含其他文章的内容,体现了成体干细胞的最新研究进展。资料综合:20篇文献中有10篇是关于成体神经干细胞在中枢神经系统中的存在部位及来源的实验研究,8篇分别通过体内和体外实验观察了成体神经干细胞向神经系统细胞的转化及其诱导因素,另外2篇文献观察了成体神经干细胞在一定条件下向其他细胞的转化。结论:哺乳动物中枢神经系统中存在成体神经干细胞,主要存在于侧脑室室下区和海马齿状回颗粒细胞下层,在多种调控信号的作用下,具有向神经系统细胞分化和向其他细胞转化的潜能。     

Hes1在成年小鼠脑中表达的免疫组织化学分析

背景:近年来的研究显示,在胚胎神经系统发育过程中,Hes1的表达调控对保持神经干细胞的数量、调控其分化至关重要.此外,成年个体内处于静止期的纤维母细胞重新获得分裂增殖的能力需要Hes1表达的上调.这表明Hes1在成体中也与某些潜在干细胞的增殖具有密切的关系.因此研究Hes1在成体神经干细胞中的表达及其与成体神经细胞生成的关系也就被提上日程.但Hes1在成年个体神经系统的表达至今未明.目的:观察和分析小鼠脑中不同部位Hes1的表达及Hes1阳性细胞的细胞类型.方法:12只成年雄性C57BL/6小鼠随机数字表法分为单染组和双染组,每组6只.单染组商接取材,采用免疫组织化学技术检测Hes1在小鼠脑中各部位的表达.双染组小鼠以200 mg/kg Brdu的剂量每天腹腔注射1次,连续注射3 d,第4天取材,采用双标记物染色观察分析海马区Hes1阳性细胞的细胞类型.结果与结论:在所有观察的解剖部位中,Hes1表达于所有存在神经细胞的部位,Brdu阳性细胞几乎全部表达Hes1,NeuN阳性细胞全部表达Hes1,而神经胶质原纤维酸性蛋白阳性细胞则完全不表达Hes1.由此可知,Hes1表达于神经细胞和神经干细胞中,胶质细胞不表达Hes1.     

Lentiviral vectors mediate efficient and stable gene transfer in adult neural stem cells in vivo

Modulation of adult neurogenesis may offer new therapeutic strategies for various brain disorders. In the adult mammalian brain the subventricular zone (SVZ) of the lateral ventricle is a region of continuous neurogenesis. Lentiviral vectors stably integrate into dividing and nondividing cells, in contrast to retroviral vectors, which integrate only into dividing cells. We compared their potential for gene transfer into both quiescent and slowly dividing stem cells as well as into more rapidly dividing progenitor cells. In contrast to retroviral vectors, stereotactic injection of lentiviral vectors into the SVZ of adult mice resulted in efficient and long-term marker gene expression in cells with characteristics of both immature type B cells and migrating precursor cells. After migration along the rostral migratory stream and differentiation, the number of enhanced green fluorescent protein (eGFP)-expressing granular and periglomerular interneurons increased over time in the ipsilateral olfactory bulb. Moreover, the number of eGFP-labeled neuronal progenitor cells in the SVZ increased over time. By intraventricular injection of lentiviral vectors we could restrict gene transfer to ependymal cells and type B astroglial-like stem cells. In conclusion, lentiviral vectors surpass retroviral vectors in efficient long-term in vivo marking of subventricular zone stem cells for basic research and therapeutic applications.     

Regulation of adult neurogenesis by psychotropic drugs and stress

Proliferation and maturation of neurons has been demonstrated to occur at a significant rate in discrete regions of adult brain, including the hippocampus and subventricular zone. Moreover, adult neurogenesis is an extremely dynamic process that is regulated in both a positive and negative manner by neuronal activity and environmental factors. It has been suggested to play a role in several important neuronal functions, including learning, memory, and response to novelty. In addition, exposure to psychotropic drugs or stress regulates the rate of neurogenesis in adult brain, suggesting a possible role for neurogenesis in the pathophysiology and treatment of neurobiological illnesses such as depression, post-traumatic stress disorder, and drug abuse. As the mechanisms that control adult neurogenesis continue to be identified, the exciting prospect of developing pharmacological agents that specifically regulate the proliferation and maturation of neurons in the adult brain could be fulfilled.     

Neurogenesis as a potential therapeutic strategy for neurodegenerative diseases

In the adult mammalian brain, new neurons are continuously generated from a proliferating population of neural progenitor/stem cells and become incorporated into the existing neuronal circuitry via a process termed adult neurogenesis. The existence of active functional adult neurogenesis raises the exciting possibility that manipulating endogenous neural progenitors, or transplanting the progeny of exogenously expanded neural progenitors, may lead to successful cell replacement therapies for various degenerative neurological diseases. Significant effort is being made to decipher the mechanisms regulating adult neurogenesis, which may allow us to translate this endogenous neuronal replacement system into therapeutic interventions for neurodegenerative diseases. This review focuses on adult neurogenesis as a strategy to derive potential therapies, and discusses future directions in the field.     

Neurogenesis as a potential therapeutic strategy for neurodegenerative diseases

In the adult mammalian brain, new neurons are continuously generated from a proliferating population of neural progenitor/stem cells and become incorporated into the existing neuronal circuitry via a process termed adult neurogenesis. The existence of active functional adult neurogenesis raises the exciting possibility that manipulating endogenous neural progenitors, or transplanting the progeny of exogenously expanded neural progenitors, may lead to successful cell replacement therapies for various degenerative neurological diseases. Significant effort is being made to decipher the mechanisms regulating adult neurogenesis, which may allow us to translate this endogenous neuronal replacement system into therapeutic interventions for neurodegenerative diseases. This review focuses on adult neurogenesis as a strategy to derive potential therapies, and discusses future directions in the field.     

Overexpression of cdk4 and cyclinD1 triggers greater expansion of neural stem cells in the adult mouse brain

Neural stem cells (NSCs) in the adult mammalian brain generate neurons and glia throughout life. However, the physiological role of adult neurogenesis and the use of NSCs for therapy are highly controversial. One factor hampering the study and manipulation of neurogenesis is that NSCs, like most adult somatic stem cells, are difficult to expand and their switch to differentiation is hard to control. In this study, we show that acute overexpression of the cdk4 (cyclin-dependent kinase 4)-cyclinD1 complex in the adult mouse hippocampus cell-autonomously increases the expansion of neural stem and progenitor cells while inhibiting neurogenesis. Importantly, we developed a system that allows the temporal control of cdk4-cyclinD1 overexpression, which can be used to increase the number of neurons generated from the pool of manipulated precursor cells. Beside providing a proof of principle that expansion versus differentiation of somatic stem cells can be controlled in vivo, our study describes, to the best of our knowledge, the first acute and inducible temporal control of neurogenesis in the mammalian brain, which may be critical for identifying the role of adult neurogenesis, using NSCs for therapy, and, perhaps, extending our findings to other adult somatic stem cells.     

Neurogenesis and brain injury: managing a renewable resource for repair

The brain shows limited ability to repair itself, but neurogenesis in certain areas of the adult brain suggests that neural stem cells may be used for structural brain repair. It will be necessary to understand how neurogenesis in the adult brain is regulated to develop strategies that harness neural stem cells for therapeutic use.     

A retroviral vector suitable for ultrasound image-guided gene delivery to mouse brain

Gene transfer to the early-stage embryonic brain using the ultrasound image-guided gene delivery (UIGD) technique has proven to be valuable for investigating brain development. Thus far, this technology has been restricted to the study of embryonic neurogenesis. When this technique is designed to be employed for the study in adult animals, a long-term stable gene expression will be required. We attempted to develop a retroviral vector suitable for expressing exogenous genes in the brains of postnatal and adult mice in the context of the UIGD technique. Retroviral vectors containing four different long terminal repeats (LTRs) (each from Moloney murine leukemia virus (MoMLV), murine stem cell virus (MSCV), myeloproliferative sarcoma virus (MPSV) and spleen focus-forming virus (SFFV)) were compared using the well-known CE vector having the EF1α internal promoter as a control. The MS vector containing MSCV LTR produced a higher viral titer and a higher level of gene expression than other vectors including CE. The MS vector drove the gene expression in cultured neural stem cells for 3 weeks. Furthermore, the MS vector could efficiently deliver the gene to the mouse central nervous system, as transgene expression was found in various regions of the brains and spinal cords as well as in all major neural cell types. The data from an in vivo luciferase imaging analysis showed that the gene expression from the MS vector was sustainable for almost 3 months. Our data suggested that the MS vector would be suitable to construct mice containing the transgene expressed in the brain or spinal cord in a quick and cost-effective manner.     

Plasticity after brain lesions: contemporary concepts

Medical management of the patient with central nervous tissue injuries has many frontiers. We now realize that the concept of the adult mammalian brain as largely static is no longer tenable. Numerous studies show that experimental manipulations can lead to growth and plasticity in the adult brain. We have confirmed that growth and plasticity, including neurogenesis and synaptogenesis, can also occur throughout the animal's natural life. New approaches may soon be designed to repopulate injured nervous tissue with appropriate cells. Surgical neural tissue transplantation research is one direction. Another approach involves the inherent plasticity of the nervous system, including neurogenesis, which may be modulated by the rehabilitation plan (the environment) with a variety of possible pharmacological approaches.     

成年神经发生及其在缺血性脑损伤治疗中的应用前景

近年来的研究表明，成年哺乳动物中枢神经系统存在神经干细胞。并且在整个成年期有持续的神经发生。中风能使齿状回颗粒下层和脑室下层的神经发生增加。新产生的神经元能够迁移到损伤区并表达已死亡神经元的标记物。这些研究为脑损伤后的自身修复带来了希望。本文作者主要对成年神经发生和调节以及中风诱导的神经发生和调节进行综述，并进一步探讨中风或其他脑损伤后神经再生的研究方向。