Emerging strategies for nerve repair and regeneration in ischemic stroke: neural stem cell therapy

Ischemic stroke is a major cause of mortality and disability worldwide, with limited treatment options available in clinical practice. The emergence of stem cell therapy has provided new hope to the field of stroke treatment via the restoration of brain neuron function. Exogenous neural stem cells are beneficial not only in cell replacement but also through the bystander effect. Neural stem cells regulate multiple physiological responses, including nerve repair, endogenous regeneration, immune f...     

Developing concepts in neural stem cells

Stem Cells in the Mammalian Brain: the 4th Brain Research Interactive Symposium, at the 2001 Annual Conference of the Society for Neuroscience, San Diego, CA, USA from November 8-10 2001.     

The neural crest: understanding stem cell function in development and disease

Complex organs like the nervous system are composed of different cell types which are all derived from multipotent stem cells. In vertebrates, a transient population of stem cells, the neural crest, generates the entire peripheral nervous system as well as non-neural progeny. The developmental processes of cellular differentiation and proliferation require precise coordination and control. Errors in the programs that regulate stem cell function can lead to defects that manifest in developmental disorders, in some cases they might even induce cancer. It is therefore of fundamental interest to understand the mechanisms of stem cell maintenance and differentiation. Using the neural crest as a model system helps us not only to understand the role of stem cells in development but might also lead to new aspects for the cure of stem cell-related diseases.     

Possible use of autologous stem cell therapies for Alzheimer's disease

The statement, "neurodegenerative diseases are incurable because neurons do not regenerate during adulthood," has been challenged, and we have now found much evidence that the matured brain is capable of regenerating neurons. In our previous study, human neural stem cells (HNSCs) transplanted into aged rat brains differentiated into neural cells and significantly improved the cognitive functions of the animals, indicating that HNSCs may be a promising candidate for neuro-replacement therapy. However, because of ethical and practical issues associated with HNSCs, development of autologous stem cell strategies may be desired. We established new technologies to differentiate adult human mesenchymal stem cells into neural cells by modifying cell fate decisions. We also found a pyrimidine derivative that increases endogenous stem cell proliferation and neurogenesis after peripheral administrations of this compound. Although these results may promise a bright future for clinical applications of stem cell strategies in Alzheimer's disease (AD) therapy, we must acknowledge the complexity of AD. For example, abnormal metabolism of the amyloid-beta precursor protein (APP) may affect stem cell biology, while the prevalence of amyloid-beta peptide (Abeta) toxicity theory in AD pathology tends to limit our focus on the physiological functions of APP. We found that excess APP in the environment causes glial differentiation of stem cells. Even though the glial activation may be useful to eliminate Abeta deposits, neuronal differentiation of stem cells is needed for replacement of degenerating neurons in the AD brain. Thus, further investigation of the influence of AD pathology on stem cell biology is required.     

Adult human neural stem cells for autologous cell replacement therapies for neurodegenerative disorders

Neural stem cells residing in the adult human brain have the potential to provide a source of tissue for self-to-self cell replacement strategies for the treatment of neurodegenerative diseases. Adult human neural stem cells (NSCs) are self renewable in culture and can generate mature neural progeny which display the characteristics of functional neurons and glia. Despite this, a number of concerns remain regarding their current suitability for treating neurodegenerative disorders. It must be demonstrated that desired neuronal types can be generated in clinically significant quantities, and can induce long-lasting functional improvements in well-characterised animal models of neurodegenerative disorders. Furthermore, the risks to patients in terms of tumour formation and side effects must be adequately assessed. Due to the paucity of data on adult human NSCs, a move from preclinical studies to clinical trials in human patients in the foreseeable future is unlikely. If clinical trials with autologous NSCs are pursued as a treatment option for neurodegenerative diseases, then lessons and insights from many years of clinical trials with fetal neural transplantation for Parkinson's and Huntington's diseases will be invaluable, and should be heeded. Issues include experimental versus therapeutic research, standardisation of methodologies, and minimisation of risks and maximisation of benefits.     

Emergent properties of neural repair: elemental biology to therapeutic concepts

Stroke is the leading cause of adult disability. The past decade has seen advances in basic science research of neural repair in stroke. The brain forms new connections after stroke, which have a causal role in recovery of function. Brain progenitors, including neuronal and glial progenitors, respond to stroke and initiate a partial formation of new neurons and glial cells. The molecular systems that underlie axonal sprouting, neurogenesis, and gliogenesis after stroke have recently been identified. Importantly, tractable drug targets exist within these molecular systems that might stimulate tissue repair. These basic science advances have taken the field to its first scientific milestone; the elemental principles of neural repair in stroke have been identified. The next stages in this field involve understanding how these elemental principles of recovery interact in the dynamic cellular systems of the repairing brain. Emergent principles arise out of the interaction of the fundamental or elemental principles in a system. In neural repair, the elemental principles of brain reorganization after stroke interact to generate higher order and distinct concepts of regenerative brain niches in cellular repair, neuronal networks in synaptic plasticity, and the distinction of molecular systems of neuroregeneration. Many of these emergent principles directly guide the development of new therapies, such as the necessity for spatial and temporal control in neural repair therapy delivery and the overlap of cancer and neural repair mechanisms. This review discusses the emergent principles of neural repair in stroke as they relate to scientific and therapeutic concepts in this field. Ann Neurol 2016;79:895–906     

信号转导通路在神经干细胞分化及其修复脊髓损伤过程中的作用

近年来神经干细胞的研究给中枢神经系统损伤患者带来了新的希望，但神经干细胞的分化诱导仍然是医学界的一大难题。文章试对神经干细胞分化发育过程的基因信号转导通路Notch信号途径、螺旋-环-螺旋转录因子家族信号途径及Wnt信号途径等作以综合分析。探讨这些基因信号转导通路对神经干细胞分化的作用及其修复脊髓损伤的前景。神经干细胞的分化发育受多种途径的共同作用，基因水平的调控，局部微环境以及各种生长因子的作用都对其分化发育有重要影响；其对脊髓损伤的修复具有重要作用。     

脑组织移植和神经干细胞研究进展

综述了近年来广泛开展的神经组织和细胞移植的各种主要方法及其进展。着重对神经干细胞这一神经科学的前沿课题进行了详细的复习。并对神经干细胞的研究方法,神经营养因子和神经干细胞的关系,神经干细胞的分化诱导及共临床方面的应用前景作了阐述。     

神经干细胞工程化的研究进展

神经干细胞具有自我更新能力和多分化潜能，随着神经干细胞分离培养技术日渐成熟和深入，许多研究者对神经干细胞进行人工改造，产生了工程化的神经干细胞，如可示踪的神经干细胞、有治疗基因的神经干细胞、把神经干细胞改造成永生化的神经干细胞。文章对神经干细胞的基本特性及近年来神经干细胞工程化的研究进展做一综述     

表观调控与神经干细胞分化(英文)

神经干细胞是当前神经科学领域的研究热点。最近的研究显示表观调控与神经干细胞的分化关系密切,而且为神经干细胞的移植治疗提供可能的细胞来源。表观调控是指在基因的DNA序列未改变的情况下,基因功能发生可遗传的变化而导致细胞表型发生改变,主要机制包括DNA甲基化、组蛋白修饰、基因印迹、染色体重组以及非编码小RNA等。本综述就表观调控对神经干细胞分化作用的最新进展作一回顾。     

表观调控与神经干细胞分化

神经干细胞是当前神经科学领域的研究热点。最近的研究显示表观调控与神经干细胞的分化关系密切,而且为神经干细胞的移植治疗提供可能的细胞来源。表观调控是指在基因的DNA序列未改变的情况下,基因功能发生可遗传的变化而导致细胞表型发生改变,主要机制包括DNA甲基化、组蛋白修饰、基因印迹、染色体重组以及非编码小RNA等。本综述就表观调控对神经干细胞分化作用的最新进展作一回顾。     

脂肪干细胞向神经细胞分化的研究现状

源于中胚层的脂肪与骨髓组织中的干细胞,均具有多向分化潜能,在特殊的环境条件诱导下,可向神经细胞分化.多种物质如氢化考地松、丙戊酸、丁羟茴醚、弗司扣林、表皮生长因子和成纤维细胞生长因子、β-巯基乙醇等可对脂肪干细胞向神经细胞的分化进行调控.脂肪来源的干细胞向神经细胞分化应用于中枢神经损伤功能改变有一定的效果,是值得深入研究的课题之一.     

骨髓基质干细胞和神经干细胞移植治疗帕金森病大鼠的效果比较**☆

目的：目前对应用神经干细胞和骨髓基质干细胞移植治疗帕金森病效果进行对比的研究很少，实验观察比较同种异体来源的中脑神经干细胞和骨髓基质干细胞对帕金森大鼠行为学及损伤脑组织形态学的影响。 方法：实验于2006-03/2007-09在河北医科大学第一医院脑老化与认知神经科学实验室完成。SD大鼠麻醉后建立右侧帕金森病模型，随机分为神经干细胞组14只、骨髓基质干细胞组10只、空白对照组10只。选取右侧纹状体2个坐标点（in mm: A +0.6；R +4.0；V -5.0）、（in mm: A -0.7；R +3.0；V -5.0），前两组每个坐标点分别注入经Brd-U标记的神经干细胞悬液、骨髓基质干细胞悬液5 μL，约1×106个细胞，空白对照组注射等量磷酸盐缓冲液。细胞移植后各组大鼠腹腔注射阿朴吗啡诱导旋转。 结果：①行为学改变：与空白对照组比较，移植2~8周神经干细胞组和骨髓基质干细胞组大鼠的旋转次数均明显减少（P < 0.01）。②纹状体切片免疫组织化学荧光染色鉴定：移植8周后，神经干细胞组和骨髓基质干细胞组均可见一定数量双标的神经元、星形胶质细胞和酪氨酸羟化酶阳性细胞，且后者的双标细胞相对多于前者。空白对照组未发现Brd-U阳性细胞、微管相关蛋白2阳性细胞及酪氨酸羟化酶阳性细胞的表达。各组损毁侧黑质酪氨酸羟化酶阳性细胞残存率基本相似（P > 0.05）。 结论：神经干细胞和骨髓基质干细胞移植均可改善帕金森病大鼠的旋转行为，且至少在脑内存活8周，并可分化成神经元、星形胶质细胞和多巴胺能神经元。     

Stem cell factor and mesenchymal and neural stem cell transplantation in a rat model of Huntington's disease

Neural and mesenchymal stem cells have been proposed as alternative sources of cells for transplantation into the brain in neurodegenerative disorders. However, the endogenous factors controlling their engraftment within the injured parenchyma remain ill-defined. Here, we demonstrate significant engraftment of undifferentiated exogenous mesenchymal or neural stem cells throughout the lesioned area in a rat model for Huntington's disease, as late as 8 weeks post-transplantation. We show that stem cell factor (SCF), strongly up-regulated within host cells in the damaged striatum, is able to activate the SCF receptor c-kit and its signaling pathway and to promote the migration and proliferation of mesenchymal and neural stem cells in vitro. Furthermore, c-kit receptor blockade alters neural stem cell distribution within the lesioned striatum. Host SCF expression is observed in atypical cells expressing glial fibrillary acidic protein and doublecortin in the lesioned striatum and in migrating doublecortin-positive progenitors. Taken together, these data demonstrate that SCF produced in situ in the lesioned striatum is an important factor in promoting the engraftment of stem cells within the lesioned brain.     

Fortuitous benefits of activity-based rehabilitation in stem cell-based therapy for spinal cord repair: enhancing graft survival

<正>Traumatic injuries to spinal cord elicit diverse signaling pathways leading to unselective and complex pathological outcomes:death of multiple classes of neural cells,formation of cystic cavities and glial scars,disruption of axonal connections,and demyelination of spared axons,all of which can contribute more or less to debilitating functional impairments found in patients with spinal     

Neurospheres: insights into neural stem cell biology

Neural stem cells (NSC) are a tissue-specific subtype of self-renewing and multipotent cells that can give rise to all neural populations. In this review, the importance of maintaining cell-cell contacts in the study of NSC is highlighted, and data obtained from some crucial single-cell studies is compared to results obtained from neurospheres, where aggregates of NSC are grown in suspension. In particular, results that indicate how this culture system may be well suited to analyze NSC plasticity, cell-cell, and cell-extracellular matrix (ECM) interactions are pointed out, and the hypothesis that cell-cell and cell-ECM contacts may be essential for NSC maintenance, survival, and proliferation is highlighted. Finally, it is suggested that neurospheres might play a role in the study of context-dependent behavior of NSC in niches by providing a system where NSC can be challenged chemically or biologically and analyzed in vitro, in a time- and context-dependent manner.     

小鼠胚胎干细胞体外向神经干细胞的分化研究

目的观察无血清培养法诱导小鼠胚胎干细胞(Embryome stem cell,ESCs)ESCs体外分化为神经干细胞(Neural stem cell,NSCs)的诱导效率.方法采用无血清培养法诱导小鼠ESCs体外分化为NSCs,对诱导不同时间点的细胞行免疫荧光,RT-PCR检测nestin的表达.结果诱导48 h开始出现nestinmRNA的表达,诱导72 h出现nestin蛋白表达.诱导120 h nestin的表达达高峰,阳性细胞率为(70.3±8.02)%.Nestin阳性细胞呈球形生长,可不断增殖.结论本诱导方法可获得较高纯度的NSCs,所获得的神经干细胞与脑内来源的NSCs有相似的生物学特性.