成年大鼠弥漫性脑损伤后海马齿状回神经元再生动态变化的实验研究

目的观察弥漫性脑损伤后大鼠海马齿状回神经前体细胞的增殖规律。方法使用BrdU标记分裂细胞、免疫组织化学方法和激光共聚焦显微镜观察弥漫性脑损伤后大鼠海马齿状回神经元再生水平的变化规律。结果成年大鼠弥漫性脑损伤后4～12d时间段内,齿状回BrdU免疫阳性细胞数量表现出明显的统计学差异(P<0.01),其中第6天时达到峰值。这些BrdU阳性细胞大部分分化为神经元。结论弥漫性脑损伤可诱导成年脑海马齿状回细胞再生水平在一定时间内上调。     

成年大鼠弥漫性脑损伤后海马神经发生与神经生长因子的表达

目的　观察弥漫性脑损伤后大鼠海马神经发生和神经生长因子 (NGF)表达水平的变化 ,从分子水平探讨成年大鼠海马齿状回神经发生机制。方法　选用成年大鼠DBI模型 ,采用BrdU标记分裂细胞、免疫组织化学及RT PCR方法观察比较弥漫性脑损伤后 1～ 1 2d大鼠海马齿状回神经前体细胞增殖水平和神经生长因子表达的变化。结果　①弥漫性脑损伤后 4～ 1 2d时间段内 ,成年大鼠海马齿状回神经发生水平显著升高 (P <0 0 1 ) ,其中第 6天时达到峰值。②弥漫性脑损伤后 1d时NGF表达水平迅速达到峰值(P <0 0 5 )。其后 ,在DBI后第 4～ 1 2d时间段内 ,NGF表达水平再次明显上调 (P <0 0 5 ) ,并维持较长一段时间。结论　弥漫性脑损伤后成年脑海马齿状回神经前体细胞增殖水平在一定时间窗内上调 ,脑损伤诱导的迟发性NGF表达水平上调参与了这一过程     

缺血性脑损伤中神经发生的研究进展

成年哺乳动物脑内的某些区域存在着神经干细胞和持续的神经发生现象,特别是位于侧脑室外侧壁的室管膜下区(SVZ)和海马齿状回颗粒下层(SGZ),局部脑缺血以后这些区域的神经发生现象明显增强,新生成的神经元与发育过程中形成的神经元在功能和结构上极其相似,且在某些因素的刺激下可向缺血区域迁移.这一发现为替代因生理、病理条件下丢...     

局灶性脑缺血再灌注后神经发生及药物对其作用的研究进展

脑缺血是临床上常见的疾病,它能造成神经元损伤,影响神经功能。神经干细胞在一定条件下可增殖分化成神经元和胶质细胞,缺血性脑损伤后能参与神经功能的修复过程。本文对神经发生的机制和影响因素、缺血后的神经发生与脑功能恢复的联系,以及药物促进神经发生在脑缺血疾病治疗中的应用及前景进行文献综述。     

脑缺血后神经发生与血管生成的联系与作用

近年来,以神经干细胞（neural stem cells,NSC）为方向的研究以促进神经再生为治疗靶点,逐渐成为神经科学研究的热点之一.成年中枢神经系统中存在NSC的主要脑区是侧脑室外侧壁的室下带（subventricular zone,SVZ）和海马齿状回的颗粒下层（subgranuhr zone,SGZ）.NSC在一定条件下可增殖分化成神经元和胶质细胞,参与神经功能的修复过程,称为神经发生（neurogenesis）.     

外源性碱性成纤维细胞生长因子对成年大鼠弥漫性脑损伤后海马齿状回神经前体细胞增殖影响的研究

目的 观察弥漫性脑损伤后成年大鼠海马齿状回神经前体细胞增殖水平动态变化的规律以及外源性碱性成纤维细胞生长因子(bFGF)对其的影响.方法 采用5-溴脱氧尿核苷 (5-bromodeoxyuridine, BrdU) 标记细胞有丝分裂、免疫组织化学方法观察成年大鼠弥漫性脑损伤后海马齿状回神经前体细胞增殖水平的变化规律以及侧脑室注射外源性bFGF对弥漫性脑损伤后齿状回神经前体细胞增殖变化的影响. 结果成年大鼠弥漫性脑损伤后齿状回BrdU免疫阳性细胞数在弥漫性脑损伤后4～8 d 时间点,差异有统计学意义(P < 0.01),其中第6天时达到峰值.弥漫性脑损伤大鼠侧脑室注射外源性bFGF后齿状回神经前体细胞增殖水平较对照组显著升高(P< 0.05). 结论 弥漫性脑损伤可诱导成年大鼠海马齿状回神经前体细胞增殖水平在一定的时间窗内上调,外源性bFGF可促进弥漫性脑损伤后齿状回神经前体细胞增殖水平的上调.     

MiRNAs在成体神经发生中的作用

成年哺乳动物大脑仍然能够产生新生神经元的发现点燃了一个新的研究领域——神经发生。目前认为研究成年后的神经发生对进一步了解大脑功能和衰老,脑肿瘤、神经系统退行性疾病的发病机制和治疗,中枢神经系统的损伤修复等均具有重要的意义。成体神经发生是一个复杂的多步骤过程,每个阶段都受细胞内在基因表达程序和细胞外微环境因素的精细调控。越来越多的证据表明miRNAs代表了一类转录后基因表达调控因子,是控制成体神经发生的基因调控网络的重要组成部分。     

成年大鼠弥漫性脑损伤后海马齿状回神经元再生动态变化的实验研究

目的：观察弥漫性脑损伤后大鼠海马齿状回神经前体细胞的增殖规律。方法：使用BrdU标记分裂细胞、免疫组织化学方法和激光共聚焦显微镜观察弥漫性脑损伤后大鼠海马齿状回神经元再生水平的变化规律。结果：成年大鼠弥漫性脑损伤后4－12d时间段内，齿状回BrdU免疫阳性细胞数量表现出明显的统计学差异（P＜0．01），其中第6天时达到峰值。这些BrdU阳性细胞大部分分化为神经元。结论：弥漫性脑损伤可诱导成年脑海马齿状回细胞再生水平在一定时间内上调。     

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。     

Wnt信号对神经发生和血管新生的调控

Wnt信号通路与神经发生和血管新生密切相关,该通路对于大脑可塑性的调节意义重大。对Wnt信号调节作用与机制进行研究,有助于了解大脑损伤后修复和再生。     

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.     

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.     

The therapeutic potential of adult neural stem cells

Neural stem cells (NSCs) are self-renewing, multipotent cells that generate the neuronal and glial cells of the nervous system. In mammals, contrary to long-held belief, neurogenesis occurs in the adult brain, and NSCs reside in the adult central nervous system. Thus, the brain may be amenable to repair following damage, and new avenues for cell-based therapy are being considered for the treatment of brain disease and injury, such as the stimulation of endogenous progenitor cells, the transplantation of adult-derived neural progenitor and stem cells, and, in particular, autologous cell transplantation. Although significant advances in this field have been made over the past decade, the adult NSC remains an elusive cell for study, and researchers are facing multiple challenges to the development of therapeutic applications from adult NSC research. Among these challenges are the identification and characterization of NSCs in vivo and in vitro, the understanding of the physiology of newly generated neuronal cells in the adult brain, the stimulation of endogenous progenitor cells to promote functional recovery, and the isolation and culture of homogenous populations of neural progenitor or stem cells from the adult brain for cell-based therapy.     

Engraftment of human nasal olfactory stem cells restores neuroplasticity in mice with hippocampal lesions

Stem cell-based therapy has been proposed as a potential means of treatment for a variety of brain disorders. Because ethical and technical issues have so far limited the clinical translation of research using embryonic/fetal cells and neural tissue, respectively, the search for alternative sources of therapeutic stem cells remains ongoing. Here, we report that upon transplantation into mice with chemically induced hippocampal lesions, human olfactory ecto-mesenchymal stem cells (OE-MSCs) - adult stem cells from human nasal olfactory lamina propria - migrated toward the sites of neural damage, where they differentiated into neurons. Additionally, transplanted OE-MSCs stimulated endogenous neurogenesis, restored synaptic transmission, and enhanced long-term potentiation. Mice that received transplanted OE-MSCs exhibited restoration of learning and memory on behavioral tests compared with lesioned, nontransplanted control mice. Similar results were obtained when OE-MSCs were injected into the cerebrospinal fluid. These data show that OE-MSCs can induce neurogenesis and contribute to restoration of hippocampal neuronal networks via trophic actions. They provide evidence that human olfactory tissue is a conceivable source of nervous system replacement cells. This stem cell subtype may be useful for a broad range of stem cell-related studies.     

脑缺血后强制性运动疗法对内源性神经干细胞及基质细胞衍生因子-1水平的影响

目的目前强制性运动疗法广泛地应用于康复领域,并被证实能够有效地促进肢体功能恢复,但其确切的机制尚不清楚。方法应用免疫组化及ELISA方法并结合行为学探讨了强制性运动疗法对脑缺血后内源性神经干细胞及间质细胞源性因子-1表达的影响。结果发现脑缺血后强制性运动疗法能够促进患侧肢体运动功能的恢复,增加大鼠侧脑室下区新生神经干细胞的数量,并能提高脑组织基质细胞衍生因子-1蛋白的表达水平。结论强制性运动疗法可能通过影响脑缺血后的神经再生过程从而达到增强中枢神经系统修复能力的作用。     

EGF amplifies the replacement of parvalbumin-expressing striatal interneurons after ischemia

EGF promotes proliferation and migration of stem/progenitor cells in the normal adult brain. The effect of epidermal growth factor on neurogenesis in ischemic brain is unknown, however. Here we show that intraventricular administration of EGF and albumin augments 100-fold neuronal replacement in the injured adult mouse striatum after cerebral ischemia. Newly born immature neurons migrate into the ischemic lesion and differentiate into mature parvalbumin-expressing neurons, replacing more than 20% of the interneurons lost by 13 weeks after ischemia and representing 2% of the total BrdU-labeled cells. These data suggest that administration of EGF and albumin could be used to manipulate endogenous neurogenesis in the injured brain and to promote brain self-repair.     

Glial cells in the mouse enteric nervous system can undergo neurogenesis in response to injury

The enteric nervous system (ENS) in mammals forms from neural crest cells during embryogenesis and early postnatal life. Nevertheless, multipotent progenitors of the ENS can be identified in the adult intestine using clonal cultures and in vivo transplantation assays. The identity of these neurogenic precursors in the adult gut and their relationship to the embryonic progenitors of the ENS are currently unknown. Using genetic fate mapping, we here demonstrate that mouse neural crest cells marked by SRY box-containing gene 10 (Sox10) generate the neuronal and glial lineages of enteric ganglia. Most neurons originated from progenitors residing in the gut during mid-gestation. Afterward, enteric neurogenesis was reduced, and it ceased between 1 and 3 months of postnatal life. Sox10-expressing cells present in the myenteric plexus of adult mice expressed glial markers, and we found no evidence that these cells participated in neurogenesis under steady-state conditions. However, they retained neurogenic potential, as they were capable of generating neurons with characteristics of enteric neurons in culture. Furthermore, enteric glia gave rise to neurons in vivo in response to chemical injury to the enteric ganglia. Our results indicate that despite the absence of constitutive neurogenesis in the adult gut, enteric glia maintain limited neurogenic potential, which can be activated by tissue dissociation or injury.     

Adult neural stem cells and repair of the adult central nervous system

Neural stem cells are present not only in the developing nervous systems, but also in the adult central nervous system of mammals, including humans. The mature central nervous system has been traditionally regarded as an unfavorable environment for the regeneration of damaged axons of mature neurons and the generation of new neurons. In the adult central nervous system, however, newly generated neurons from adult neural stem cells in specific regions exhibit a striking ability to migrate, send out long axonal and dendritic projections, integrate into pre-existing neuronal circuits, and contribute to normal brain functions. Adult stem cells with potential neural capacity recently have been isolated from various neural and nonneural sources. Rapid advances in the stem cell biology have raised exciting possibilities of replacing damaged or lost neurons by activation of endogenous neural stem cells and/or transplantation of in vitro-expanded stem cells and/or their neuronal progeny. Before the full potential of adult stem cells can be realized for regenerative medicine, we need to identify the sources of stem cells, to understand mechanisms regulating their proliferation, fate specification, and, most importantly in the case of neuronal lineages, to characterize their functional properties. Equally important, we need to understand the neural development processes in the normal and diseased adult central nervous system environment, which is quite different from the embryonic central nervous system, where neural development has been traditionally investigated. Here we will review some recent progress of adult neural stem cell research that is applicable to developmental neurobiology and also has potential implications in clinical neuroscience.