阿尔茨海默病与Wnt信号通路及神经干细胞的关系

背景：阿尔茨海默病的病因涉及遗传、环境、免疫等多种因素和机制,大量研究表明Wnt信号通路与之密切相关,也有研究表明,Wnt信号通路对神经干细胞的增殖发挥着决定性作用。 目的：对阿尔茨海默病的病理过程与Wnt信号通路的关系以及Wnt信号通路与神经干细胞增殖分化进行综述,为阿尔茨海默病的治疗提供理论依据。 方法：通过Pubmed数据库检索有关阿尔茨海默病病理过程与Wnt信号通路及Wnt信号通路与神经干细胞关联的相关文献,检索词为“Alzheimer’s disease、Wnt signaling pathway、NSCs、stem cell differentiation、amyloid-β protein、Protein Tau”。纳入与阿尔茨海默病和Wnt信号通路相关的文献,排除重复性研究,保留50篇文献进行综述。 结果与结论：目前通过神经干细胞移植来治疗以神经元的缺失为特征的神经退行性疾病已成为研究的热点,而如何调控神经干细胞向特定神经元分化成为了研究的难点,信号转导在神经干细胞的分化中起重要的作用,其中Wnt信号通路是调节神经干细胞增殖及分化的细胞外的重要因素。Wnt信号通路的失活可以促进阿尔茨海默病的病理过程,相反激活Wnt信号通路可以保护海马神经元,同时促进神经干细胞的分化,为阿尔茨海默病的治疗提供新的思路。     

Wnt信号与神经干细胞分化

背景:研究表明,移植入宿主体内的神经干细胞可分化为神经元或神经胶质细胞。Wnt信号通路与神经干细胞的分化密切相关。通过调节Wnt信号通路可控制神经干细胞的定向分化。目的:对神经干细胞分化及其与Wnt信号通路的关系进行综述.方法:应用计算机检索2002-02/2010-03 Medline数据库、Ovid数据库、CNKI、EBSCO数据库与神经干细胞相关文献。检索词为"神经干细胞,神经再生,Wnt信号,神经元,分化"。纳入与神经干细胞分化及Wnt信号系统相关文献,排除重复性研究,保留30篇文献进行综述。结果与结论:神经干细胞是一类具有自我更新和多向分化潜能的细胞,能分化形成机体中枢神经系统几乎所有类型的细胞。Wnt信号通路在神经干细胞的分化中起重要作用。文章从神经干细胞、Wnt信号通路、Wnt信号通路与神经干细胞的分化等方面分别进行了叙述。然而,Wnt信号通路控制神经干细胞分化的具体机制还不是很清楚。     

Notch和Wnt信号通路对神经干细胞增殖分化的影响

Notch和Wnt信号通路是调节神经干细胞(neural stem cells,NSCs)增殖、分化的重要通路,Notch信号通路的靶基因Hes1、Hes5及HES相关蛋白等分化抑制信号,通过旁侧抑制机制阻止NSCs的分化,并促进其自我更新;通过NICD与CSL DNA结合蛋白的直接结合,形成GFAP的转录激活复合物,上调GFAP的表达,从而促进NSCs向星形胶质细胞的分化。Wnt信号通过Wnt/β-catenin信号通路对细胞周期素D1和D2的转录调节,调控NSCs细胞周期的进程,使其量增殖;然而,过表达的Wnt3a和Wnt7a蛋白能够抑制NSCs的增殖,促进NSCs向神经元方向分化。     

间充质干细胞增殖、衰老及分化:Wnt信号通路经典与非经典的调控作用

背景:间充质干细胞作为再生医学及组织工程领域中的重要种子细胞来源,对其不同生物学特性的调控机制一直是目前研究的热点。目的:综述Wnt信号通路调控间充质干细胞增殖、衰老及分化的研究进展。方法:应用计算机检索2002至2014年PubMed数据库及CNKI数据库,以"mesenchymal stem cells,Wnt signaling pathway,proliferation,senescence,differentiation"或"间充质干细胞,Wnt信号通路,增殖,衰老,分化"为关键词进行检索,重点对44篇文章进行分析。结果与结论:Wnt信号通路广泛参与调控间充质干细胞多种生物学特性。经典Wnt信号通路对间充质干细胞增殖及向成骨细胞分化具有双向调控作用,并能够促进其衰老及向神经细胞分化,抑制其向脂肪细胞分化;非经典Wnt信号通路则参与促进间充质干细胞衰老及向成骨细胞分化,抑制其增殖及向脂肪细胞分化,不参与其向神经细胞分化,为其应用于骨组织工程、神经损伤修复等领域提供了新的研究靶点。     

Wnt信号通路在成骨细胞中的作用:成骨还是破骨?

背景:研究表明,Wnt信号通路参与调节骨髓间充质干细胞向成骨细胞分化,促进成骨细胞增殖和分化,抑制成骨细胞的程序性死亡,间接影响破骨细胞的功能。目的:分析Wnt/β-连环蛋白信号通路与骨疾病的关系。方法:通过计算机检索CNKI和Elsevier数据库中2000年1月至2014年1月文献,关键词为"Wnt/β-连环蛋白、成骨细胞、骨髓间充质干细胞、骨质疏松,骨关节炎"。选择与Wnt/β-连环蛋白信号通路对成骨细胞及骨疾病影响有关的文章内容进行归纳分析。结果与结论:Wnt信号通路包括Wnt/β-连环蛋白信号通路(Wnt经典信号通路);Wnt/Ca2+信号通路;Wnt/PCP(平面细胞极性)信号通路等。Wnt信号途径是体内重要的信号调节系统之一,对成骨细胞、破骨细胞和软骨细胞的分化、增殖和程序性死亡过程中扮演重要角色。在类风湿关节炎患者体内Wnt信号途径主要通过成骨细胞发挥作用。其成骨细胞中Wnt信号途径的抑制因子上调,能够降低骨保护素/受体活化因子配体比值,促进破骨细胞分化成熟。研究Wnt通路的组分及其作用,不仅有助于骨疾病的特定治疗,而且有利于预防骨质疏松及其他关节性等疾病。     

经典Wnt信号通路对细胞成骨分化的调控作用

Wnt信号通路是参与体内多种器官发育和组织新陈代谢的保守性通路,可分为经典和非经典Wnt信号通路.其中,经典Wnt信号通路通过调节下游的成骨相关转录因子调控细胞成骨分化、骨基质形成和矿化,且在细胞分化的不同阶段发挥不同的调控作用.此外,经典Wnt信号通路还调控牙周组织干细胞成骨分化,该作用受外界微环境的影响.加深对经典Wnt信号通路的认识有助于治疗相关的骨疾病.     

神经退行性疾病中的自噬与再生研究进展

神经退行性疾病是由于神经元纤维的缠结和神经元的丢失所致,而产生功能障碍的现象,神经干细胞(NSCs)的损伤和生成减少也会引起神经退行性疾病的产生。自噬可以降解受损的细胞和细胞器,自噬在NSCs的增殖和分化中起着重要作用。mTOR和Notch都可以通过调节自噬来控制NSCs的生成,抑制mTOR信号通过干扰自噬作用于年龄相关的神经退行性疾病,自噬的改变可以影响Notch信号对NSCs分化的影响,本文归纳总结了自噬与再生在神经退行性疾病中作用的研究进展。     

Wnt3a与Wnt5a信号途径转换对造血干细胞衰老的影响

造血干细胞(HSCs)衰老是机体造血免疫功能衰老的重要原因,在衰老相关疾病的发生中起着关键作用。一定条件下,经典Wnt3a/β-catenin的激活明显有利于保持HSCs的极性与年轻态、自我更新与增殖、分化能力;非经典Wnt5a信号通路的激活则可通过进一步激活细胞内Cdc42蛋白活化等,促发HSCs衰老,并间接抑制Wnt3a/β-catenin通路。对Wnt3a向Wnt5a信号通路转换及其干预的研究不但阐释了HSCs衰老发生的机制,更明确了如何延缓衰老,提供了解决衰老相关疾病及保持年轻态的新策略。     

Wnt信号通路调控免疫应答的研究进展

Wnt蛋白是一类分泌型糖蛋白,通过自分泌或旁分泌发挥作用,是一组调控胚胎形成期间细胞间信号传导、高度保守的分泌型信号分子。Wnt信号通路分为β-catenin依赖的经典信号通路以及非经典信号通路,广泛参与细胞的增殖、迁移和分化等过程。值得关注的是,Wnt信号通路调控巨噬细胞、T细胞、B细胞等多种免疫细胞的分化与发育,并通过多种机制调控免疫应答过程。此外,Wnt信号通路对肝星状细胞、内皮细胞等具有免疫特性细胞的生物学功能也发挥调控作用。本文对Wnt信号通路调控免疫应答的研究进展作一综述。     

经典Wnt信号通路对少突胶质前体细胞生长发育的调控

少突胶质前体细胞(OPCs)经历增殖、迁移、分化为成熟少突胶质细胞(OLs),包绕轴突形成髓鞘,维持轴突正常功能及神经冲动传导。OPCs的生长发育受多种信号分子及通路的影响,其中经典Wnt信号通路与OPCs正常及病理状态下的增殖、迁移和分化过程密切相关,通路中相关分子的变化导致该通路的活化均会影响OPCs的发育,进而影响髓鞘的形成与修复再生。     

Wnt signaling in neuroprotection and stem cell differentiation

In the past several years, we postulated that the loss of Wnt signaling was implicated in the pathology of Alzheimer's disease (AD). Since then, our lab and other groups have confirmed the involvement of the Wnt signaling in some aspects of AD. So far, we have demonstrated that activation of Wnt signaling protects neurons against neurotoxic injuries, including both amyloid-beta (Abeta) fibrils and Abeta oligomers by using either lithium, an inhibitor of the glycogen-synthase-kinase-3beta (GSK-3beta), or different Wnt ligands. Also, we have found that several molecules which activate well known neurotransmitter systems and other signaling system, are able by crosstalk to activate Wnt/beta-catenin signaling in order to protect neurons against both Abeta fibrils or Abeta oligomers. In particular, the activation of non-canonical Wnt signaling was able to protect postsynaptic regions and dendritic spines against Abeta oligomers. Furthermore Wnt signaling ligands also affect stem cells, and they are also involved in cell fate decision during neurogenesis and embryonic development as well as in adult stem cells differentiation in the nervous system. The Wnt signaling plays a key role modulating their cell differentiation or proliferation states. Altogether, these findings in both stem cell biology and neuroprotection, may introduce new approaches in the treatment of neurodegenerative diseases, including drug screening and therapies against neurodegenerative diseases which activates the Wnt signaling pathway.     

Wnt途径及其拮抗剂与肿瘤的关系

Wnt途径是重要的细胞信号转导途径,在细胞的增殖、分化中发挥重要作用。Wnt途径的异常与多种肿瘤的发生或转移有关。而Wnt拮抗剂则可以拮抗Wnt途径。因此深入研究Wnt信号通路及其拮抗剂,设计出阻断Wnt通路的物质,可为将来肿瘤的治疗提供一种可行性的途径。     

Beta-catenin signaling promotes proliferation of progenitor cells in the adult mouse subventricular zone

The subventricular zone (SVZ) is the largest germinal zone in the mature rodent brain, and it continuously produces young neurons that migrate to the olfactory bulb. Neural stem cells in this region generate migratory neuroblasts via highly proliferative transit-amplifying cells. The Wnt/beta-catenin signaling pathway partially regulates the proliferation and neuronal differentiation of neural progenitor cells in the embryonic brain. Here, we studied the role of beta-catenin signaling in the adult mouse SVZ. beta-Catenin-dependent expression of a destabilized form of green fluorescent protein was detected in progenitor cells in the adult SVZ of Axin2-d2EGFP reporter mice. Retrovirus-mediated expression of a stabilized beta-catenin promoted the proliferation of Mash1+ cells and inhibited their differentiation into neuroblasts. Conversely, the expression of Dkk1, an inhibitor of Wnt signaling, reduced the proliferation of Mash1+ cells. In addition, an inhibitor of GSK3 beta promoted the proliferation of Mash1+ cells and increased the number of new neurons in the olfactory bulb 14 days later. These results suggest that beta-catenin signaling plays a role in the proliferation of progenitor cells in the SVZ of the adult mouse brain.     

Role of the Wnt/β-catenin network in regulating hematopoiesis

The Wnt/beta-catenin pathway plays a significant role in several aspects of cell biology, including the stimulation of gene expression, growth, and mobility. Wnt proteins activate at least three cascades: Wnt/beta-catenin, Wnt/Ca(2+), and planar cell polarity. beta-Catenin is not only a very important element of many intracellular signaling pathways, including the Wnt pathway, but it also takes part in creating intercellular adhesive junctions. When overexpressed or mutated it functions as an oncogen. The Wnt/beta-catenin signaling pathway has been shown to play an important role in controlling the proliferation, survival, and differentiation of hematopoietic cells. Thus any aberrant signaling through this pathway may have a negative influence on hematopoiesis. Indeed, some recent findings suggest that Wnt/beta-catenin signaling is dysregulated in leukemias and lymphomas. All these data position the Wnt/beta-catenin signaling network as a critically important regulator of hematopoiesis and justify future efforts to better understand its role in the process of physiological and pathological hematopoiesis. The present review summarizes recent advances in this field.     

The emerging role of Wnt signaling dysregulation in the understanding and modification of age-associated diseases

Wnt signaling is a highly conserved pathway that participates in multiple aspects of cellular function during development and in adults. In particular, this pathway has been implicated in cell fate determination, proliferation and cell polarity establishment. In the brain, it contributes to synapse formation, axonal remodeling, dendrite outgrowth, synaptic activity, neurogenesis and behavioral plasticity. The expression and distribution of Wnt components in different organs vary with age, which may have important implications for preserving tissue homeostasis. The dysregulation of Wnt signaling has been implicated in age-associated diseases, such as cancer and some neurodegenerative conditions. This is a relevant research topic, as an important research avenue for therapeutic targeting of the Wnt pathway in regenerative medicine has recently been opened. In this review, we discuss the recent findings on the regulation of Wnt components during aging, particularly in brain functioning, and the implications of Wnt signaling in age-related diseases.     

Wnt信号转导途径与髓母细胞瘤

髓母细胞瘤是多发于儿童小脑的恶性肿瘤,其预后很差。Wnt信号转导途径对多种生物发育、细胞的增殖和分化起着重要的作用,如异常表达或激活该途径会导致各种疾病甚至肿瘤发生。在经典Wnt途径中β-连环蛋白是其关键成员。Wnt蛋白与跨膜受体Fz蛋白结合后，破坏多蛋白降解复合物，积累的β-连环蛋白进入胞核与转录因子Tcf/Lef形成复合体，从而激活下游靶基因。目前研究表明Wnt信号转导途径与髓母细胞瘤的致癌作用密切相关。     

Wnt16b基因扩增影响细胞增殖及肿瘤微环境的研究进展

Wnt蛋白家族是一类在进化上高度保守的家族,与胚胎发育、器官分化相关,在细胞的生长、增殖、分化及凋亡等生物学行为方面发挥重要的调控作用.研究显示,Wnt信号通路紊乱与许多疾病尤其是肿瘤密切相关.Wnt16b作为Wnt蛋白家族的一员,在骨骼的生长分化过程中起关键作用.近年研究发现,Wnt16b基因在多种肿瘤组织中高扩增,提示Wnt16b基因可能在肿瘤的发展、迁移、化疗耐药等方面起重要作用.本文重点就Wnt16b基因扩增与细胞增殖及肿瘤微环境的关联研究进行综述.     

Wnt和Notch信号通路在肿瘤干细胞自我更新中的作用

肿瘤干细胞是一类能够导致肿瘤发生的具有自我更新能力的细胞，它与干细胞具有很多相似性，其中最重要的一点是自我更新能力。它们具有相似的自我更新调节通路，如：Wnt，Notch和Shh(Sonic hedgehog)。Wnt和Notch信号通路通过其受体和配体的相互作用在自我更新的增殖和分化中都起着重要的作用，两者均能促进干细胞增殖而抑制其分化，但各自侧重不同。此外，Wnt和Notch信号通路之间相互作用、协调共同完成干细胞的自我更新。对肿瘤干细胞的Wnt和Notch信号通路研究将为未来肿瘤的靶向治疗提供新的方向。