神经干细胞在神经系统疾病中的研究应用进展

随着神经干细胞理论的提出,为神经系统疾病的治疗带来了很大的希望。神经干细胞(NSCs)是指自我更新、且具有分化为神经元、星形胶质细胞、少突胶质细胞等多向分化潜能的细胞。当中枢神经系统受到损伤或退行性变时,内源性神经干细胞开始启动神经修复,但受到数量及微环境的影响,作用非常有限。近年,人们采用各种体外培养方法,可以获得一定数量的外源性神经干细胞,在神经干细胞移植治疗各种神经系统疾病,包括缺血性脑卒中、帕金森病、阿尔茨海默病和脊髓损伤等方面做了很多动物及临床前研究。本文综述神经干细胞移植在神经系统疾病治疗中的应用。     

神经干细胞向神经元分化调控的研究进展

神经干细胞是一类具有分裂潜能和自更新能力的母细胞,它可以通过对称分裂和不对称分裂方式产生神经组织的各类细胞,包括神经元、星形胶质细胞和少突胶质细胞。中枢神经系统受到损伤后,神经元和胶质细胞的损伤导致了临床症状,内源性神经干细胞的修复作用不大,原因是干细胞的数量有限,微环境的不允许。移植的神经干细胞进入体内后,由于受到多种因素的影响,常保持未分化状态或大部分分化为胶质细胞。神经干细胞向神经元分化的调控机制及其影响因素直接决定神经干细胞源性神经元的比例和神经元之间功能性突触的数量。现就其研究进展做一综述。     

缺氧预处理神经干细胞移植对大鼠急性脊髓损伤后神经胶质细胞凋亡及脊髓空洞形成的影响

目的:研究缺氧预处理神经干细胞(NSCs)移植对大鼠急性脊髓损伤(ASCI)后神经胶质细胞凋亡及脊髓空洞形成的影响。方法:将30只SD大鼠分为假手术对照组;脊髓损伤组;去铁敏组;普通NSCs组;缺氧预处理NSCs组。制成脊髓损伤模型,移植后观察脊髓神经胶质细胞凋亡情况及脊髓空洞形成情况。结果:经去铁敏缺氧预处理培养的NSCs与常规培养的NSCs无明显形态学变化。移植术后7d,缺氧预处理NSCs移植能显著减少脊髓损伤周围区神经胶质细胞的凋亡数量,减少脊髓空洞形成。结论:缺氧预处理NSCs移植能明显抑制大鼠急性脊髓损伤后神经胶质细胞凋亡,减少脊髓空洞的形成。     

缺氧预处理神经干细胞移植对大鼠急性脊髓损伤后神经胶质细胞凋亡及脊髓空洞形成的影响

目的:研究缺氧预处理神经干细胞(NSCs)移植对大鼠急性脊髓损伤(ASCI)后神经胶质细胞凋亡及脊髓空洞形成的影响.方法:将30只SD大鼠分为假手术对照组;脊髓损伤组;去铁敏组;普通NSCs组;缺氧预处理NSCs组.制成脊髓损伤模型,移植后观察脊髓神经胶质细胞凋亡情况及脊髓空洞形成情况.结果:经去铁敏缺氧预处理培养的NSCs与常规培养的NSCs无明显形态学变化.移植术后7d,缺氧预处理NSCs移植能显著减少脊髓损伤周围区神经胶质细胞的凋亡数量,减少脊髓空洞形成.结论:缺氧预处理NSCs移植能明显抑制大鼠急性脊髓损伤后神经胶质细胞凋亡,减少脊髓空洞的形成.     

小胶质细胞对神经干细胞调控机制的研究进展

脑损伤与神经炎症密切相关,小胶质细胞是这一过程中的关键因素。小胶质细胞可以获得促炎或抗炎的特性,但这如何影响神经干细胞 (NSCs)仍有争议。小胶质细胞在不同的条件下,可以极化为M1型小胶质细胞和M2型小胶质细胞。不同类型的小胶质细胞对NSCs的调控作用不同。但目前关于这方面的研究并未详细阐明具体的作用机制。本文就不同分化类型的小胶质细胞对NSCs调控机制的研究进展进行综述。     

神经干细胞激活的研究进展

神经干细胞是一类具有自我更新和多向分化潜能的细胞。在特定的条件下能够分化成神经元、星形胶质细胞和少突胶质细胞,从而参与神经发生和损伤修复。通常情况下,成体神经干细胞大多数处于静息状态。最新研究表明,在病理状况下,静息态的神经干细胞可以被激活,经增殖、迁移和分化,从而在损伤的部位进行神经元的再生和环路重建。该文主要对静息态和激活态神经干细胞的特征以及静息态神经干细胞激活的细胞和分子机制等方面进行了综述。     

神经干细胞的自我更新与衰老

近年来出现一种阐明机体衰老机制的新学说——干细胞衰老学说。虽然干细胞拥有极强的自我更新能力,但仍会出现衰老现象,且这种衰老通常是不可改变的。神经干细胞(NSCs)是神经系统中恒定存在的具有自我更新和多向分化潜能的一类原始细胞,它可以分化为神经元和多种胶质细胞。目前NSCs移植治疗神经退行性疾病和中枢神经系统损伤的研究已日渐深入,但因NSCs的自我更新及衰老等问题影响了NSCs的寿命及活力,从而导致移植的NSCs无法在体内长期存活,这是干细胞临床应用面临的一大难题,因此NSCs的自我更新及衰老问题正受到越来越多的学者和医生的关注。本文简要综述了NSCs自我更新与衰老机制的基础,旨在为NSCs临床应用及干细胞组织工程研究提供理论依据。     

自噬在神经干细胞中作用的研究进展

神经干细胞(neural stem cells,NSCs)移植是神经退行性疾病新的治疗途径,但移植细胞在动物模型的存活率和分化率需进一步提高。因此了解调节NSCs存活和死亡的机制,对于发展以干细胞移植为基础的治疗方法至关重要。自噬是维持细胞稳态的重要途径,可通过影响NSCs的存活和增殖等生物学行为进而改变NSCs的命运。本文就自噬和NSCs关系做一综述,从存活、凋亡、增殖和分化及其相关机制等方面展示自噬对NSCs命运的影响。     

人源胚胎神经干细胞移植可对抗大鼠的脑缺血/再灌注损伤

本文旨在研究人源胚胎神经干细胞(human embryonic neural stem cells,h NSCs)移植到脑缺血/再灌注损伤大鼠脑内后的迁移、分化,以及对大鼠脑卒中的疗效。我们在大脑中动脉栓塞(middle cerebral artery occlusion,MCAO)1 h的大鼠模型上,于血流再灌注后第7天注射h NSCs到缺血侧侧脑室,通过焦油紫染色测量大鼠的脑梗死体积,通过检测大鼠的感觉运动行为评估其神经功能的恢复水平,通过免疫荧光共标观察移植后的h NSCs在脑内的迁移与分化。结果显示,h NSCs移植后能够显著减小脑卒中大鼠脑梗死体积,并改善脑卒中大鼠的转棒、错步和转角等运动行为能力;侧脑室注射的h NSCs优先向胼胝体以及梗死区周边迁移,迁移到胼胝体的h NSCs可以分化成少突胶质细胞和星形胶质细胞,迁移到梗死区周边的细胞能够分化成神经元。以上这些结果提示,侧脑室移植的h NSCs可能通过向特定脑区的迁移和分化发挥对脑缺血/再灌注损伤大鼠的保护作用。     

神经干细胞的研究现状及运用前景

近年来的研究表明胚胎期和成年期动物的神经组织及人脑中可以分离出神经干细胞.神经干细胞能不断增殖并且具有分化成神经元、星型胶质细胞和少突胶质细胞的能力.神经干细胞的这种特性为中枢神经系统退行性病变和损伤的治疗打下了基础.对神经干细胞的分布、生物学特性、鉴定、增殖与分化及其治疗中枢神经系统疾病中的应用前景进行了综述.     

Adult neural stem cells bridge their niche

Major developments in the neural stem cell (NSC) field in recent years provide new insights into the nature of the NSC niche. In this perspective, we integrate recent anatomical data on the organization of the two main neurogenic niches in the adult brain, the ventricular-subventricular zone (V-SVZ) and the subgranular zone (SGZ), with signaling pathways that control the behavior of NSCs. NSCs in the adult brain stretch into physiologically distinct compartments of their niche. We propose how adult NSCs' morphology may allow these cells to integrate multiple signaling pathways arising from unique locations of their niche.     

Functional roles of glycoconjugates in the maintenance of stemness and differentiation process of neural stem cells

Neural stem cells (NSCs) possess a high proliferative potential and capacity for self-renewal with retention of multipotency to differentiate into brain-forming cells. NSCs have gained a considerable attention because of their potential application in treatment strategies on the basis of transplantation for neurodegenerative disorders and nerve injuries. Although several signaling pathways have been reportedly involved in the fate determination process of NSCs, the molecular mechanisms underlying the maintenance of neural cell stemness and differentiation process remain largely unknown. Glycoconjugates expressed in the NSC niche in the brain offer markers of NSCs; moreover, they serve as cell regulators, which are actively involved in the modulation of signal transduction. The glycans function on NCS surfaces by recruiting growth factor receptors to specific microdomains as components of glycolipids, thereby mediating the ligand–receptor interactions both indirectly and directly as components of proteoglycans and interacting with specific lectin-type receptors as components of ligand glycoproteins. In this review, we outline current knowledge of the possible functional mechanisms of glycoconjugates to determine cell fates, which are associated with their expression pattern and structural characteristic features.     

Developmental cues and persistent neurogenic potential within an <Emphasis Type="Italic">in vitro</Emphasis> neural niche

Background  

Neurogenesis, the production of neural cell-types from neural stem cells (NSCs), occurs during development as well as within select regions of the adult brain. NSCs in the adult subependymal zone (SEZ) exist in a well-categorized niche microenvironment established by surrounding cells and their molecular products. The components of this niche maintain the NSCs and their definitive properties, including the ability to self-renew and multipotency (neuronal and glial differentiation).     

Safrole oxide is a useful tool for investigating the effect of apoptosis in vascular endothelial cells on neural stem cell survival and differentiation in vitro

Previously, we found safrole oxide could promote VEC apoptosis, however, it is not known whether it can induce NSC apoptosis. It is reported that neural stem cells (NSCs) are localized in a vascular niche. But the effects of apoptosis in vascular endothelial cells (VEC) on NSC growth and differentiation are not clear. To answer these questions, in this study, we co-cultured NSCs with VECs in order to imitate the situation in vivo, in which NSCs are associated with the endothelium, and treated the single-cultured NSCs and the co-cultured NSCs with safrole oxide. The results showed that safrole oxide (10-100 microg/mL) had no effects on NSC growth. Based on these results, we treated the co-culture system with this small molecule. The results showed that the NSCs differentiation, into neurons and gliacytes was induced by VECs untreated with safrole oxide. But in the co-culture system treated with safrole oxide, the NSCs underwent apoptosis. The data suggested that when VEC apoptosis occurred in the co-culture system, the NSC survival and differentiation could not be maintained, and NSCs died by apoptosis. Our finding provided a useful tool for investigating the effect of apoptosis in vascular endothelial cells on neural stem cell survival and differentiation in vitro.     

NAAGS基因修饰神经干细胞在创伤性颅脑损伤治疗中的研究

目的：探讨移植NAAG合酶（NAAG synthetase,NAAGS）基因修饰的神经干细胞（Neural Stem Cells,NSCs）能否促进创伤性颅脑损伤大鼠神经功能的恢复。方法：利用电穿孔转染大鼠NSCs,通过脑立体定向仪分别将PBS（模型组）、NSCs（NSCs组）、转基因NSCs（NAAGS＋NSCs组）移植到创伤性颅脑损伤（Traumatic Brain Injury,TBI）大鼠局部损伤灶边缘,通过NSS评分评价移植后大鼠神经功能的变化以及用TUNEL法检测NSCs的凋亡情况,并采用放射免疫法分析脑组织中促炎因子水平。结果：Nss评分结果显示NAAGs＋NSCs组和NSCs组在第7、14、21天神经功能评分均低于模型组（P〈0．05）;NAAGS＋NSCs组在第14和21天神经功能评分低于NSCs组（P〈0．05）;在各时间点细胞移植组比模型组的神经细胞凋亡数明显减少;转基因NSCs移植能明显降低TBI脑组织中促炎因子水平。结论：转基因NSCs移植后可以合成NAAGS促进TBI大鼠神经功能的恢复。     

Age-dependent changes in the subcallosal zone neurogenesis of mice

There are several known neurogenic areas including subventricular zone and subgranular layer in the dentate gyrus of the hippocampus. Both germinal centers exhibit an age-dependent decline in cell proliferation and neurogenesis, which may be associated with age-related decline in brain function. We recently identified the subcallosal zone (SCZ) as a novel neural stem cell niche with a potential to spontaneously produce new neuroblasts. We examined whether SCZ neurogenesis is also regulated by the age of mice. The number of newly generated neuroblasts was reduced in the SCZ with age, and only marginal number of DCX-labeled neuroblasts was found in 6-month-old SCZ, which is most likely due to reduced proliferation of progenitor cells and loss of neural stem cells (NSCs). This age-dependent changes in the SCZ occurred earlier than that of other neurogenic brain regions. The neurosphere assay in vitro confirmed the depletion of NSCs within the SCZ of young adults. However, marked induction of neuroblast production in the SCZ was seen in 6-month-old mice after traumatic brain injury. Taken together, these results indicate that a rapid decline in SCZ neurogenesis in mice is due to depletion of NSCs and reduced capacity to produce neuroblasts.     

Neural stem cells: involvement in adult neurogenesis and CNS repair

Recent advances in stem cell research, including the selective expansion of neural stem cells (NSCs) in vitro, the induction of particular neural cells from embryonic stem cells in vitro, the identification of NSCs or NSC-like cells in the adult brain and the detection of neurogenesis in the adult brain (adult neurogenesis), have laid the groundwork for the development of novel therapies aimed at inducing regeneration in the damaged central nervous system (CNS). There are two major strategies for inducing regeneration in the damaged CNS: (i) activation of the endogenous regenerative capacity and (ii) cell transplantation therapy. In this review, we summarize the recent findings from our group and others on NSCs, with respect to their role in insult-induced neurogenesis (activation of adult NSCs, proliferation of transit-amplifying cells, migration of neuroblasts and survival and maturation of the newborn neurons), and implications for therapeutic interventions, together with tactics for using cell transplantation therapy to treat the damaged CNS.     

The Roles of Hypoxia-Inducible Factors in Regulating Neural Stem Cells Migration to Glioma Stem Cells and Determinating Their Fates

The mortality of patients with malignant gliomas remains high despite the advancement in multi-modal therapy including surgery, radio- and chemotherapy. Glioma stem cells (GSCs), sharing some characteristics with normal neural stem cells (NSCs), contribute to the cellular origin for primary gliomas and the recurrence of malignant gliomas after current conventional therapy. Accordingly, targeting GSCs proves to be a promising avenue of therapeutic intervention. The specific tropism of NSCs to GSCs provides a novel platform for targeted delivery of therapeutic agents. Tropism and mobilization of NSCs are enhanced by hypoxia through upregulating chemotactic cytokines and activating several signaling pathways. Moreover, hypoxia-inducible factors (HIFs) produced under hypoxic microenvironment of the stem cell niche play critical roles in the growth and stemness phenotypes regulation of both NSCs and GSCs. However, the definite cellular and molecular mechanisms of HIFs involvement in the process remain obscure. In this review, we focus on the pivotal roles of HIFs in migration of NSCs to GSCs and potential roles of HIFs in dictating the fates of migrated NSCs and targeted GSCs.