柔脑膜细胞具有神经干细胞特性的实验研究
|
摘要
长期以来脑膜被视为是仅具有保护作用的非神经组织,在结构和功能上与脑实质有本质的不同,但在上世纪90年代Mercier等应用形态学方法清晰地勾勒出柔脑膜细胞与脑实质内胶质细胞、神经元之间有网状的复杂联系,从而提出柔脑膜细胞参与脑内某些生理或病理过程的可能性,引发了对柔脑膜功能的深入思考。新近的一些研究发现:脑膜中的柔脑膜细胞(leptomeningeal cells)表达和分泌多种细胞因子和生物活性物质,参与中枢的免疫调节和诱导发育神经元的迁移定位,并与小脑功能的完善及脑内酶屏障的构成密切相关。
但是,柔脑膜细胞与神经元生长、分化的关系还存在争议。有研究认为柔脑膜细胞分泌的抑制神经突起生长的因子是神经元损伤后修复的障碍;也有研究指出柔脑膜细胞能分泌神经生长因子等多种促神经突起再生的因子,并作为滋养层支持神经干细胞的体外生长。新近的研究还注意到成年大鼠柔脑膜层有神经干细胞标记物Lex/ssea-1的表达。这些结果提示柔脑膜细胞与神经系统损伤修复、尤其与神经干细胞之间可能存在着某种特殊联系,为进一步探索柔脑膜细胞的功能提供了新思路。
针对以上问题,我们以柔脑膜细胞为研究对象,设计了五组实验,从在体和体外细胞培养的角度,结合应用柔脑膜铺片、细胞培养、免疫组织化学染色、免疫荧光标记、BrdU掺入实验、Western blot等研究方法,对柔脑膜细胞可能具有的神经干细胞特性做了初步探讨。第一组实验观察了正常成年以及不同生长发育期大鼠脑内柔脑膜细胞是否表达经典的神经干细胞标志巢蛋白(nestin);第二组实验在成功建立单纯柔脑膜细胞培养体系的基础上,检测了柔脑膜细胞能否表现出自我更新以及多向分化等神经干细胞的生物特性;第三组至第五组实验分别观察了不同调控因素(白细胞介素-6、抗抑郁药物以及机械损伤)对于柔脑膜来源神经干细胞增殖分化的影响。
主要结果有:
实验一
一、正常成年SD大鼠及Balb/c小鼠的柔脑膜层中均可检测到神经干细胞特异性标记物nestin的表达,但表达水平低,主要局限于脑腹侧及大脑镰两侧的脑膜组织。两种动物柔脑膜组织中阳性细胞的形态与分布存在差异。
二、不同生长发育期SD大鼠的柔脑膜细胞中nestin蛋白表达水平随生长发育呈进行性降低。柔脑膜铺片中除nestin/Thy1.1双标阳性的柔脑膜细胞外,也有GFAP/nestin阳性细胞存在。以上结果说明,不同生长发育期SD大鼠的柔脑膜细胞均可表达神经干细胞标志nestin,即具有神经前体细胞的增殖潜能,但此潜能随生长发育而进行性减弱。
实验二
一、比较脑膜组织在不同培养条件下柔脑膜细胞的纯度,发现以DMEM/5%FCS/5%HS培养时,培养体系中除柔脑膜细胞外,还存在约30%的星形胶质细胞和少量神经元;以DMEM/1%FCS/9%HS培养时,柔脑膜细胞纯度达90%以上,几乎没有神经元沾染。后者继续传代可使其纯度达97%以上,仅有极少数星形胶质细胞存活。结果提示改变培养条件及多次传代是建立单纯柔脑膜细胞体系的有效方法。
二、检测单纯培养的柔脑膜细胞是否具有神经干细胞的基本生物学特性。发现:给予含生长因子EGF/bFGF的无血清条件性培养基后,柔脑膜细胞可自我增殖形成神经球样结构,其成球性呈bFGF浓度依赖性;再以胎牛血清诱导分化,可见除Thy1.1阳性的柔脑膜细胞外,还可分化为β-tubulin III、GFAP、RIP阳性的神经元及胶质细胞;并且柔脑膜细胞经多次传代仍可形成克隆球及多向分化,但能力逐渐减弱。
以上结果说明,间充质来源的柔脑膜细胞经体外分离培养后能够表现出自我更新以及多向分化等神经干细胞的基本生物学特性,并可分化形成神经元。
实验三
一、白细胞介素-6(IL-6)可以诱导柔脑膜来源的神经球向神经元及胶质细胞多向分化,并显著提高分化神经元的比例。以多种神经元标记物鉴定分化神经元性质,提示其为5-HT阳性的未成熟神经元。
二、免疫细胞化学染色及Western blotting结果均提示,IL-6孵育可显著上调其自身受体(IL-6Rα及gp130)在柔脑膜来源神经球内的表达,为柔脑膜细胞感受IL-6信号并发生应答反应提供了形态学基础。
三、上述体系中,IL-6也引起磷酸化ERK1/2及STAT3分子在柔脑膜来源神经球中的表达。而分别给予其特异性抑制剂PD98059及AG490后,发现ERK1/2通路磷酸化的抑制可影响神经球向神经元及胶质细胞的分化,而STAT3通路磷酸化的抑制则以星形胶质细胞分化的受抑为主。同时, STAT3分子磷酸化提示gp130处于活化状态。
以上结果说明,细胞因子IL-6可促进柔脑膜来源神经干细胞向神经元分化,而分化神经元呈5-HT反应阳性。IL-6刺激引起了其自身受体及磷酸化ERK1/2及STAT3信号分子在该细胞体系中的表达,提示上述细胞内分子机制可能参与了柔脑膜细胞向神经元、胶质细胞的分化。
实验四
一、以抗抑郁药物西酞普兰孵育柔脑膜来源的神经球,发现:西酞普兰能够维持神经球的克隆化生长、促进细胞增殖,并引起细胞内ERK1/2、STAT3信号分子磷酸化;以信号通路抑制剂预处理的结果显示,西酞普兰诱导细胞增殖的效应表现为ERK1/2通路依赖性。
二、观察西酞普兰孵育对柔脑膜来源的已贴壁分化的神经干细胞的影响,发现:西酞普兰可促进神经干细胞继续分化,并显著上调分化神经元的比例;同时也引起了分化细胞内磷酸化ERK1/2、STAT3分子的表达。以信号通路抑制剂预处理的结果显示,上述体系中神经元和胶质细胞的分化分别表现为ERK1/2或STAT3通路依赖性。
以上结果说明,西酞普兰可以诱导柔脑膜来源神经干细胞的增殖,也可促进其向神经元分化。但是调控细胞增殖分化的机制不同,分别表现为ERK1/2通路或ERK1/2及STAT3通路依赖性。
实验五
一、建立柔脑膜细胞的体外机械损伤模型,检测机械损伤对细胞增殖及逆分化的影响。结果显示:划伤刺激促进了柔脑膜细胞增殖,但不能诱导其表达nestin蛋白;而含生长因子的无血清条件性培养基可诱导损伤细胞形成神经球,后者在血清存在时向神经元及胶质细胞分化。
二、观察损伤的柔脑膜细胞对正常星形胶质细胞增殖及逆分化的影响,发现:损伤的柔脑膜细胞可以诱导正常星形胶质细胞增殖并表达nestin,后者也可形成神经球并向神经元、胶质细胞分化。
以上结果说明,机械损伤虽然不能直接诱导柔脑膜细胞分化为神经前体细胞,但可以刺激细胞分泌某些活性物质,诱导与之共培养的星形胶质细胞增殖并逆分化为神经前体细胞。并且,细胞微环境对于细胞能否表现出神经干细胞特性具有重要意义。
结论
本研究从不同的角度证实:起源于间充质组织的柔脑膜细胞能够表现出神经干细胞的基本特性,自我增殖并在适当条件下分化为神经元、星形胶质细胞和少突胶质细胞;不同性质的刺激(细胞因子、抗抑郁药物以及机械损伤等)可调控其增殖分化;神经系统损伤时,柔脑膜细胞可能分泌活性物质而参与诱导脑内内源性神经干细胞的增殖活化。根据以上结果,我们提出了脑膜细胞可能是脑内潜在的神经干细胞的观点。这些初步发现将为我们更加全面、深入地认识柔脑膜细胞的功能奠定了基础,为神经损伤后的干细胞修复提供了新的思路。
Traditionally, meninges have been thought to be only a protective apparatus and structurally and functionally separated from brain parenchyma. In 1990s, Mercier et al challenged this prevailing view by using immunohistochemical methods to vividly mark the cellular network formed by leptomeningeal cells, glial cells and neurons. This conception of meningeo-glial network calls for a reconsideration of the role of meninges and appears to reflect the possibility of leptomeningeal cells’involvement in physiological or pathological processes in CNS. Increasing evidences show that meninges are composed by various cells besides fibroblasts, which facilitate their complicated functions. Leptomeningeal cell, a special kind of fibroblast-like cell in CNS, has become a hot topic. For example, it is recognized that leptomeningeal cells can express and secret various cytokines and biological molecules, participate in the neuroimmunomodulation in CNS, be actively involved in neuronal cells differentiation and migration, and play key role in cerebellum maturation and enzyme-barrier constitution.
However, the role of leptomeningeal cells in inducing neuronal growth and differentiation is still unclear. Some researchers held the opinion that leptomeningeal cells produced inhibiting molecules to form the barriers of neural regeneration. In contrast, other evidences demonstrated that leptomeningeal cells mainly promote the neurites growth by secreting neurotrophic factors, such as neural growth factors, and served as“feeder-layers”to sustain the proliferation of neural stem cells. Recently, it was showed that Lex/ssea-1, a specific marker for neural stem cell, was also expressed by cells in leptomeninges in adult rats. All of these results indicate that leptomeningeal cells might play special roles in neurogenesis and interact with neural stem cells, unveiling the study of leptomeningeal cells’characteristics and novel potentials.
Accordingly, aiming to elucidate the possible identity of leptomeningeal cells as neural stem cells, we designed five sets of experiments in this study, which were made on animal models and cultured cells, respectively. The methods used were leptomeningeal wholemount preparation, cell culture, immunohistochemistry, immunofluorescence, BrdU incorporation and Western blotting analysis. In the first part of study, we detected the expression of nestin protein, a specific marker for neural stem cell, by the leptomeningeal cells in rats of different developmental stages. In the second part of study, after establishment of a relatively pure culture system of leptomeningeal cells, we detected whether these cells could exhibit self-renewal and differentiation potentials. Then in the following experiments, we observed the effects of three kinds of regulation factors, which included interleukin-6, anti-depression drugs and mechanical injury respectively, on the proliferation and differentiation of leptomeninges-derived neural stem cells.
The main results are as follows:
Part One
1.It was showed that leptomeningeal cells in adult SD rats and adult Balb/c mice could express nestin, a specific marker for neural stem cell. However, the expression level was quite low and the positive cells were only limited in special location of leptomeninges, mainly referred to which overlaid on the ventral brain and cerebral falx. In addition, the morphology and the distribution of positive cells in leptomeninges were different between two species of animals.
2.It was detected that leptomeningeal cells expressed nestin in rats at different developmental stages and the expression level diminished gradually as development advancing. Moreover, we found that cells in wholemount preparation were not only double-immunostained by nestin/Thy1.1, but also by GFAP/nestin.
These results indicate that nestin, a specific marker for neural stem cells, could be expressed by leptomeningeal cells in rats of different developmental stages. That is to say, leptomeningeal cells possessed stem cell-like proliferation potential, although this feature was diminished as the development advancing
Part Two
1.After leptomeningeal cells were cultured in different condition, we compared the purity and cellular property in these culture systems. When cultured in DMEM containing 5% FCS and 5% HS, leptomeningeal cells were mixed with 30% of astrocytes and few neurons, But in DMEM/1%FCS/9%HS, the leptomeningeal cells accounted for more than 90% of the total cells and glia and neurons were rarely seen. In addition, sequential passages of the latter system improved the cellular purity to more than 97% and only a few astrocytes were found in this culture system. Therefore, changing media and passage during culture processes were effective to establish a pure culture system for leptomeningeal cells.
2.Accordingly, we detected whether cultured leptomeningeal cells could exhibit essential characteristics of neural stem cell. The results showed that in the presence of EGF/bFGF containing serum-free conditioned medium, leptomeningeal cells proliferated to develop into neurosphere-like morphology. This process was in a bFGF-dependent manner. Then serum administration induced these leptomeningeal cells to differentiate into the neuronal and glial lineage cells, marked byβ-tubulinIII, GFAP and RIP respectively. Moreover, it was showed that after repetitious passages, leptomeningeal cells still generated neurospheres and multipotentially differentiated, though such capacity declined gradually.
These results indicate that the mesenchyma-derived leptomeningeal cells possess the capacity of neural stem cell to self-renew and differentiate multipotentially, especially producing neurons.
Part Three
1.It was revealed that Interleukin-6 administration not only led the leptomeninges-derived neurospheres to generate neurons and glial cells, but also elevated the percentage of neuronal lineage cells. Then using different neuronal markers, these newly formed neurons were found to be 5-HT positive immature neurons.
2.It was revealed by the immunocytochemical and Western blotting results that IL-6 administration up-regulated the expression of its own receptor(sIL-6Rαand gp130)in these leptomeninges-derived neurospheres. In this regard, the presence of IL-6 receptors enabled cells to sense and react to IL-6 stimulation.
3.In above system, IL-6 also induced the phosphorylation of ERK1/2 and STAT3 molecules in the cells. Then we administrated pharmacological inhibitors individually before IL-6 incubation, as PD98059 and AG490. It was revealed that PD98059 pre-treatment decreased the generation of neurons and glial cells, while AG490 administration only down-regulated the GFAP level. In addition, the phosphorylation of STAT3 molecules also indicated the activation of gp130.
These data suggest that IL-6 could promote the differentiation of leptomeninges-derived neural stem cell into neurons, which were mainly serotonergic immature neurons. In addition, IL-6 administration increases the expression of its own receptors and the phosphorylation of signal molecules, ERK1/2 and STAT3, in these cells. Thus, these molecules may cooperatively involve in the differentiation of leptomeninges-derived neurospheres induced by IL-6 stimulation.
Part Four
1 . After incubated the leptomeninges-derived neurospheres with citalopram, one kind of anti-depression drugs, we detected that citalopram not only supported the clonal morphology and the proliferation of cells, but also induced the phosphorylation of ERK1/2 and STAT3 signal molecules. Moreover, using pharmacological inhibitors of these two molecules further indicated an ERK1/2-dependent effect of citalopram on the cellular proliferation.
2.On the other hand, we also detected an effect of citalopram on the differentiation potentials of leptomeninges-derived neural stem cells. It was showed that when the neurospheres had attached to the coverslip and tended to differentiate, citalopram administration could not only significantly promote their differentiation processes, but also improve the neurogenesis. Similarly, it induced the phosphorylation of ERK1/2 and STAT3 in these cells, while the gliogenesis and neurogenesis exhibited these two pathways related manner respectively.
These data suggest that citalopram could promote the proliferation and neurogenesis of leptomeninges-derived neural stem cells. But the regulation mechanisms are quite different. In other word, the cellular proliferation involves ERK1/2 pathways only, while the differentiation is dependent on both pathways.
Part Five
1.We established a leptomeningeal cells’mechanical injury model and examined the capacity of these cells to proliferate or de-differentiate. It was revealed that, though the injury promoted the proliferation of cells, the expression of nestin couldn’t be detected simultaneously in these cells. However, in this injury model, cells were found to be able to generate neurospheres in the presence of growth factors containing serum-free medium, and differentiate into neuronal or glial lineage cells when re-incubated with serum.
2.To explore the effects of injured leptomeningeal cells on the normal astrocytes, we co-cultured these two cells to detect the latter cells’capacity of proliferation and de-differentiation. It was showed that normal astrocytes could proliferate and express nestin protein in the presence of injured leptomeningeal cells. In addition, astrocytes in this system could also develop into neurospheres and then generate neurons or glial cells when cultured in serum-free or serum containing medium respectively.
These results indicate that though the mechanical injury couldn’t induce the leptomeningeal cells to de-differentiate into neural progenitors directly, it increases the production of certain diffusible factors by the cells which then induced the de-differentiation and proliferation of astrocytes. Moreover, the environmental factors play key roles in directing cells to exhibit neural stem cell-like potentials.
Conclusion
It can be verified by the present study that the mesenchyma-derived leptomeningeal cells possess the essential characteristics of neural stem cells. They can self-renew and proliferate, and then differentiate mutipotentially into neuronal and glial lineage cells under certain circumstances. In addition, different kinds of stimuli, such as cytokines, anti-depression drugs and mechanical injury, can involve in their proliferation or differentiation processes. Also, injury may lead the leptomeningeal cells to secret some factors to induce the activation and proliferation of neural stem cells in situ in CNS. In a word, it is helpful for us to establish a comprehensive and in-depth understanding of leptomeningeal cells’functions, which will well ground their clinical application.
但是,柔脑膜细胞与神经元生长、分化的关系还存在争议。有研究认为柔脑膜细胞分泌的抑制神经突起生长的因子是神经元损伤后修复的障碍;也有研究指出柔脑膜细胞能分泌神经生长因子等多种促神经突起再生的因子,并作为滋养层支持神经干细胞的体外生长。新近的研究还注意到成年大鼠柔脑膜层有神经干细胞标记物Lex/ssea-1的表达。这些结果提示柔脑膜细胞与神经系统损伤修复、尤其与神经干细胞之间可能存在着某种特殊联系,为进一步探索柔脑膜细胞的功能提供了新思路。
针对以上问题,我们以柔脑膜细胞为研究对象,设计了五组实验,从在体和体外细胞培养的角度,结合应用柔脑膜铺片、细胞培养、免疫组织化学染色、免疫荧光标记、BrdU掺入实验、Western blot等研究方法,对柔脑膜细胞可能具有的神经干细胞特性做了初步探讨。第一组实验观察了正常成年以及不同生长发育期大鼠脑内柔脑膜细胞是否表达经典的神经干细胞标志巢蛋白(nestin);第二组实验在成功建立单纯柔脑膜细胞培养体系的基础上,检测了柔脑膜细胞能否表现出自我更新以及多向分化等神经干细胞的生物特性;第三组至第五组实验分别观察了不同调控因素(白细胞介素-6、抗抑郁药物以及机械损伤)对于柔脑膜来源神经干细胞增殖分化的影响。
主要结果有:
实验一
一、正常成年SD大鼠及Balb/c小鼠的柔脑膜层中均可检测到神经干细胞特异性标记物nestin的表达,但表达水平低,主要局限于脑腹侧及大脑镰两侧的脑膜组织。两种动物柔脑膜组织中阳性细胞的形态与分布存在差异。
二、不同生长发育期SD大鼠的柔脑膜细胞中nestin蛋白表达水平随生长发育呈进行性降低。柔脑膜铺片中除nestin/Thy1.1双标阳性的柔脑膜细胞外,也有GFAP/nestin阳性细胞存在。以上结果说明,不同生长发育期SD大鼠的柔脑膜细胞均可表达神经干细胞标志nestin,即具有神经前体细胞的增殖潜能,但此潜能随生长发育而进行性减弱。
实验二
一、比较脑膜组织在不同培养条件下柔脑膜细胞的纯度,发现以DMEM/5%FCS/5%HS培养时,培养体系中除柔脑膜细胞外,还存在约30%的星形胶质细胞和少量神经元;以DMEM/1%FCS/9%HS培养时,柔脑膜细胞纯度达90%以上,几乎没有神经元沾染。后者继续传代可使其纯度达97%以上,仅有极少数星形胶质细胞存活。结果提示改变培养条件及多次传代是建立单纯柔脑膜细胞体系的有效方法。
二、检测单纯培养的柔脑膜细胞是否具有神经干细胞的基本生物学特性。发现:给予含生长因子EGF/bFGF的无血清条件性培养基后,柔脑膜细胞可自我增殖形成神经球样结构,其成球性呈bFGF浓度依赖性;再以胎牛血清诱导分化,可见除Thy1.1阳性的柔脑膜细胞外,还可分化为β-tubulin III、GFAP、RIP阳性的神经元及胶质细胞;并且柔脑膜细胞经多次传代仍可形成克隆球及多向分化,但能力逐渐减弱。
以上结果说明,间充质来源的柔脑膜细胞经体外分离培养后能够表现出自我更新以及多向分化等神经干细胞的基本生物学特性,并可分化形成神经元。
实验三
一、白细胞介素-6(IL-6)可以诱导柔脑膜来源的神经球向神经元及胶质细胞多向分化,并显著提高分化神经元的比例。以多种神经元标记物鉴定分化神经元性质,提示其为5-HT阳性的未成熟神经元。
二、免疫细胞化学染色及Western blotting结果均提示,IL-6孵育可显著上调其自身受体(IL-6Rα及gp130)在柔脑膜来源神经球内的表达,为柔脑膜细胞感受IL-6信号并发生应答反应提供了形态学基础。
三、上述体系中,IL-6也引起磷酸化ERK1/2及STAT3分子在柔脑膜来源神经球中的表达。而分别给予其特异性抑制剂PD98059及AG490后,发现ERK1/2通路磷酸化的抑制可影响神经球向神经元及胶质细胞的分化,而STAT3通路磷酸化的抑制则以星形胶质细胞分化的受抑为主。同时, STAT3分子磷酸化提示gp130处于活化状态。
以上结果说明,细胞因子IL-6可促进柔脑膜来源神经干细胞向神经元分化,而分化神经元呈5-HT反应阳性。IL-6刺激引起了其自身受体及磷酸化ERK1/2及STAT3信号分子在该细胞体系中的表达,提示上述细胞内分子机制可能参与了柔脑膜细胞向神经元、胶质细胞的分化。
实验四
一、以抗抑郁药物西酞普兰孵育柔脑膜来源的神经球,发现:西酞普兰能够维持神经球的克隆化生长、促进细胞增殖,并引起细胞内ERK1/2、STAT3信号分子磷酸化;以信号通路抑制剂预处理的结果显示,西酞普兰诱导细胞增殖的效应表现为ERK1/2通路依赖性。
二、观察西酞普兰孵育对柔脑膜来源的已贴壁分化的神经干细胞的影响,发现:西酞普兰可促进神经干细胞继续分化,并显著上调分化神经元的比例;同时也引起了分化细胞内磷酸化ERK1/2、STAT3分子的表达。以信号通路抑制剂预处理的结果显示,上述体系中神经元和胶质细胞的分化分别表现为ERK1/2或STAT3通路依赖性。
以上结果说明,西酞普兰可以诱导柔脑膜来源神经干细胞的增殖,也可促进其向神经元分化。但是调控细胞增殖分化的机制不同,分别表现为ERK1/2通路或ERK1/2及STAT3通路依赖性。
实验五
一、建立柔脑膜细胞的体外机械损伤模型,检测机械损伤对细胞增殖及逆分化的影响。结果显示:划伤刺激促进了柔脑膜细胞增殖,但不能诱导其表达nestin蛋白;而含生长因子的无血清条件性培养基可诱导损伤细胞形成神经球,后者在血清存在时向神经元及胶质细胞分化。
二、观察损伤的柔脑膜细胞对正常星形胶质细胞增殖及逆分化的影响,发现:损伤的柔脑膜细胞可以诱导正常星形胶质细胞增殖并表达nestin,后者也可形成神经球并向神经元、胶质细胞分化。
以上结果说明,机械损伤虽然不能直接诱导柔脑膜细胞分化为神经前体细胞,但可以刺激细胞分泌某些活性物质,诱导与之共培养的星形胶质细胞增殖并逆分化为神经前体细胞。并且,细胞微环境对于细胞能否表现出神经干细胞特性具有重要意义。
结论
本研究从不同的角度证实:起源于间充质组织的柔脑膜细胞能够表现出神经干细胞的基本特性,自我增殖并在适当条件下分化为神经元、星形胶质细胞和少突胶质细胞;不同性质的刺激(细胞因子、抗抑郁药物以及机械损伤等)可调控其增殖分化;神经系统损伤时,柔脑膜细胞可能分泌活性物质而参与诱导脑内内源性神经干细胞的增殖活化。根据以上结果,我们提出了脑膜细胞可能是脑内潜在的神经干细胞的观点。这些初步发现将为我们更加全面、深入地认识柔脑膜细胞的功能奠定了基础,为神经损伤后的干细胞修复提供了新的思路。
Traditionally, meninges have been thought to be only a protective apparatus and structurally and functionally separated from brain parenchyma. In 1990s, Mercier et al challenged this prevailing view by using immunohistochemical methods to vividly mark the cellular network formed by leptomeningeal cells, glial cells and neurons. This conception of meningeo-glial network calls for a reconsideration of the role of meninges and appears to reflect the possibility of leptomeningeal cells’involvement in physiological or pathological processes in CNS. Increasing evidences show that meninges are composed by various cells besides fibroblasts, which facilitate their complicated functions. Leptomeningeal cell, a special kind of fibroblast-like cell in CNS, has become a hot topic. For example, it is recognized that leptomeningeal cells can express and secret various cytokines and biological molecules, participate in the neuroimmunomodulation in CNS, be actively involved in neuronal cells differentiation and migration, and play key role in cerebellum maturation and enzyme-barrier constitution.
However, the role of leptomeningeal cells in inducing neuronal growth and differentiation is still unclear. Some researchers held the opinion that leptomeningeal cells produced inhibiting molecules to form the barriers of neural regeneration. In contrast, other evidences demonstrated that leptomeningeal cells mainly promote the neurites growth by secreting neurotrophic factors, such as neural growth factors, and served as“feeder-layers”to sustain the proliferation of neural stem cells. Recently, it was showed that Lex/ssea-1, a specific marker for neural stem cell, was also expressed by cells in leptomeninges in adult rats. All of these results indicate that leptomeningeal cells might play special roles in neurogenesis and interact with neural stem cells, unveiling the study of leptomeningeal cells’characteristics and novel potentials.
Accordingly, aiming to elucidate the possible identity of leptomeningeal cells as neural stem cells, we designed five sets of experiments in this study, which were made on animal models and cultured cells, respectively. The methods used were leptomeningeal wholemount preparation, cell culture, immunohistochemistry, immunofluorescence, BrdU incorporation and Western blotting analysis. In the first part of study, we detected the expression of nestin protein, a specific marker for neural stem cell, by the leptomeningeal cells in rats of different developmental stages. In the second part of study, after establishment of a relatively pure culture system of leptomeningeal cells, we detected whether these cells could exhibit self-renewal and differentiation potentials. Then in the following experiments, we observed the effects of three kinds of regulation factors, which included interleukin-6, anti-depression drugs and mechanical injury respectively, on the proliferation and differentiation of leptomeninges-derived neural stem cells.
The main results are as follows:
Part One
1.It was showed that leptomeningeal cells in adult SD rats and adult Balb/c mice could express nestin, a specific marker for neural stem cell. However, the expression level was quite low and the positive cells were only limited in special location of leptomeninges, mainly referred to which overlaid on the ventral brain and cerebral falx. In addition, the morphology and the distribution of positive cells in leptomeninges were different between two species of animals.
2.It was detected that leptomeningeal cells expressed nestin in rats at different developmental stages and the expression level diminished gradually as development advancing. Moreover, we found that cells in wholemount preparation were not only double-immunostained by nestin/Thy1.1, but also by GFAP/nestin.
These results indicate that nestin, a specific marker for neural stem cells, could be expressed by leptomeningeal cells in rats of different developmental stages. That is to say, leptomeningeal cells possessed stem cell-like proliferation potential, although this feature was diminished as the development advancing
Part Two
1.After leptomeningeal cells were cultured in different condition, we compared the purity and cellular property in these culture systems. When cultured in DMEM containing 5% FCS and 5% HS, leptomeningeal cells were mixed with 30% of astrocytes and few neurons, But in DMEM/1%FCS/9%HS, the leptomeningeal cells accounted for more than 90% of the total cells and glia and neurons were rarely seen. In addition, sequential passages of the latter system improved the cellular purity to more than 97% and only a few astrocytes were found in this culture system. Therefore, changing media and passage during culture processes were effective to establish a pure culture system for leptomeningeal cells.
2.Accordingly, we detected whether cultured leptomeningeal cells could exhibit essential characteristics of neural stem cell. The results showed that in the presence of EGF/bFGF containing serum-free conditioned medium, leptomeningeal cells proliferated to develop into neurosphere-like morphology. This process was in a bFGF-dependent manner. Then serum administration induced these leptomeningeal cells to differentiate into the neuronal and glial lineage cells, marked byβ-tubulinIII, GFAP and RIP respectively. Moreover, it was showed that after repetitious passages, leptomeningeal cells still generated neurospheres and multipotentially differentiated, though such capacity declined gradually.
These results indicate that the mesenchyma-derived leptomeningeal cells possess the capacity of neural stem cell to self-renew and differentiate multipotentially, especially producing neurons.
Part Three
1.It was revealed that Interleukin-6 administration not only led the leptomeninges-derived neurospheres to generate neurons and glial cells, but also elevated the percentage of neuronal lineage cells. Then using different neuronal markers, these newly formed neurons were found to be 5-HT positive immature neurons.
2.It was revealed by the immunocytochemical and Western blotting results that IL-6 administration up-regulated the expression of its own receptor(sIL-6Rαand gp130)in these leptomeninges-derived neurospheres. In this regard, the presence of IL-6 receptors enabled cells to sense and react to IL-6 stimulation.
3.In above system, IL-6 also induced the phosphorylation of ERK1/2 and STAT3 molecules in the cells. Then we administrated pharmacological inhibitors individually before IL-6 incubation, as PD98059 and AG490. It was revealed that PD98059 pre-treatment decreased the generation of neurons and glial cells, while AG490 administration only down-regulated the GFAP level. In addition, the phosphorylation of STAT3 molecules also indicated the activation of gp130.
These data suggest that IL-6 could promote the differentiation of leptomeninges-derived neural stem cell into neurons, which were mainly serotonergic immature neurons. In addition, IL-6 administration increases the expression of its own receptors and the phosphorylation of signal molecules, ERK1/2 and STAT3, in these cells. Thus, these molecules may cooperatively involve in the differentiation of leptomeninges-derived neurospheres induced by IL-6 stimulation.
Part Four
1 . After incubated the leptomeninges-derived neurospheres with citalopram, one kind of anti-depression drugs, we detected that citalopram not only supported the clonal morphology and the proliferation of cells, but also induced the phosphorylation of ERK1/2 and STAT3 signal molecules. Moreover, using pharmacological inhibitors of these two molecules further indicated an ERK1/2-dependent effect of citalopram on the cellular proliferation.
2.On the other hand, we also detected an effect of citalopram on the differentiation potentials of leptomeninges-derived neural stem cells. It was showed that when the neurospheres had attached to the coverslip and tended to differentiate, citalopram administration could not only significantly promote their differentiation processes, but also improve the neurogenesis. Similarly, it induced the phosphorylation of ERK1/2 and STAT3 in these cells, while the gliogenesis and neurogenesis exhibited these two pathways related manner respectively.
These data suggest that citalopram could promote the proliferation and neurogenesis of leptomeninges-derived neural stem cells. But the regulation mechanisms are quite different. In other word, the cellular proliferation involves ERK1/2 pathways only, while the differentiation is dependent on both pathways.
Part Five
1.We established a leptomeningeal cells’mechanical injury model and examined the capacity of these cells to proliferate or de-differentiate. It was revealed that, though the injury promoted the proliferation of cells, the expression of nestin couldn’t be detected simultaneously in these cells. However, in this injury model, cells were found to be able to generate neurospheres in the presence of growth factors containing serum-free medium, and differentiate into neuronal or glial lineage cells when re-incubated with serum.
2.To explore the effects of injured leptomeningeal cells on the normal astrocytes, we co-cultured these two cells to detect the latter cells’capacity of proliferation and de-differentiation. It was showed that normal astrocytes could proliferate and express nestin protein in the presence of injured leptomeningeal cells. In addition, astrocytes in this system could also develop into neurospheres and then generate neurons or glial cells when cultured in serum-free or serum containing medium respectively.
These results indicate that though the mechanical injury couldn’t induce the leptomeningeal cells to de-differentiate into neural progenitors directly, it increases the production of certain diffusible factors by the cells which then induced the de-differentiation and proliferation of astrocytes. Moreover, the environmental factors play key roles in directing cells to exhibit neural stem cell-like potentials.
Conclusion
It can be verified by the present study that the mesenchyma-derived leptomeningeal cells possess the essential characteristics of neural stem cells. They can self-renew and proliferate, and then differentiate mutipotentially into neuronal and glial lineage cells under certain circumstances. In addition, different kinds of stimuli, such as cytokines, anti-depression drugs and mechanical injury, can involve in their proliferation or differentiation processes. Also, injury may lead the leptomeningeal cells to secret some factors to induce the activation and proliferation of neural stem cells in situ in CNS. In a word, it is helpful for us to establish a comprehensive and in-depth understanding of leptomeningeal cells’functions, which will well ground their clinical application.
引文
[1] Mercier F, Hatton GI: Immunocytochemical basis for a meningeo-glial network. J Comp Neurol 2000, 420(4):445-465.
[2] Super H, Martinez A, Soriano E: Degeneration of Cajal-Retzius cells in the developing cerebral cortex of the mouse after ablation of meningeal cells by 6-hydroxydopamine. Brain Res Dev Brain Res 1997, 98(1):15-20.
[3] 周永志,张世明: 脑膜的合成及分泌功能. 国外医学神经病学神经外科学分册 2004, 31:575-578.
[4] 蔡文琴 李: 发育神经生物学. 北京: 科学出版社; 1999.
[5] 刘斌 高: 人体胚胎学. 北京: 人民卫生出版社; 1996.
[6] 杨琳,高英茂(主译): 格氏解剖学. 沈阳: 辽宁教育出版社; 1999.
[7] Mitsikostas DD, Sanchez del Rio M: Receptor systems mediating c-fos expression within trigeminal nucleus caudalis in animal models of migraine. Brain Res Brain Res Rev 2001, 35(1):20-35.
[8] De Col R, Koulchitsky SV, Messlinger KB: Nitric oxide synthase inhibition lowers activity of neurons with meningeal input in the rat spinal trigeminal nucleus. Neuroreport 2003, 14(2):229-232.
[9] Webb AA: Potential sources of neck and back pain in clinical conditions of dogs and cats: a review. Vet J 2003, 165(3):193-213.
[10] Zhang ET, Inman CB, Weller RO: Interrelationships of the pia mater and the perivascular (Virchow-Robin) spaces in the human cerebrum. J Anat 1990, 170:111-123.
[11] Hutchings M, Weller RO: Anatomical relationships of the pia mater to cerebral blood vessels in man. J Neurosurg 1986, 65(3):316-325.
[12] Greenberg RW, Lane EL, Cinnamon J, Farmer P, Hyman RA: The cranial meninges: anatomic considerations. Semin Ultrasound CT MR 1994, 15(6):454-465.
[13] Grossman SA, Krabak MJ: Leptomeningeal carcinomatosis. Cancer Treat Rev 1999, 25(2):103-119.
[14] Colombo JA, Napp MI, Puissant V: Leptomeningeal and skin fibroblasts: two different cell types? Int J Dev Neurosci 1994, 12(1):57-61.
[15] Kaplan GP, Hartman BK, Creveling CR: Immunohistochemical localization ofcatechol-O-methyltransferase in circumventricular organs of the rat: potential variations in the blood-brain barrier to native catechols. Brain Res 1981, 229(2):323-335.
[16] Kern C, Mautz DS, Bernards CM: Epinephrine is metabolized by the spinal meninges of monkeys and pigs. Anesthesiology 1995, 83(5):1078-1081.
[17] Zajac JM, Charnay Y, Soleilhic JM, Sales N, Roques BP: Enkephalin-degrading enzymes and angiotensin-converting enzyme in human and rat meninges. FEBS Lett 1987, 216(1):118-122.
[18] Lopez-Figueroa MO, Day HE, Lee S, Rivier C, Akil H, Watson SJ: Temporal and anatomical distribution of nitric oxide synthase mRNA expression and nitric oxide production during central nervous system inflammation. Brain Res 2000, 852(1):239-246.
[19] McCann SM, Licinio J, Wong ML, Yu WH, Karanth S, Rettorri V: The nitric oxide hypothesis of aging. Exp Gerontol 1998, 33(7-8):813-826.
[20] Kluge WH, Kluge HH, Hochstetter A, Vollandt R, Seidel F, Venbrocks R: Acetylcholinesterase in lumbar and ventricular cerebrospinal fluid. Clin Chim Acta 2001, 305(1-2):55-63.
[21] Hartlage-Rubsamen M, Lemke R, Schliebs R: Interleukin-1beta, inducible nitric oxide synthase, and nuclear factor-kappaB are induced in morphologically distinct microglia after rat hippocampal lipopolysaccharide/interferon-gamma injection. J Neurosci Res 1999, 57(3):388-398.
[22] Ebersberger A: Physiology of meningeal innervation: aspects and consequences of chemosensitivity of meningeal nociceptors. Microsc Res Tech 2001, 53(2):138-146.
[23] Lehtimaki KA, Peltola J, Koskikallio E, Keranen T, Honkaniemi J: Expression of cytokines and cytokine receptors in the rat brain after kainic acid-induced seizures. Brain Res Mol Brain Res 2003, 110(2):253-260.
[24] Fricke B, Andres KH, Von During M: Nerve fibers innervating the cranial and spinal meninges: morphology of nerve fiber terminals and their structural integration. Microsc Res Tech 2001, 53(2):96-105.
[25] Yoshida K, Gage FH: Fibroblast growth factors stimulate nerve growth factor synthesis and secretion by astrocytes. Brain Res 1991, 538(1):118-126.
[26] Struckhoff G: Transforming growth factor beta 1 and parathyroid hormone-related protein control the secretion of dipeptidyl peptidase II by rat astrocytes. NeurosciLett 1995, 189(2):117-120.
[27] Reiss K, Mentlein R, Sievers J, Hartmann D: Stromal cell-derived factor 1 is secreted by meningeal cells and acts as chemotactic factor on neuronal stem cells of the cerebellar external granular layer. Neuroscience 2002, 115(1):295-305.
[28] Struckhoff G: Cocultures of meningeal and astrocytic cells--a model for the formation of the glial-limiting membrane. Int J Dev Neurosci 1995, 13(6):595-606.
[29] Niclou SP, Franssen EH, Ehlert EM, Taniguchi M, Verhaagen J: Meningeal cell-derived semaphorin 3A inhibits neurite outgrowth. Mol Cell Neurosci 2003, 24(4):902-912.
[30] Fawcett JW, Asher RA: The glial scar and central nervous system repair. Brain Res Bull 1999, 49(6):377-391.
[31] Wujek JR, Akeson RA: Extracellular matrix derived from astrocytes stimulates neuritic outgrowth from PC12 cells in vitro. Brain Res 1987, 431(1):87-97.
[32] Ishikawa K, Kabeya K, Shinoda M, Katakai K, Mori M, Tatemoto K: Meninges play a neurotrophic role in the regeneration of vasopressin nerves after hypophysectomy. Brain Res 1995, 677(1):20-28.
[33] Webb K, Budko E, Neuberger TJ, Chen S, Schachner M, Tresco PA: Substrate-bound human recombinant L1 selectively promotes neuronal attachment and outgrowth in the presence of astrocytes and fibroblasts. Biomaterials 2001, 22(10):1017-1028.
[34] Takano M, Horie M, Narahara M, Miyake M, Okamoto H: Expression of kininogen mRNAs and plasma kallikrein mRNA by cultured neurons, astrocytes and meningeal cells in the rat brain. Immunopharmacology 1999, 45(1-3):121-126.
[35] Tamura S, Morikawa Y, Senba E: Localization of oncostatin M receptor beta in adult and developing CNS. Neuroscience 2003, 119(4):991-997.
[36] Ganfornina MD, Sanchez D, Pagano A, Tonachini L, Descalzi-Cancedda F, Martinez S: Molecular characterization and developmental expression pattern of the chicken apolipoprotein D gene: implications for the evolution of vertebrate lipocalins. Dev Dyn 2005, 232(1):191-199.
[37] Hartmann D, Ziegenhagen MW, Sievers J: Meningeal cells stimulate neuronal migration and the formation of radial glial fascicles from the cerebellar external granular layer. Neurosci Lett 1998, 244(3):129-132.
[38] von Knebel Doeberitz C, Sievers J, Sadler M, Pehlemann FW, Berry M, Halliwell P: Destruction of meningeal cells over the newborn hamster cerebellum with6-hydroxydopamine prevents foliation and lamination in the rostral cerebellum. Neuroscience 1986, 17(2):409-426.
[39] Ishikawa K, Ohe Y, Tatemoto K: Synthesis and secretion of insulin-like growth factor (IGF)-II and IGF binding protein-2 by cultivated brain meningeal cells. Brain Res 1995, 697(1-2):122-129.
[40] Brettschneider J, Riepe MW, Petereit HF, Ludolph AC, Tumani H: Meningeal derived cerebrospinal fluid proteins in different forms of dementia: is a meningopathy involved in normal pressure hydrocephalus? J Neurol Neurosurg Psychiatry 2004, 75(11):1614-1616.
[41] Choo A, Padmanabhan J, Chin A, Fong WJ, Oh SK: Immortalized feeders for the scale-up of human embryonic stem cells in feeder and feeder-free conditions. J Biotechnol 2006, 122(1):130-141.
[42] Hayashi H, Morizane A, Koyanagi M, Ono Y, Sasai Y, Hashimoto N, Takahashi J: Meningeal cells induce dopaminergic neurons from embryonic stem cells. Eur J Neurosci 2008, 27(2):261-268.
[43] Khademhosseini A, Ferreira L, Blumling J, 3rd, Yeh J, Karp JM, Fukuda J, Langer R: Co-culture of human embryonic stem cells with murine embryonic fibroblasts on microwell-patterned substrates. Biomaterials 2006, 27(36):5968-5977.
[44] Xie CQ, Lin G, Yuan D, Wang J, Liu TC, Lu GX: Proliferative feeder cells support prolonged expansion of human embryonic stem cells. Cell Biol Int 2005, 29(8):623-628.
[45] Capela A, Temple S: LeX/ssea-1 is expressed by adult mouse CNS stem cells, identifying them as nonependymal. Neuron 2002, 35(5):865-875.
[46] Feurer DJ, Weller RO: Barrier functions of the leptomeninges: a study of normal meninges and meningiomas in tissue culture. Neuropathol Appl Neurobiol 1991, 17(5):391-405.
[47] Krahn V: Leukodiapedesis and leukocyte migration in the leptomeninges and in the subarachnoid space. J Neurol 1981, 226(1):43-52.
[48] van Dam AM, Poole S, Schultzberg M, Zavala F, Tilders FJ: Effects of peripheral administration of LPS on the expression of immunoreactive interleukin-1 alpha, beta, and receptor antagonist in rat brain. Ann N Y Acad Sci 1998, 840:128-138.
[49] Quan N, Stern EL, Whiteside MB, Herkenham M: Induction of pro-inflammatory cytokine mRNAs in the brain after peripheral injection of subseptic doses of lipopolysaccharide in the rat. J Neuroimmunol 1999, 93(1-2):72-80.
[50] Xia Y, Krukoff TL: Differential neuronal activation in the hypothalamic paraventricular nucleus and autonomic/neuroendocrine responses to I.C.V. endotoxin. Neuroscience 2003, 121(1):219-231.
[51] Polentarutti N, Bottazzi B, Di Santo E, Blasi E, Agnello D, Ghezzi P, Introna M, Bartfai T, Richards G, Mantovani A: Inducible expression of the long pentraxin PTX3 in the central nervous system. J Neuroimmunol 2000, 106(1-2):87-94.
[52] Proescholdt MG, Chakravarty S, Foster JA, Foti SB, Briley EM, Herkenham M: Intracerebroventricular but not intravenous interleukin-1beta induces widespread vascular-mediated leukocyte infiltration and immune signal mRNA expression followed by brain-wide glial activation. Neuroscience 2002, 112(3):731-749.
[53] Konsman JP, Tridon V, Dantzer R: Diffusion and action of intracerebroventricularly injected interleukin-1 in the CNS. Neuroscience 2000, 101(4):957-967.
[54] Plunkett JA, Yu CG, Easton JM, Bethea JR, Yezierski RP: Effects of interleukin-10 (IL-10) on pain behavior and gene expression following excitotoxic spinal cord injury in the rat. Exp Neurol 2001, 168(1):144-154.
[55] Schiltz JC, Sawchenko PE: Distinct brain vascular cell types manifest inducible cyclooxygenase expression as a function of the strength and nature of immune insults. J Neurosci 2002, 22(13):5606-5618.
[56] Cao C, Matsumura K, Yamagata K, Watanabe Y: Endothelial cells of the rat brain vasculature express cyclooxygenase-2 mRNA in response to systemic interleukin-1 beta: a possible site of prostaglandin synthesis responsible for fever. Brain Res 1996, 733(2):263-272.
[57] Muraki T, Fujimori K, Ishizaka M, Ohe Y, Urade Y, Okajima F, Ishikawa K: Effects of interleukin-1beta and prostaglandin E2 on prostaglandin D synthase production in cultivated rat leptomeningeal cells. J Cereb Blood Flow Metab 2004, 24(4):409-418.
[58] Fujimori K, Fujitani Y, Kadoyama K, Kumanogoh H, Ishikawa K, Urade Y: Regulation of lipocalin-type prostaglandin D synthase gene expression by Hes-1 through E-box and interleukin-1 beta via two NF-kappa B elements in rat leptomeningeal cells. J Biol Chem 2003, 278(8):6018-6026.
[59] Herkenham M, Lee HY, Baker RA: Temporal and spatial patterns of c-fos mRNA induced by intravenous interleukin-1: a cascade of non-neuronal cellular activation at the blood-brain barrier. J Comp Neurol 1998, 400(2):175-196.
[60] Gonzalez-Gonzalez IM, Cubelos B, Gimenez C, Zafra F: Immunohistochemicallocalization of the amino acid transporter SNAT2 in the rat brain. Neuroscience 2005, 130(1):61-73.
[61] McMenamin PG, Wealthall RJ, Deverall M, Cooper SJ, Griffin B: Macrophages and dendritic cells in the rat meninges and choroid plexus: three-dimensional localisation by environmental scanning electron microscopy and confocal microscopy. Cell Tissue Res 2003, 313(3):259-269.
[62] Matyszak MK, Perry VH: The potential role of dendritic cells in immune-mediated inflammatory diseases in the central nervous system. Neuroscience 1996, 74(2):599-608.
[63] Ibrahim MA, Chain BM, Katz DR: The injured cell: the role of the dendritic cell system as a sentinel receptor pathway. Immunol Today 1995, 16(4):181-186.
[64] Lowenstein PR: Immunology of viral-vector-mediated gene transfer into the brain: an evolutionary and developmental perspective. Trends Immunol 2002, 23(1):23-30.
[65] Pashenkov M, Link H: Dendritic cells and immune responses in the central nervous system. Trends Immunol 2002, 23(2):69-70; author reply 70.
[66] Rozniecki JJ, Dimitriadou V, Lambracht-Hall M, Pang X, Theoharides TC: Morphological and functional demonstration of rat dura mater mast cell-neuron interactions in vitro and in vivo. Brain Res 1999, 849(1-2):1-15.
[67] Reuter U, Bolay H, Jansen-Olesen I, Chiarugi A, Sanchez del Rio M, Letourneau R, Theoharides TC, Waeber C, Moskowitz MA: Delayed inflammation in rat meninges: implications for migraine pathophysiology. Brain 2001, 124(Pt 12):2490-2502.
[68] Serviere J, Dubayle D, Menetrey D: Increase of rat medial habenular mast cell numbers by systemic administration of cyclophosphamide. Toxicol Lett 2003, 145(2):143-152.
[69] Theoharides TC, Dimitriadou V, Letourneau R, Rozniecki JJ, Vliagoftis H, Boucher W: Synergistic action of estradiol and myelin basic protein on mast cell secretion and brain myelin changes resembling early stages of demyelination. Neuroscience 1993, 57(3):861-871.
[70] Goldman SA, Nottebohm F: Neuronal production, migration, and differentiation in a vocal control nucleus of the adult female canary brain. Proc Natl Acad Sci U S A 1983, 80(8):2390-2394.
[71] Richards LJ, Kilpatrick TJ, Bartlett PF: De novo generation of neuronal cells fromthe adult mouse brain. Proc Natl Acad Sci U S A 1992, 89(18):8591-8595.
[72] Reynolds BA, Weiss S: Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system. Science 1992, 255(5052):1707-1710.
[73] Eriksson PS, Perfilieva E, Bjork-Eriksson T, Alborn AM, Nordborg C, Peterson DA, Gage FH: Neurogenesis in the adult human hippocampus. Nat Med 1998, 4(11):1313-1317.
[74] Johansson CB, Svensson M, Wallstedt L, Janson AM, Frisen J: Neural stem cells in the adult human brain. Exp Cell Res 1999, 253(2):733-736.
[75] Gage FH: Mammalian neural stem cells. Science 2000, 287(5457):1433-1438.
[76] Thomas LB, Gates MA, Steindler DA: Young neurons from the adult subependymal zone proliferate and migrate along an astrocyte, extracellular matrix-rich pathway. Glia 1996, 17(1):1-14.
[77] Bjorklund A, Lindvall O: Self-repair in the brain. Nature 2000, 405(6789):892-893, 895.
[78] Tureyen K, Vemuganti R, Sailor KA, Bowen KK, Dempsey RJ: Transient focal cerebral ischemia-induced neurogenesis in the dentate gyrus of the adult mouse. J Neurosurg 2004, 101(5):799-805.
[79] Tzeng SF, Wu JP: Responses of microglia and neural progenitors to mechanical brain injury. Neuroreport 1999, 10(11):2287-2292.
[80] Doetsch F, Caille I, Lim DA, Garcia-Verdugo JM, Alvarez-Buylla A: Subventricular zone astrocytes are neural stem cells in the adult mammalian brain. Cell 1999, 97(6):703-716.
[81] Abe K: Therapeutic potential of neurotrophic factors and neural stem cells against ischemic brain injury. J Cereb Blood Flow Metab 2000, 20(10):1393-1408.
[82] Kondo T, Raff M: Oligodendrocyte precursor cells reprogrammed to become multipotential CNS stem cells. Science 2000, 289(5485):1754-1757.
[83] Bjornson CR, Rietze RL, Reynolds BA, Magli MC, Vescovi AL: Turning brain into blood: a hematopoietic fate adopted by adult neural stem cells in vivo. Science 1999, 283(5401):534-537.
[84] Clarke DL, Johansson CB, Wilbertz J, Veress B, Nilsson E, Karlstrom H, Lendahl U, Frisen J: Generalized potential of adult neural stem cells. Science 2000, 288(5471):1660-1663.
[85] Andrades JA, Han B, Becerra J, Sorgente N, Hall FL, Nimni ME: A recombinant human TGF-beta1 fusion protein with collagen-binding domain promotesmigration, growth, and differentiation of bone marrow mesenchymal cells. Exp Cell Res 1999, 250(2):485-498.
[86] Lendahl U, Zimmerman LB, McKay RD: CNS stem cells express a new class of intermediate filament protein. Cell 1990, 60(4):585-595.
[87] Almazan G, Vela JM, Molina-Holgado E, Guaza C: Re-evaluation of nestin as a marker of oligodendrocyte lineage cells. Microsc Res Tech 2001, 52(6):753-765.
[88] Dahlstrand J, Zimmerman LB, McKay RD, Lendahl U: Characterization of the human nestin gene reveals a close evolutionary relationship to neurofilaments. J Cell Sci 1992, 103 ( Pt 2):589-597.
[89] Lothian C, Lendahl U: An evolutionarily conserved region in the second intron of the human nestin gene directs gene expression to CNS progenitor cells and to early neural crest cells. Eur J Neurosci 1997, 9(3):452-462.
[90] Pekny M, Johansson CB, Eliasson C, Stakeberg J, Wallen A, Perlmann T, Lendahl U, Betsholtz C, Berthold CH, Frisen J: Abnormal reaction to central nervous system injury in mice lacking glial fibrillary acidic protein and vimentin. J Cell Biol 1999, 145(3):503-514.
[91] Vaittinen S, Lukka R, Sahlgren C, Rantanen J, Hurme T, Lendahl U, Eriksson JE, Kalimo H: Specific and innervation-regulated expression of the intermediate filament protein nestin at neuromuscular and myotendinous junctions in skeletal muscle. Am J Pathol 1999, 154(2):591-600.
[92] Sosunov AA, Chelyshev Iu A, McKhann G, Krugliakov PP, Balykova OP, Shikhanov NP: [Neurogenesis in the adult mammalian brain]. Ontogenez 2002, 33(6):405-420.
[93] Xu Y, Tamamaki N, Noda T, Kimura K, Itokazu Y, Matsumoto N, Dezawa M, Ide C: Neurogenesis in the ependymal layer of the adult rat 3rd ventricle. Exp Neurol 2005, 192(2):251-264.
[94] Ernst C, Christie BR: The putative neural stem cell marker, nestin, is expressed in heterogeneous cell types in the adult rat neocortex. Neuroscience 2006, 138(1):183-188.
[95] Yue F, Chen B, Wu D, Dong K, Zeng SE, Zhang Y: Biological properties of neural progenitor cells isolated from the hippocampus of adult cynomolgus monkeys. Chin Med J (Engl) 2006, 119(2):110-116.
[96] Li Y, Chopp M: Temporal profile of nestin expression after focal cerebral ischemia in adult rat. Brain Res 1999, 838(1-2):1-10.
[97] Tonchev AB, Yamashima T, Zhao L, Okano HJ, Okano H: Proliferation of neural and neuronal progenitors after global brain ischemia in young adult macaque monkeys. Mol Cell Neurosci 2003, 23(2):292-301.
[98] Krugliakova EP, Khovriakov AV, Shikhanov NP, McKhann IG, Vael I, Krugliakov PP, Sosunov AA: [Nestin-expressing cells in the human hippocampus]. Morfologiia 2004, 126(6):19-25.
[99] Shih CC, Weng Y, Mamelak A, LeBon T, Hu MC, Forman SJ: Identification of a candidate human neurohematopoietic stem-cell population. Blood 2001, 98(8):2412-2422.
[100] Craig CG, Tropepe V, Morshead CM, Reynolds BA, Weiss S, van der Kooy D: In vivo growth factor expansion of endogenous subependymal neural precursor cell populations in the adult mouse brain. J Neurosci 1996, 16(8):2649-2658.
[101] Kalyani AJ, Mujtaba T, Rao MS: Expression of EGF receptor and FGF receptor isoforms during neuroepithelial stem cell differentiation. J Neurobiol 1999, 38(2):207-224.
[102] Kuhn HG, Winkler J, Kempermann G, Thal LJ, Gage FH: Epidermal growth factor and fibroblast growth factor-2 have different effects on neural progenitors in the adult rat brain. J Neurosci 1997, 17(15):5820-5829.
[103] Brickman YG, Ford MD, Gallagher JT, Nurcombe V, Bartlett PF, Turnbull JE: Structural modification of fibroblast growth factor-binding heparan sulfate at a determinative stage of neural development. J Biol Chem 1998, 273(8):4350-4359.
[104] Wozniak W: Brain-derived neurotrophic factor (BDNF): role in neuronal development and survival. Folia Morphol (Warsz) 1993, 52(4):173-181.
[105] Kim DH, Jahng TA: Continuous brain-derived neurotrophic factor (BDNF) infusion after methylprednisolone treatment in severe spinal cord injury. J Korean Med Sci 2004, 19(1):113-122.
[106] Brown A, Ricci MJ, Weaver LC: NGF message and protein distribution in the injured rat spinal cord. Exp Neurol 2004, 188(1):115-127
[107] Galli R, Pagano SF, Gritti A, Vescovi AL: Regulation of neuronal differentiation in human CNS stem cell progeny by leukemia inhibitory factor. Dev Neurosci 2000, 22(1-2):86-95.
[108] Ling ZD, Potter ED, Lipton JW, Carvey PM: Differentiation of mesencephalic progenitor cells into dopaminergic neurons by cytokines. Exp Neurol 1998, 149(2):411-423.
[109] Gomes WA, Mehler MF, Kessler JA: Transgenic overexpression of BMP4 increases astroglial and decreases oligodendroglial lineage commitment. Dev Biol 2003, 255(1):164-177.
[110] Chenn A, Walsh CA: Regulation of cerebral cortical size by control of cell cycle exit in neural precursors. Science 2002, 297(5580):365-369.
[111] Turnley AM, Bartlett PF: Cytokines that signal through the leukemia inhibitory factor receptor-beta complex in the nervous system. J Neurochem 2000, 74(3):889-899.
[112] Molne M, Studer L, Tabar V, Ting YT, Eiden MV, McKay RD: Early cortical precursors do not undergo LIF-mediated astrocytic differentiation. J Neurosci Res 2000, 59(3):301-311
[113] Erlandsson A, Enarsson M, Forsberg-Nilsson K: Immature neurons from CNS stem cells proliferate in response to platelet-derived growth factor. J Neurosci 2001, 21(10):3483-3491.
[114] Takahashi J, Palmer TD, Gage FH: Retinoic acid and neurotrophins collaborate to regulate neurogenesis in adult-derived neural stem cell cultures. J Neurobiol 1999, 38(1):65-81.
[115] Amoureux MC, Cunningham BA, Edelman G.M, Crossin KL: N-CAM binding inhibits the proliferation of hippocampal progenitor cells and promotes their differentiation to a neuronal phenotype. J Neurosci 2000, 20(10):3631-3640.
[116] Bruno L, Hoffmann R, McBlane F, Brown J, Gupta R, Joshi C, Pearson S, Seidl T, Heyworth C, Enver T: Molecular signatures of self-renewal, differentiation, and lineage choice in multipotential hemopoietic progenitor cells in vitro. Mol Cell Biol 2004, 24(2):741-756.
[117] Carvey PM, Ling ZD, Sortwell CE, Pitzer MR, McGuire SO, Storch A, Collier TJ: A clonal line of mesencephalic progenitor cells converted to dopamine neurons by hematopoietic cytokines: a source of cells for transplantation in Parkinson's disease. Exp Neurol 2001, 171(1):98-108.
[118] Namiki J, Tator CH: Cell proliferation and nestin expression in the ependyma of the adult rat spinal cord after injury. J Neuropathol Exp Neurol 1999, 58(5):489-498.
[119] Armstrong RJ, Barker RA: Neurodegeneration: a failure of neuroregeneration? Lancet 2001, 358(9288):1174-1176.
[120] Jin K, Peel AL, Mao XO, Xie L, Cottrell BA, Henshall DC, Greenberg DA: Increased hippocampal neurogenesis in Alzheimer's disease. Proc Natl Acad Sci US A 2004, 101(1):343-347.
[121] Snyder EY, Taylor RM, Wolfe JH: Neural progenitor cell engraftment corrects lysosomal storage throughout the MPS VII mouse brain. Nature 1995, 374(6520):367-370.
[122] Wexler E, Palmer T: Where, oh where, have my stem cells gone? Trends Neurosci 2002, 25(5):225-227.
[123] Petroske E, Meredith GE, Callen S, Totterdell S, Lau YS: Mouse model of Parkinsonism: a comparison between subacute MPTP and chronic MPTP/probenecid treatment. Neuroscience 2001, 106(3):589-601.
[124] Kay JN, Blum M: Differential response of ventral midbrain and striatal progenitor cells to lesions of the nigrostriatal dopaminergic projection. Dev Neurosci 2000, 22(1-2):56-67.
[125] Peterson DA: Stem cells in brain plasticity and repair. Curr Opin Pharmacol 2002, 2(1):34-42.
[126] Nakatomi H, Kuriu T, Okabe S, Yamamoto S, Hatano O, Kawahara N, Tamura A, Kirino T, Nakafuku M: Regeneration of hippocampal pyramidal neurons after ischemic brain injury by recruitment of endogenous neural progenitors. Cell 2002, 110(4):429-441.
[127] Takagi Y, Nozaki K, Takahashi J, Yodoi J, Ishikawa M, Hashimoto N: Proliferation of neuronal precursor cells in the dentate gyrus is accelerated after transient forebrain ischemia in mice. Brain Res 1999, 831(1-2):283-287.
[128] 陈东风,杜少辉,李伊为: 龟板对局灶性脑缺血再灌注后 Nestin 表达的影响. 解剖学杂志 2002, 25(4):315-319.
[129] 程龙,朱培纯,司银楚: 三七总皂甙对去大脑皮层血管后成年大鼠前脑侧脑室室管膜下层 Nestin 和 bFGF 表达的作用. 北京中医药大学学报 2003, 26(3):18-20.
[130] 杜少辉,张悦,黄洁: 牛珀至宝微丸对局灶性脑缺血再灌注后 Nestin 表达的影响. 中国中医基础医学杂志 2002, 8(10):17-21.
[131] Dash PK,. Mach SA, Moore AN: Enhanced neurogenesis in the rodent hippocampus following traumatic brain injury. J Neurosci Res 2001, 63(4):313-319.
[132] Hagan M, Wennersten A, Meijer X, Holmin S, Wahlberg L, Mathiesen T: Neuroprotection by human neural progenitor cells after experimental contusion inrats. Neurosci Lett 2003, 351(3):149-152.
[133] Svendsen CN, Caldwell MA, Shen J, ter Borg MG, Rosser AE, Tyers P, Karmiol S, Dunnett SB: Long-term survival of human central nervous system progenitor cells transplanted into a rat model of Parkinson's disease. Exp Neurol 1997, 148(1):135-146.
[134] Benedetti S, Pirola B, Pollo B, Magrassi L, Bruzzone MG, Rigamonti D, Galli R, Selleri S, Di Meco F, De Fraja C, Vescovi A, Cattaneo E, Finocchiaro G: Gene therapy of experimental brain tumors using neural progenitor cells. Nat Med 2000, 6(4):447-450.
[135] Aboody KS, Brown A, Rainov NG, Bower KA, Liu S, Yang W, Small JE, Herrlinger U, Ourednik V, Black PM, Breakefield XO, Snyder EY: Neural stem cells display extensive tropism for pathology in adult brain: evidence from intracranial gliomas. Proc Natl Acad Sci U S A 2000, 97(23):12846-12851.
[136] Prockop DJ: Marrow stromal cells as stem cells for nonhematopoietic tissues. Science 1997, 276(5309):71-74.
[137] Kopen GC, Prockop DJ, Phinney DG: Marrow stromal cells migrate throughout forebrain and cerebellum, and they differentiate into astrocytes after injection into neonatal mouse brains. Proc Natl Acad Sci U S A 1999, 96(19):10711-10716.
[138] Brazelton TR, Rossi FM, Keshet GI, Blau HM: From marrow to brain: expression of neuronal phenotypes in adult mice. Science 2000, 290(5497):1775-1779.
[139] Mezey E, Chandross KJ, Harta G, Maki RA, McKercher SR: Turning blood into brain: cells bearing neuronal antigens generated in vivo from bone marrow. Science 2000, 290(5497):1779-1782.
[140] Li Y, Chopp M, Chen J, Wang L, Gautam SC, Xu YX, Zhang Z: Intrastriatal transplantation of bone marrow nonhematopoietic cells improves functional recovery after stroke in adult mice. J Cereb Blood Flow Metab 2000, 20(9):1311-1319.
[141] Chen J, Li Y, Wang L, Zhang Z, Lu D, Lu M, Chopp M: Therapeutic benefit of intravenous administration of bone marrow stromal cells after cerebral ischemia in rats. Stroke 2001, 32(4):1005-1011
[142] Sanchez-Ramos J, Song S, Cardozo-Pelaez F, Hazzi C, Stedeford T, Willing A, Freeman TB, Saporta S, Janssen W, Patel N, Cooper DR, Sanberg PR: Adult bone marrow stromal cells differentiate into neural cells in vitro. Exp Neurol 2000, 164(2):247-256.
[143] Woodbury D, Schwarz EJ, Prockop DJ, Black IB: Adult rat and human bone marrow stromal cells differentiate into neurons. J Neurosci Res 2000, 61(4):364-370.
[144] Deng W, Obrocka M, Fischer I, Prockop DJ: In vitro differentiation of human marrow stromal cells into early progenitors of neural cells by conditions that increase intracellular cyclic AMP. Biochem Biophys Res Commun 2001, 282(1):148-152.
[145] Hofstetter CP, Schwarz EJ, Hess D, Widenfalk J, Manira AE, Prockop DJ, Olson L: Marrow stromal cells form guiding strands in the injured spinal cord and promote recovery. Proc Natl Acad Sci U S A 2002, 99(4):2199-2204.
[146] Wurmser AE, Gage FH: Stem cells: cell fusion causes confusion. Nature 2002, 416(6880):485-487.
[147] Condorelli G., Borello U, De Angelis L, Latronico M, Sirabella D, Coletta M, Galli R, Balconi G, Follenzi A, Frati G, Cusella De Angelis MG, Gioglio L, Amuchastegui S, Adorini L, Naldini L, Vescovi A, Dejana E, Cossu G: Cardiomyocytes induce endothelial cells to trans-differentiate into cardiac muscle: implications for myocardium regeneration. Proc Natl Acad Sci U S A 2001, 98(19):10733-10738.
[148] Ying QL, Nichols J, Evans EP, Smith AG: Changing potency by spontaneous fusion. Nature 2002, 416(6880):545-548.
[149] Terada N, Hamazaki T, Oka M, Hoki M, Mastalerz DM, Nakano Y, Meyer EM, Morel L, Petersen BE, Scott EW: Bone marrow cells adopt the phenotype of other cells by spontaneous cell fusion. Nature 2002, 416(6880):542-545.
[150] Hassan-Zahraee M, Ladiwala U, Lavoie PM, McCrea E, Sekaly RP, Owens T, Antel JP: Superantigen presenting capacity of human astrocytes. J Neuroimmunol 2000, 102(2):131-136.
[151] LeBlanc AC, Chen HY, Autilio-Gambetti L, Gambetti P: Differential APP gene expression in rat cerebral cortex, meninges, and primary astroglial, microglial and neuronal cultures. FEBS Lett 1991, 292(1-2):171-178.
[152] Matsuguchi T, Musikacharoen T, Ogawa T, Yoshikai Y: Gene expressions of Toll-like receptor 2, but not Toll-like receptor 4, is induced by LPS and inflammatory cytokines in mouse macrophages. J Immunol 2000, 165(10):5767-5772.
[153] Triantafilou M, Triantafilou K: Lipopolysaccharide recognition: CD14, TLRs andthe LPS-activation cluster. Trends Immunol 2002, 23(6):301-304.
[154] Nockher WA, Wick M, Pfister HW: Cerebrospinal fluid levels of soluble CD14 in inflammatory and non-inflammatory diseases of the CNS: upregulation during bacterial infections and viral meningitis. J Neuroimmunol 1999, 101(2):161-169.
[155] Martin MU, Wesche H: Summary and comparison of the signaling mechanisms of the Toll/interleukin-1 receptor family. Biochim Biophys Acta 2002, 1592(3):265-280.
[156] Grossman SA, Krabak MJ: Leptomeningeal carcinomatosis. Cancer Treat Rev 1999, 25(2):103-119.
[157] Bianchi G, Banfi A, Mastrogiacomo M, Notaro R, Luzzatto L, Cancedda R, Quarto R: Ex vivo enrichment of mesenchymal cell progenitors by fibroblast growth factor 2. Exp Cell Res 2003, 287(1):98-105.
[158] Laskowski A, Schmidt W, Dinkel K, Martinez-Sanchez M, Reymann KG: bFGF and EGF modulate trauma-induced proliferation and neurogenesis in juvenile organotypic hippocampal slice cultures. Brain Res 2005, 1037(1-2):78-89.
[159] Lachapelle F, Avellana-Adalid V, Nait-Oumesmar B, Baron-Van Evercooren A: Fibroblast growth factor-2 (FGF-2) and platelet-derived growth factor AB (PDGF AB) promote adult SVZ-derived oligodendrogenesis in vivo. Mol Cell Neurosci 2002, 20(3):390-403.
[160] Ciccolini F, Svendsen CN: Fibroblast growth factor 2 (FGF-2) promotes acquisition of epidermal growth factor (EGF) responsiveness in mouse striatal precursor cells: identification of neural precursors responding to both EGF and FGF-2. J Neurosci 1998, 18(19):7869-7880.
[161] Liu IH, Chen SJ, Ku HH, Kao CL, Tsai FT, Hsu WM, Lo CW, Kuo YH, Kuo CD, Lee CH, Chiou SH: Comparison of the proliferation and differentiation ability between adult rat retinal stem cells and cerebral cortex-derived neural stem cells. Ophthalmologica 2005, 219(3):171-176.
[162] Balasubramaniyan V, de Haas AH, Bakels R, Koper A, Boddeke HW, Copray JC: Functionally deficient neuronal differentiation of mouse embryonic neural stem cells in vitro. Neurosci Res 2004, 49(2):261-265.
[163] Ren W, Guo Q, Yang Y, Chen F: bFGF and heparin but not laminin are necessary factors in the mediums that affect NSCs differentiation into cholinergic neurons. Neurol Res 2006, 28(1):87-90.
[164] Barkho BZ, Song H, Aimone JB, Smrt RD, Kuwabara T, Nakashima K, Gage FH,Zhao X: Identification of astrocyte-expressed factors that modulate neural stem/progenitor cell differentiation. Stem Cells Dev 2006, 15(3):407-421.
[165] Mondal D, Pradhan L, LaRussa VF: Signal transduction pathways involved in the lineage-differentiation of NSCs: can the knowledge gained from blood be used in the brain? Cancer Invest 2004, 22(6):925-943.
[166] Taga T, Fukuda S: Role of IL-6 in the neural stem cell differentiation. Clin Rev Allergy Immunol 2005, 28(3):249-256.
[167] Pitman M, Emery B, Binder M, Wang S, Butzkueven H, Kilpatrick TJ: LIF receptor signaling modulates neural stem cell renewal. Mol Cell Neurosci 2004, 27(3):255-266.
[168] Oshima K, Teo DT, Senn P, Starlinger V, Heller S: LIF promotes neurogenesis and maintains neural precursors in cell populations derived from spiral ganglion stem cells. BMC Dev Biol 2007, 7:112.
[169] Koblar SA, Turnley AM, Classon BJ, Reid KL, Ware CB, Cheema SS, Murphy M, Bartlett PF: Neural precursor differentiation into astrocytes requires signaling through the leukemia inhibitory factor receptor. Proc Natl Acad Sci U S A 1998, 95(6):3178-3181.
[170] Emsley JG., Hagg T: Endogenous and exogenous ciliary neurotrophic factor enhances forebrain neurogenesis in adult mice. Exp Neurol 2003, 183(2):298-310.
[171] Shimazaki T, Shingo T, Weiss S: The ciliary neurotrophic factor/leukemia inhibitory factor/gp130 receptor complex operates in the maintenance of mammalian forebrain neural stem cells. J Neurosci 2001, 21(19):7642-7653.
[172] Sammons J, Ahmed N, El-Sheemy M, Hassan HT: The role of BMP-6, IL-6, and BMP-4 in mesenchymal stem cell-dependent bone development: effects on osteoblastic differentiation induced by parathyroid hormone and vitamin D(3). Stem Cells Dev 2004, 13(3):273-280.
[173] Jin G, Tan X, Tian M, Qin J, Zhu H, Huang Z, Xu H: The controlled differentiation of human neural stem cells into TH-immunoreactive (ir) neurons in vitro. Neurosci Lett 2005, 386(2):105-110.
[174] Dziewczapolski G, Lie DC, Ray J, Gage FH, Shults CW: Survival and differentiation of adult rat-derived neural progenitor cells transplanted to the striatum of hemiparkinsonian rats. Exp Neurol 2003, 183(2):653-664.
[175] Lee SH, Lumelsky N, Studer L, Auerbach JM, McKay RD: Efficient generation of midbrain and hindbrain neurons from mouse embryonic stem cells. Nat Biotechnol2000, 18(6):675-679.
[176] Studer L, Tabar V, McKay RD: Transplantation of expanded mesencephalic precursors leads to recovery in parkinsonian rats. Nat Neurosci 1998, 1(4):290-295.
[177] Sugaya K: Neuroreplacement therapy and stem cell biology under disease conditions. Cell Mol Life Sci 2003, 60(9):1891-1902.
[178] Salli U, Reddy AP, Salli N, Lu NZ, Kuo HC, Pau FK, Wolf DP, Bethea CL: Serotonin neurons derived from rhesus monkey embryonic stem cells: similarities to CNS serotonin neurons. Exp Neurol 2004, 188(2):351-364.
[179] Zhou J, Iacovitti L: Mechanisms governing the differentiation of a serotonergic phenotype in culture. Brain Res 2000, 877(1):37-46.
[180] Cowen DS: Serotonin and neuronal growth factors - a convergence of signaling pathways. J Neurochem 2007, 101(5):1161-1171.
[181] Xia Z, DePierre JW, Nassberger L: Tricyclic antidepressants inhibit IL-6, IL-1 beta and TNF-alpha release in human blood monocytes and IL-2 and interferon-gamma in T cells. Immunopharmacology 1996, 34(1):27-37.
[182] Konsman JP, Vigues S, Mackerlova L, Bristow A, Blomqvist A: Rat brain vascular distribution of interleukin-1 type-1 receptor immunoreactivity: relationship to patterns of inducible cyclooxygenase expression by peripheral inflammatory stimuli. J Comp Neurol 2004, 472(1):113-129.
[183] Williams JA, Shacter E: Regulation of macrophage cytokine production by prostaglandin E2. Distinct roles of cyclooxygenase-1 and -2. J Biol Chem 1997, 272(41):25693-25699.
[184] Ghezzi P, Sacco S, Agnello D, Marullo A, Caselli G, Bertini R: Lps induces IL-6 in the brain and in serum largely through TNF production. Cytokine 2000, 12(8):1205-1210.
[185] Geisterfer M, Richards CD, Gauldie J: Cytokines oncostatin M and interleukin 1 regulate the expression of the IL-6 receptor (gp80, gp130). Cytokine 1995, 7(6):503-509.
[186] Thabard W, Collette M, Mellerin MP, Puthier D, Barille S, Bataille R, Amiot M: IL-6 upregulates its own receptor on some human myeloma cell lines. Cytokine 2001, 14(6):352-356.
[187] Wang T, Wang BR, Zhao HZ, Kuang F, Duan XL, Ju G. Lipopolysaccharide up-regulates IL-6Rα expression in culturedleptomeningeal cells via activation of ERK1/2 pathway. Neurochemical Res 2008 Mar 21(Epub ahead of print)
[188] Dobrovolskaia MA, Vogel SN: Toll receptors, CD14, and macrophage activation and deactivation by LPS. Microbes Infect 2002, 4(9):903-914.
[189] Chakravarty S, Herkenham M: Toll-like receptor 4 on nonhematopoietic cells sustains CNS inflammation during endotoxemia, independent of systemic cytokines. J Neurosci 2005, 25(7):1788-1796.
[190] Armstrong L, Hughes O, Yung S, Hyslop L, Stewart R, Wappler I, Peters H, Walter T, Stojkovic P, Evans J, Stojkovic M, Lako M: The role of PI3K/AKT, MAPK/ERK and NFkappabeta signalling in the maintenance of human embryonic stem cell pluripotency and viability highlighted by transcriptional profiling and functional analysis. Hum Mol Genet 2006, 15(11):1894-1913.
[191] Campos LS, Leone DP, Relvas JB, Brakebusch C, Fassler R, Suter U, ffrench-Constant C: Beta1 integrins activate a MAPK signalling pathway in neural stem cells that contributes to their maintenance. Development 2004, 131(14):3433-3444.
[192] Hao Y, Creson T, Zhang L, Li P, Du F, Yuan P, Gould TD, Manji HK, Chen G: Mood stabilizer valproate promotes ERK pathway-dependent cortical neuronal growth and neurogenesis. J Neurosci 2004, 24(29):6590-6599.
[193] Bonni A, Sun Y, Nadal-Vicens M, Bhatt A, Frank DA, Rozovsky I, Stahl N, Yancopoulos GD, Greenberg ME: Regulation of gliogenesis in the central nervous system by the JAK-STAT signaling pathway. Science 1997, 278(5337):477-483.
[194] McKay R: Stem cells in the central nervous system. Science 1997, 276(5309):66-71.
[195] Takizawa T, Yanagisawa M, Ochiai W, Yasukawa K, Ishiguro T, Nakashima K, Taga T: Directly linked soluble IL-6 receptor-IL-6 fusion protein induces astrocyte differentiation from neuroepithelial cells via activation of STAT3. Cytokine 2001, 13(5):272-279.
[196] He F, Ge W, Martinowich K, Becker-Catania S, Coskun V, Zhu W, Wu H, Castro D, Guillemot F, Fan G, de Vellis J, Sun YE: A positive autoregulatory loop of Jak-STAT signaling controls the onset of astrogliogenesis. Nat Neurosci 2005, 8(5):616-625.
[197] Sun Y, Nadal-Vicens M, Misono S, Lin MZ, Zubiaga A, Hua X, Fan G, GreenbergME: Neurogenin promotes neurogenesis and inhibits glial differentiation by independent mechanisms. Cell 2001, 104(3):365-376.
[198] Yanagisawa M, Nakashima K, Arakawa H, Ikenaka K, Yoshida K, Kishimoto T, Hisatsune T, Taga T: Astrocyte differentiation of fetal neuroepithelial cells by interleukin-11 via activation of a common cytokine signal transducer, gp130, and a transcription factor, STAT3. J Neurochem 2000, 74(4):1498-1504.
[199] Erices A, Conget P, Rojas C, Minguell JJ: Gp130 activation by soluble interleukin-6 receptor/interleukin-6 enhances osteoblastic differentiation of human bone marrow-derived mesenchymal stem cells. Exp Cell Res 2002, 280(1):24-32.
[200] Grandoso L, Torrecilla M, Pineda J, Ugedo L: alpha(2)-Adrenoceptor involvement in the in vitro inhibitory effect of citalopram on a subpopulation of rat locus coeruleus neurons. Eur J Pharmacol 2005, 517(1-2):51-58.
[201] Laeng P, Pitts RL, Lemire AL, Drabik CE, Weiner A, Tang H, Thyagarajan R, Mallon BS, Altar CA: The mood stabilizer valproic acid stimulates GABA neurogenesis from rat forebrain stem cells. J Neurochem 2004, 91(1):238-251.
[202] Hashimoto R, Senatorov V, Kanai H, Leeds P, Chuang DM: Lithium stimulates progenitor proliferation in cultured brain neurons. Neuroscience 2003, 117(1):55-61.
[203] Madsen TM, Treschow A, Bengzon J, Bolwig TG, Lindvall O, Tingstrom A: Increased neurogenesis in a model of electroconvulsive therapy. Biol Psychiatry 2000, 47(12):1043-1049.
[204] Malberg JE, Eisch AJ, Nestler EJ, Duman RS: Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. J Neurosci 2000, 20(24):9104-9110.
[205] Manev H, Uz T, Smalheiser NR, Manev R: Antidepressants alter cell proliferation in the adult brain in vivo and in neural cultures in vitro. Eur J Pharmacol 2001, 411(1-2):67-70.
[206] Jacobs BL, Praag H, Gage FH: Adult brain neurogenesis and psychiatry: a novel theory of depression. Mol Psychiatry 2000, 5(3):262-269.
[207] Nibuya M, Morinobu S, Duman RS: Regulation of BDNF and trkB mRNA in rat brain by chronic electroconvulsive seizure and antidepressant drug treatments. J Neurosci 1995, 15(11):7539-7547.
[208] Nibuya M, Nestler EJ, Duman RS: Chronic antidepressant administration increases the expression of cAMP response element binding protein (CREB) in rathippocampus. J Neurosci 1996, 16(7):2365-2372.
[209] Thome J, Sakai N, Shin K, Steffen C, Zhang YJ, Impey S, Storm D, Duman RS: cAMP response element-mediated gene transcription is upregulated by chronic antidepressant treatment. J Neurosci 2000, 20(11):4030-4036.
[210] Finkbeiner S: CREB couples neurotrophin signals to survival messages. Neuron 2000, 25(1):11-14.
[211] Palmer TD, Takahashi J, Gage FH: The adult rat hippocampus contains primordial neural stem cells. Mol Cell Neurosci 1997, 8(6):389-404.
[212] Brezun JM, Daszuta A: Serotonin may stimulate granule cell proliferation in the adult hippocampus, as observed in rats grafted with foetal raphe neurons. Eur J Neurosci 2000, 12(1):391-396.
[213] Kubera M, Simbirtsev A, Mathison R, Maes M: Effects of repeated fluoxetine and citalopram administration on cytokine release in C57BL/6 mice. Psychiatry Res 2000, 96(3):255-266.
[214] Einat H, Yuan P, Gould TD, Li J, Du J, Zhang L, Manji HK, Chen G: The role of the extracellular signal-regulated kinase signaling pathway in mood modulation. J Neurosci 2003, 23(19):7311-7316.
[215] Yuan PX, Huang LD, Jiang YM, Gutkind JS, Manji HK, Chen G: The mood stabilizer valproic acid activates mitogen-activated protein kinases and promotes neurite growth. J Biol Chem 2001, 276(34):31674-31683.
[216] Sahin Kaya S, Mahmood A, Li Y, Yavuz E, Chopp M: Expression of nestin after traumatic brain injury in rat brain. Brain Res 1999, 840(1-2):153-157.
[217] Lang B, Liu HL, Liu R, Feng GD, Jiao XY, Ju G: Astrocytes in injured adult rat spinal cord may acquire the potential of neural stem cells. Neuroscience 2004, 128(4):775-783.
[218] Faulkner JR, Herrmann JE, Woo MJ, Tansey KE, Doan NB, Sofroniew MV: Reactive astrocytes protect tissue and preserve function after spinal cord injury. J Neurosci 2004, 24(9):2143-2155.
[219] Iseda T, Nishio T, Kawaguchi S, Yamanoto M, Kawasaki T, Wakisaka S: Spontaneous regeneration of the corticospinal tract after transection in young rats: a key role of reactive astrocytes in making favorable and unfavorable conditions for regeneration. Neuroscience 2004, 126(2):365-374.
[220] Chen J, Leong SY, Schachner M: Differential expression of cell fate determinants in neurons and glial cells of adult mouse spinal cord after compression injury. Eur JNeurosci 2005, 22(8):1895-1906.
[221] Frisen J, Johansson CB, Torok C, Risling M, Lendahl U: Rapid, widespread, and longlasting induction of nestin contributes to the generation of glial scar tissue after CNS injury. J Cell Biol 1995, 131(2):453-464.
[222] Song H, Stevens CF, Gage FH: Astroglia induce neurogenesis from adult neural stem cells. Nature 2002, 417(6884):39-44.
[2] Super H, Martinez A, Soriano E: Degeneration of Cajal-Retzius cells in the developing cerebral cortex of the mouse after ablation of meningeal cells by 6-hydroxydopamine. Brain Res Dev Brain Res 1997, 98(1):15-20.
[3] 周永志,张世明: 脑膜的合成及分泌功能. 国外医学神经病学神经外科学分册 2004, 31:575-578.
[4] 蔡文琴 李: 发育神经生物学. 北京: 科学出版社; 1999.
[5] 刘斌 高: 人体胚胎学. 北京: 人民卫生出版社; 1996.
[6] 杨琳,高英茂(主译): 格氏解剖学. 沈阳: 辽宁教育出版社; 1999.
[7] Mitsikostas DD, Sanchez del Rio M: Receptor systems mediating c-fos expression within trigeminal nucleus caudalis in animal models of migraine. Brain Res Brain Res Rev 2001, 35(1):20-35.
[8] De Col R, Koulchitsky SV, Messlinger KB: Nitric oxide synthase inhibition lowers activity of neurons with meningeal input in the rat spinal trigeminal nucleus. Neuroreport 2003, 14(2):229-232.
[9] Webb AA: Potential sources of neck and back pain in clinical conditions of dogs and cats: a review. Vet J 2003, 165(3):193-213.
[10] Zhang ET, Inman CB, Weller RO: Interrelationships of the pia mater and the perivascular (Virchow-Robin) spaces in the human cerebrum. J Anat 1990, 170:111-123.
[11] Hutchings M, Weller RO: Anatomical relationships of the pia mater to cerebral blood vessels in man. J Neurosurg 1986, 65(3):316-325.
[12] Greenberg RW, Lane EL, Cinnamon J, Farmer P, Hyman RA: The cranial meninges: anatomic considerations. Semin Ultrasound CT MR 1994, 15(6):454-465.
[13] Grossman SA, Krabak MJ: Leptomeningeal carcinomatosis. Cancer Treat Rev 1999, 25(2):103-119.
[14] Colombo JA, Napp MI, Puissant V: Leptomeningeal and skin fibroblasts: two different cell types? Int J Dev Neurosci 1994, 12(1):57-61.
[15] Kaplan GP, Hartman BK, Creveling CR: Immunohistochemical localization ofcatechol-O-methyltransferase in circumventricular organs of the rat: potential variations in the blood-brain barrier to native catechols. Brain Res 1981, 229(2):323-335.
[16] Kern C, Mautz DS, Bernards CM: Epinephrine is metabolized by the spinal meninges of monkeys and pigs. Anesthesiology 1995, 83(5):1078-1081.
[17] Zajac JM, Charnay Y, Soleilhic JM, Sales N, Roques BP: Enkephalin-degrading enzymes and angiotensin-converting enzyme in human and rat meninges. FEBS Lett 1987, 216(1):118-122.
[18] Lopez-Figueroa MO, Day HE, Lee S, Rivier C, Akil H, Watson SJ: Temporal and anatomical distribution of nitric oxide synthase mRNA expression and nitric oxide production during central nervous system inflammation. Brain Res 2000, 852(1):239-246.
[19] McCann SM, Licinio J, Wong ML, Yu WH, Karanth S, Rettorri V: The nitric oxide hypothesis of aging. Exp Gerontol 1998, 33(7-8):813-826.
[20] Kluge WH, Kluge HH, Hochstetter A, Vollandt R, Seidel F, Venbrocks R: Acetylcholinesterase in lumbar and ventricular cerebrospinal fluid. Clin Chim Acta 2001, 305(1-2):55-63.
[21] Hartlage-Rubsamen M, Lemke R, Schliebs R: Interleukin-1beta, inducible nitric oxide synthase, and nuclear factor-kappaB are induced in morphologically distinct microglia after rat hippocampal lipopolysaccharide/interferon-gamma injection. J Neurosci Res 1999, 57(3):388-398.
[22] Ebersberger A: Physiology of meningeal innervation: aspects and consequences of chemosensitivity of meningeal nociceptors. Microsc Res Tech 2001, 53(2):138-146.
[23] Lehtimaki KA, Peltola J, Koskikallio E, Keranen T, Honkaniemi J: Expression of cytokines and cytokine receptors in the rat brain after kainic acid-induced seizures. Brain Res Mol Brain Res 2003, 110(2):253-260.
[24] Fricke B, Andres KH, Von During M: Nerve fibers innervating the cranial and spinal meninges: morphology of nerve fiber terminals and their structural integration. Microsc Res Tech 2001, 53(2):96-105.
[25] Yoshida K, Gage FH: Fibroblast growth factors stimulate nerve growth factor synthesis and secretion by astrocytes. Brain Res 1991, 538(1):118-126.
[26] Struckhoff G: Transforming growth factor beta 1 and parathyroid hormone-related protein control the secretion of dipeptidyl peptidase II by rat astrocytes. NeurosciLett 1995, 189(2):117-120.
[27] Reiss K, Mentlein R, Sievers J, Hartmann D: Stromal cell-derived factor 1 is secreted by meningeal cells and acts as chemotactic factor on neuronal stem cells of the cerebellar external granular layer. Neuroscience 2002, 115(1):295-305.
[28] Struckhoff G: Cocultures of meningeal and astrocytic cells--a model for the formation of the glial-limiting membrane. Int J Dev Neurosci 1995, 13(6):595-606.
[29] Niclou SP, Franssen EH, Ehlert EM, Taniguchi M, Verhaagen J: Meningeal cell-derived semaphorin 3A inhibits neurite outgrowth. Mol Cell Neurosci 2003, 24(4):902-912.
[30] Fawcett JW, Asher RA: The glial scar and central nervous system repair. Brain Res Bull 1999, 49(6):377-391.
[31] Wujek JR, Akeson RA: Extracellular matrix derived from astrocytes stimulates neuritic outgrowth from PC12 cells in vitro. Brain Res 1987, 431(1):87-97.
[32] Ishikawa K, Kabeya K, Shinoda M, Katakai K, Mori M, Tatemoto K: Meninges play a neurotrophic role in the regeneration of vasopressin nerves after hypophysectomy. Brain Res 1995, 677(1):20-28.
[33] Webb K, Budko E, Neuberger TJ, Chen S, Schachner M, Tresco PA: Substrate-bound human recombinant L1 selectively promotes neuronal attachment and outgrowth in the presence of astrocytes and fibroblasts. Biomaterials 2001, 22(10):1017-1028.
[34] Takano M, Horie M, Narahara M, Miyake M, Okamoto H: Expression of kininogen mRNAs and plasma kallikrein mRNA by cultured neurons, astrocytes and meningeal cells in the rat brain. Immunopharmacology 1999, 45(1-3):121-126.
[35] Tamura S, Morikawa Y, Senba E: Localization of oncostatin M receptor beta in adult and developing CNS. Neuroscience 2003, 119(4):991-997.
[36] Ganfornina MD, Sanchez D, Pagano A, Tonachini L, Descalzi-Cancedda F, Martinez S: Molecular characterization and developmental expression pattern of the chicken apolipoprotein D gene: implications for the evolution of vertebrate lipocalins. Dev Dyn 2005, 232(1):191-199.
[37] Hartmann D, Ziegenhagen MW, Sievers J: Meningeal cells stimulate neuronal migration and the formation of radial glial fascicles from the cerebellar external granular layer. Neurosci Lett 1998, 244(3):129-132.
[38] von Knebel Doeberitz C, Sievers J, Sadler M, Pehlemann FW, Berry M, Halliwell P: Destruction of meningeal cells over the newborn hamster cerebellum with6-hydroxydopamine prevents foliation and lamination in the rostral cerebellum. Neuroscience 1986, 17(2):409-426.
[39] Ishikawa K, Ohe Y, Tatemoto K: Synthesis and secretion of insulin-like growth factor (IGF)-II and IGF binding protein-2 by cultivated brain meningeal cells. Brain Res 1995, 697(1-2):122-129.
[40] Brettschneider J, Riepe MW, Petereit HF, Ludolph AC, Tumani H: Meningeal derived cerebrospinal fluid proteins in different forms of dementia: is a meningopathy involved in normal pressure hydrocephalus? J Neurol Neurosurg Psychiatry 2004, 75(11):1614-1616.
[41] Choo A, Padmanabhan J, Chin A, Fong WJ, Oh SK: Immortalized feeders for the scale-up of human embryonic stem cells in feeder and feeder-free conditions. J Biotechnol 2006, 122(1):130-141.
[42] Hayashi H, Morizane A, Koyanagi M, Ono Y, Sasai Y, Hashimoto N, Takahashi J: Meningeal cells induce dopaminergic neurons from embryonic stem cells. Eur J Neurosci 2008, 27(2):261-268.
[43] Khademhosseini A, Ferreira L, Blumling J, 3rd, Yeh J, Karp JM, Fukuda J, Langer R: Co-culture of human embryonic stem cells with murine embryonic fibroblasts on microwell-patterned substrates. Biomaterials 2006, 27(36):5968-5977.
[44] Xie CQ, Lin G, Yuan D, Wang J, Liu TC, Lu GX: Proliferative feeder cells support prolonged expansion of human embryonic stem cells. Cell Biol Int 2005, 29(8):623-628.
[45] Capela A, Temple S: LeX/ssea-1 is expressed by adult mouse CNS stem cells, identifying them as nonependymal. Neuron 2002, 35(5):865-875.
[46] Feurer DJ, Weller RO: Barrier functions of the leptomeninges: a study of normal meninges and meningiomas in tissue culture. Neuropathol Appl Neurobiol 1991, 17(5):391-405.
[47] Krahn V: Leukodiapedesis and leukocyte migration in the leptomeninges and in the subarachnoid space. J Neurol 1981, 226(1):43-52.
[48] van Dam AM, Poole S, Schultzberg M, Zavala F, Tilders FJ: Effects of peripheral administration of LPS on the expression of immunoreactive interleukin-1 alpha, beta, and receptor antagonist in rat brain. Ann N Y Acad Sci 1998, 840:128-138.
[49] Quan N, Stern EL, Whiteside MB, Herkenham M: Induction of pro-inflammatory cytokine mRNAs in the brain after peripheral injection of subseptic doses of lipopolysaccharide in the rat. J Neuroimmunol 1999, 93(1-2):72-80.
[50] Xia Y, Krukoff TL: Differential neuronal activation in the hypothalamic paraventricular nucleus and autonomic/neuroendocrine responses to I.C.V. endotoxin. Neuroscience 2003, 121(1):219-231.
[51] Polentarutti N, Bottazzi B, Di Santo E, Blasi E, Agnello D, Ghezzi P, Introna M, Bartfai T, Richards G, Mantovani A: Inducible expression of the long pentraxin PTX3 in the central nervous system. J Neuroimmunol 2000, 106(1-2):87-94.
[52] Proescholdt MG, Chakravarty S, Foster JA, Foti SB, Briley EM, Herkenham M: Intracerebroventricular but not intravenous interleukin-1beta induces widespread vascular-mediated leukocyte infiltration and immune signal mRNA expression followed by brain-wide glial activation. Neuroscience 2002, 112(3):731-749.
[53] Konsman JP, Tridon V, Dantzer R: Diffusion and action of intracerebroventricularly injected interleukin-1 in the CNS. Neuroscience 2000, 101(4):957-967.
[54] Plunkett JA, Yu CG, Easton JM, Bethea JR, Yezierski RP: Effects of interleukin-10 (IL-10) on pain behavior and gene expression following excitotoxic spinal cord injury in the rat. Exp Neurol 2001, 168(1):144-154.
[55] Schiltz JC, Sawchenko PE: Distinct brain vascular cell types manifest inducible cyclooxygenase expression as a function of the strength and nature of immune insults. J Neurosci 2002, 22(13):5606-5618.
[56] Cao C, Matsumura K, Yamagata K, Watanabe Y: Endothelial cells of the rat brain vasculature express cyclooxygenase-2 mRNA in response to systemic interleukin-1 beta: a possible site of prostaglandin synthesis responsible for fever. Brain Res 1996, 733(2):263-272.
[57] Muraki T, Fujimori K, Ishizaka M, Ohe Y, Urade Y, Okajima F, Ishikawa K: Effects of interleukin-1beta and prostaglandin E2 on prostaglandin D synthase production in cultivated rat leptomeningeal cells. J Cereb Blood Flow Metab 2004, 24(4):409-418.
[58] Fujimori K, Fujitani Y, Kadoyama K, Kumanogoh H, Ishikawa K, Urade Y: Regulation of lipocalin-type prostaglandin D synthase gene expression by Hes-1 through E-box and interleukin-1 beta via two NF-kappa B elements in rat leptomeningeal cells. J Biol Chem 2003, 278(8):6018-6026.
[59] Herkenham M, Lee HY, Baker RA: Temporal and spatial patterns of c-fos mRNA induced by intravenous interleukin-1: a cascade of non-neuronal cellular activation at the blood-brain barrier. J Comp Neurol 1998, 400(2):175-196.
[60] Gonzalez-Gonzalez IM, Cubelos B, Gimenez C, Zafra F: Immunohistochemicallocalization of the amino acid transporter SNAT2 in the rat brain. Neuroscience 2005, 130(1):61-73.
[61] McMenamin PG, Wealthall RJ, Deverall M, Cooper SJ, Griffin B: Macrophages and dendritic cells in the rat meninges and choroid plexus: three-dimensional localisation by environmental scanning electron microscopy and confocal microscopy. Cell Tissue Res 2003, 313(3):259-269.
[62] Matyszak MK, Perry VH: The potential role of dendritic cells in immune-mediated inflammatory diseases in the central nervous system. Neuroscience 1996, 74(2):599-608.
[63] Ibrahim MA, Chain BM, Katz DR: The injured cell: the role of the dendritic cell system as a sentinel receptor pathway. Immunol Today 1995, 16(4):181-186.
[64] Lowenstein PR: Immunology of viral-vector-mediated gene transfer into the brain: an evolutionary and developmental perspective. Trends Immunol 2002, 23(1):23-30.
[65] Pashenkov M, Link H: Dendritic cells and immune responses in the central nervous system. Trends Immunol 2002, 23(2):69-70; author reply 70.
[66] Rozniecki JJ, Dimitriadou V, Lambracht-Hall M, Pang X, Theoharides TC: Morphological and functional demonstration of rat dura mater mast cell-neuron interactions in vitro and in vivo. Brain Res 1999, 849(1-2):1-15.
[67] Reuter U, Bolay H, Jansen-Olesen I, Chiarugi A, Sanchez del Rio M, Letourneau R, Theoharides TC, Waeber C, Moskowitz MA: Delayed inflammation in rat meninges: implications for migraine pathophysiology. Brain 2001, 124(Pt 12):2490-2502.
[68] Serviere J, Dubayle D, Menetrey D: Increase of rat medial habenular mast cell numbers by systemic administration of cyclophosphamide. Toxicol Lett 2003, 145(2):143-152.
[69] Theoharides TC, Dimitriadou V, Letourneau R, Rozniecki JJ, Vliagoftis H, Boucher W: Synergistic action of estradiol and myelin basic protein on mast cell secretion and brain myelin changes resembling early stages of demyelination. Neuroscience 1993, 57(3):861-871.
[70] Goldman SA, Nottebohm F: Neuronal production, migration, and differentiation in a vocal control nucleus of the adult female canary brain. Proc Natl Acad Sci U S A 1983, 80(8):2390-2394.
[71] Richards LJ, Kilpatrick TJ, Bartlett PF: De novo generation of neuronal cells fromthe adult mouse brain. Proc Natl Acad Sci U S A 1992, 89(18):8591-8595.
[72] Reynolds BA, Weiss S: Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system. Science 1992, 255(5052):1707-1710.
[73] Eriksson PS, Perfilieva E, Bjork-Eriksson T, Alborn AM, Nordborg C, Peterson DA, Gage FH: Neurogenesis in the adult human hippocampus. Nat Med 1998, 4(11):1313-1317.
[74] Johansson CB, Svensson M, Wallstedt L, Janson AM, Frisen J: Neural stem cells in the adult human brain. Exp Cell Res 1999, 253(2):733-736.
[75] Gage FH: Mammalian neural stem cells. Science 2000, 287(5457):1433-1438.
[76] Thomas LB, Gates MA, Steindler DA: Young neurons from the adult subependymal zone proliferate and migrate along an astrocyte, extracellular matrix-rich pathway. Glia 1996, 17(1):1-14.
[77] Bjorklund A, Lindvall O: Self-repair in the brain. Nature 2000, 405(6789):892-893, 895.
[78] Tureyen K, Vemuganti R, Sailor KA, Bowen KK, Dempsey RJ: Transient focal cerebral ischemia-induced neurogenesis in the dentate gyrus of the adult mouse. J Neurosurg 2004, 101(5):799-805.
[79] Tzeng SF, Wu JP: Responses of microglia and neural progenitors to mechanical brain injury. Neuroreport 1999, 10(11):2287-2292.
[80] Doetsch F, Caille I, Lim DA, Garcia-Verdugo JM, Alvarez-Buylla A: Subventricular zone astrocytes are neural stem cells in the adult mammalian brain. Cell 1999, 97(6):703-716.
[81] Abe K: Therapeutic potential of neurotrophic factors and neural stem cells against ischemic brain injury. J Cereb Blood Flow Metab 2000, 20(10):1393-1408.
[82] Kondo T, Raff M: Oligodendrocyte precursor cells reprogrammed to become multipotential CNS stem cells. Science 2000, 289(5485):1754-1757.
[83] Bjornson CR, Rietze RL, Reynolds BA, Magli MC, Vescovi AL: Turning brain into blood: a hematopoietic fate adopted by adult neural stem cells in vivo. Science 1999, 283(5401):534-537.
[84] Clarke DL, Johansson CB, Wilbertz J, Veress B, Nilsson E, Karlstrom H, Lendahl U, Frisen J: Generalized potential of adult neural stem cells. Science 2000, 288(5471):1660-1663.
[85] Andrades JA, Han B, Becerra J, Sorgente N, Hall FL, Nimni ME: A recombinant human TGF-beta1 fusion protein with collagen-binding domain promotesmigration, growth, and differentiation of bone marrow mesenchymal cells. Exp Cell Res 1999, 250(2):485-498.
[86] Lendahl U, Zimmerman LB, McKay RD: CNS stem cells express a new class of intermediate filament protein. Cell 1990, 60(4):585-595.
[87] Almazan G, Vela JM, Molina-Holgado E, Guaza C: Re-evaluation of nestin as a marker of oligodendrocyte lineage cells. Microsc Res Tech 2001, 52(6):753-765.
[88] Dahlstrand J, Zimmerman LB, McKay RD, Lendahl U: Characterization of the human nestin gene reveals a close evolutionary relationship to neurofilaments. J Cell Sci 1992, 103 ( Pt 2):589-597.
[89] Lothian C, Lendahl U: An evolutionarily conserved region in the second intron of the human nestin gene directs gene expression to CNS progenitor cells and to early neural crest cells. Eur J Neurosci 1997, 9(3):452-462.
[90] Pekny M, Johansson CB, Eliasson C, Stakeberg J, Wallen A, Perlmann T, Lendahl U, Betsholtz C, Berthold CH, Frisen J: Abnormal reaction to central nervous system injury in mice lacking glial fibrillary acidic protein and vimentin. J Cell Biol 1999, 145(3):503-514.
[91] Vaittinen S, Lukka R, Sahlgren C, Rantanen J, Hurme T, Lendahl U, Eriksson JE, Kalimo H: Specific and innervation-regulated expression of the intermediate filament protein nestin at neuromuscular and myotendinous junctions in skeletal muscle. Am J Pathol 1999, 154(2):591-600.
[92] Sosunov AA, Chelyshev Iu A, McKhann G, Krugliakov PP, Balykova OP, Shikhanov NP: [Neurogenesis in the adult mammalian brain]. Ontogenez 2002, 33(6):405-420.
[93] Xu Y, Tamamaki N, Noda T, Kimura K, Itokazu Y, Matsumoto N, Dezawa M, Ide C: Neurogenesis in the ependymal layer of the adult rat 3rd ventricle. Exp Neurol 2005, 192(2):251-264.
[94] Ernst C, Christie BR: The putative neural stem cell marker, nestin, is expressed in heterogeneous cell types in the adult rat neocortex. Neuroscience 2006, 138(1):183-188.
[95] Yue F, Chen B, Wu D, Dong K, Zeng SE, Zhang Y: Biological properties of neural progenitor cells isolated from the hippocampus of adult cynomolgus monkeys. Chin Med J (Engl) 2006, 119(2):110-116.
[96] Li Y, Chopp M: Temporal profile of nestin expression after focal cerebral ischemia in adult rat. Brain Res 1999, 838(1-2):1-10.
[97] Tonchev AB, Yamashima T, Zhao L, Okano HJ, Okano H: Proliferation of neural and neuronal progenitors after global brain ischemia in young adult macaque monkeys. Mol Cell Neurosci 2003, 23(2):292-301.
[98] Krugliakova EP, Khovriakov AV, Shikhanov NP, McKhann IG, Vael I, Krugliakov PP, Sosunov AA: [Nestin-expressing cells in the human hippocampus]. Morfologiia 2004, 126(6):19-25.
[99] Shih CC, Weng Y, Mamelak A, LeBon T, Hu MC, Forman SJ: Identification of a candidate human neurohematopoietic stem-cell population. Blood 2001, 98(8):2412-2422.
[100] Craig CG, Tropepe V, Morshead CM, Reynolds BA, Weiss S, van der Kooy D: In vivo growth factor expansion of endogenous subependymal neural precursor cell populations in the adult mouse brain. J Neurosci 1996, 16(8):2649-2658.
[101] Kalyani AJ, Mujtaba T, Rao MS: Expression of EGF receptor and FGF receptor isoforms during neuroepithelial stem cell differentiation. J Neurobiol 1999, 38(2):207-224.
[102] Kuhn HG, Winkler J, Kempermann G, Thal LJ, Gage FH: Epidermal growth factor and fibroblast growth factor-2 have different effects on neural progenitors in the adult rat brain. J Neurosci 1997, 17(15):5820-5829.
[103] Brickman YG, Ford MD, Gallagher JT, Nurcombe V, Bartlett PF, Turnbull JE: Structural modification of fibroblast growth factor-binding heparan sulfate at a determinative stage of neural development. J Biol Chem 1998, 273(8):4350-4359.
[104] Wozniak W: Brain-derived neurotrophic factor (BDNF): role in neuronal development and survival. Folia Morphol (Warsz) 1993, 52(4):173-181.
[105] Kim DH, Jahng TA: Continuous brain-derived neurotrophic factor (BDNF) infusion after methylprednisolone treatment in severe spinal cord injury. J Korean Med Sci 2004, 19(1):113-122.
[106] Brown A, Ricci MJ, Weaver LC: NGF message and protein distribution in the injured rat spinal cord. Exp Neurol 2004, 188(1):115-127
[107] Galli R, Pagano SF, Gritti A, Vescovi AL: Regulation of neuronal differentiation in human CNS stem cell progeny by leukemia inhibitory factor. Dev Neurosci 2000, 22(1-2):86-95.
[108] Ling ZD, Potter ED, Lipton JW, Carvey PM: Differentiation of mesencephalic progenitor cells into dopaminergic neurons by cytokines. Exp Neurol 1998, 149(2):411-423.
[109] Gomes WA, Mehler MF, Kessler JA: Transgenic overexpression of BMP4 increases astroglial and decreases oligodendroglial lineage commitment. Dev Biol 2003, 255(1):164-177.
[110] Chenn A, Walsh CA: Regulation of cerebral cortical size by control of cell cycle exit in neural precursors. Science 2002, 297(5580):365-369.
[111] Turnley AM, Bartlett PF: Cytokines that signal through the leukemia inhibitory factor receptor-beta complex in the nervous system. J Neurochem 2000, 74(3):889-899.
[112] Molne M, Studer L, Tabar V, Ting YT, Eiden MV, McKay RD: Early cortical precursors do not undergo LIF-mediated astrocytic differentiation. J Neurosci Res 2000, 59(3):301-311
[113] Erlandsson A, Enarsson M, Forsberg-Nilsson K: Immature neurons from CNS stem cells proliferate in response to platelet-derived growth factor. J Neurosci 2001, 21(10):3483-3491.
[114] Takahashi J, Palmer TD, Gage FH: Retinoic acid and neurotrophins collaborate to regulate neurogenesis in adult-derived neural stem cell cultures. J Neurobiol 1999, 38(1):65-81.
[115] Amoureux MC, Cunningham BA, Edelman G.M, Crossin KL: N-CAM binding inhibits the proliferation of hippocampal progenitor cells and promotes their differentiation to a neuronal phenotype. J Neurosci 2000, 20(10):3631-3640.
[116] Bruno L, Hoffmann R, McBlane F, Brown J, Gupta R, Joshi C, Pearson S, Seidl T, Heyworth C, Enver T: Molecular signatures of self-renewal, differentiation, and lineage choice in multipotential hemopoietic progenitor cells in vitro. Mol Cell Biol 2004, 24(2):741-756.
[117] Carvey PM, Ling ZD, Sortwell CE, Pitzer MR, McGuire SO, Storch A, Collier TJ: A clonal line of mesencephalic progenitor cells converted to dopamine neurons by hematopoietic cytokines: a source of cells for transplantation in Parkinson's disease. Exp Neurol 2001, 171(1):98-108.
[118] Namiki J, Tator CH: Cell proliferation and nestin expression in the ependyma of the adult rat spinal cord after injury. J Neuropathol Exp Neurol 1999, 58(5):489-498.
[119] Armstrong RJ, Barker RA: Neurodegeneration: a failure of neuroregeneration? Lancet 2001, 358(9288):1174-1176.
[120] Jin K, Peel AL, Mao XO, Xie L, Cottrell BA, Henshall DC, Greenberg DA: Increased hippocampal neurogenesis in Alzheimer's disease. Proc Natl Acad Sci US A 2004, 101(1):343-347.
[121] Snyder EY, Taylor RM, Wolfe JH: Neural progenitor cell engraftment corrects lysosomal storage throughout the MPS VII mouse brain. Nature 1995, 374(6520):367-370.
[122] Wexler E, Palmer T: Where, oh where, have my stem cells gone? Trends Neurosci 2002, 25(5):225-227.
[123] Petroske E, Meredith GE, Callen S, Totterdell S, Lau YS: Mouse model of Parkinsonism: a comparison between subacute MPTP and chronic MPTP/probenecid treatment. Neuroscience 2001, 106(3):589-601.
[124] Kay JN, Blum M: Differential response of ventral midbrain and striatal progenitor cells to lesions of the nigrostriatal dopaminergic projection. Dev Neurosci 2000, 22(1-2):56-67.
[125] Peterson DA: Stem cells in brain plasticity and repair. Curr Opin Pharmacol 2002, 2(1):34-42.
[126] Nakatomi H, Kuriu T, Okabe S, Yamamoto S, Hatano O, Kawahara N, Tamura A, Kirino T, Nakafuku M: Regeneration of hippocampal pyramidal neurons after ischemic brain injury by recruitment of endogenous neural progenitors. Cell 2002, 110(4):429-441.
[127] Takagi Y, Nozaki K, Takahashi J, Yodoi J, Ishikawa M, Hashimoto N: Proliferation of neuronal precursor cells in the dentate gyrus is accelerated after transient forebrain ischemia in mice. Brain Res 1999, 831(1-2):283-287.
[128] 陈东风,杜少辉,李伊为: 龟板对局灶性脑缺血再灌注后 Nestin 表达的影响. 解剖学杂志 2002, 25(4):315-319.
[129] 程龙,朱培纯,司银楚: 三七总皂甙对去大脑皮层血管后成年大鼠前脑侧脑室室管膜下层 Nestin 和 bFGF 表达的作用. 北京中医药大学学报 2003, 26(3):18-20.
[130] 杜少辉,张悦,黄洁: 牛珀至宝微丸对局灶性脑缺血再灌注后 Nestin 表达的影响. 中国中医基础医学杂志 2002, 8(10):17-21.
[131] Dash PK,. Mach SA, Moore AN: Enhanced neurogenesis in the rodent hippocampus following traumatic brain injury. J Neurosci Res 2001, 63(4):313-319.
[132] Hagan M, Wennersten A, Meijer X, Holmin S, Wahlberg L, Mathiesen T: Neuroprotection by human neural progenitor cells after experimental contusion inrats. Neurosci Lett 2003, 351(3):149-152.
[133] Svendsen CN, Caldwell MA, Shen J, ter Borg MG, Rosser AE, Tyers P, Karmiol S, Dunnett SB: Long-term survival of human central nervous system progenitor cells transplanted into a rat model of Parkinson's disease. Exp Neurol 1997, 148(1):135-146.
[134] Benedetti S, Pirola B, Pollo B, Magrassi L, Bruzzone MG, Rigamonti D, Galli R, Selleri S, Di Meco F, De Fraja C, Vescovi A, Cattaneo E, Finocchiaro G: Gene therapy of experimental brain tumors using neural progenitor cells. Nat Med 2000, 6(4):447-450.
[135] Aboody KS, Brown A, Rainov NG, Bower KA, Liu S, Yang W, Small JE, Herrlinger U, Ourednik V, Black PM, Breakefield XO, Snyder EY: Neural stem cells display extensive tropism for pathology in adult brain: evidence from intracranial gliomas. Proc Natl Acad Sci U S A 2000, 97(23):12846-12851.
[136] Prockop DJ: Marrow stromal cells as stem cells for nonhematopoietic tissues. Science 1997, 276(5309):71-74.
[137] Kopen GC, Prockop DJ, Phinney DG: Marrow stromal cells migrate throughout forebrain and cerebellum, and they differentiate into astrocytes after injection into neonatal mouse brains. Proc Natl Acad Sci U S A 1999, 96(19):10711-10716.
[138] Brazelton TR, Rossi FM, Keshet GI, Blau HM: From marrow to brain: expression of neuronal phenotypes in adult mice. Science 2000, 290(5497):1775-1779.
[139] Mezey E, Chandross KJ, Harta G, Maki RA, McKercher SR: Turning blood into brain: cells bearing neuronal antigens generated in vivo from bone marrow. Science 2000, 290(5497):1779-1782.
[140] Li Y, Chopp M, Chen J, Wang L, Gautam SC, Xu YX, Zhang Z: Intrastriatal transplantation of bone marrow nonhematopoietic cells improves functional recovery after stroke in adult mice. J Cereb Blood Flow Metab 2000, 20(9):1311-1319.
[141] Chen J, Li Y, Wang L, Zhang Z, Lu D, Lu M, Chopp M: Therapeutic benefit of intravenous administration of bone marrow stromal cells after cerebral ischemia in rats. Stroke 2001, 32(4):1005-1011
[142] Sanchez-Ramos J, Song S, Cardozo-Pelaez F, Hazzi C, Stedeford T, Willing A, Freeman TB, Saporta S, Janssen W, Patel N, Cooper DR, Sanberg PR: Adult bone marrow stromal cells differentiate into neural cells in vitro. Exp Neurol 2000, 164(2):247-256.
[143] Woodbury D, Schwarz EJ, Prockop DJ, Black IB: Adult rat and human bone marrow stromal cells differentiate into neurons. J Neurosci Res 2000, 61(4):364-370.
[144] Deng W, Obrocka M, Fischer I, Prockop DJ: In vitro differentiation of human marrow stromal cells into early progenitors of neural cells by conditions that increase intracellular cyclic AMP. Biochem Biophys Res Commun 2001, 282(1):148-152.
[145] Hofstetter CP, Schwarz EJ, Hess D, Widenfalk J, Manira AE, Prockop DJ, Olson L: Marrow stromal cells form guiding strands in the injured spinal cord and promote recovery. Proc Natl Acad Sci U S A 2002, 99(4):2199-2204.
[146] Wurmser AE, Gage FH: Stem cells: cell fusion causes confusion. Nature 2002, 416(6880):485-487.
[147] Condorelli G., Borello U, De Angelis L, Latronico M, Sirabella D, Coletta M, Galli R, Balconi G, Follenzi A, Frati G, Cusella De Angelis MG, Gioglio L, Amuchastegui S, Adorini L, Naldini L, Vescovi A, Dejana E, Cossu G: Cardiomyocytes induce endothelial cells to trans-differentiate into cardiac muscle: implications for myocardium regeneration. Proc Natl Acad Sci U S A 2001, 98(19):10733-10738.
[148] Ying QL, Nichols J, Evans EP, Smith AG: Changing potency by spontaneous fusion. Nature 2002, 416(6880):545-548.
[149] Terada N, Hamazaki T, Oka M, Hoki M, Mastalerz DM, Nakano Y, Meyer EM, Morel L, Petersen BE, Scott EW: Bone marrow cells adopt the phenotype of other cells by spontaneous cell fusion. Nature 2002, 416(6880):542-545.
[150] Hassan-Zahraee M, Ladiwala U, Lavoie PM, McCrea E, Sekaly RP, Owens T, Antel JP: Superantigen presenting capacity of human astrocytes. J Neuroimmunol 2000, 102(2):131-136.
[151] LeBlanc AC, Chen HY, Autilio-Gambetti L, Gambetti P: Differential APP gene expression in rat cerebral cortex, meninges, and primary astroglial, microglial and neuronal cultures. FEBS Lett 1991, 292(1-2):171-178.
[152] Matsuguchi T, Musikacharoen T, Ogawa T, Yoshikai Y: Gene expressions of Toll-like receptor 2, but not Toll-like receptor 4, is induced by LPS and inflammatory cytokines in mouse macrophages. J Immunol 2000, 165(10):5767-5772.
[153] Triantafilou M, Triantafilou K: Lipopolysaccharide recognition: CD14, TLRs andthe LPS-activation cluster. Trends Immunol 2002, 23(6):301-304.
[154] Nockher WA, Wick M, Pfister HW: Cerebrospinal fluid levels of soluble CD14 in inflammatory and non-inflammatory diseases of the CNS: upregulation during bacterial infections and viral meningitis. J Neuroimmunol 1999, 101(2):161-169.
[155] Martin MU, Wesche H: Summary and comparison of the signaling mechanisms of the Toll/interleukin-1 receptor family. Biochim Biophys Acta 2002, 1592(3):265-280.
[156] Grossman SA, Krabak MJ: Leptomeningeal carcinomatosis. Cancer Treat Rev 1999, 25(2):103-119.
[157] Bianchi G, Banfi A, Mastrogiacomo M, Notaro R, Luzzatto L, Cancedda R, Quarto R: Ex vivo enrichment of mesenchymal cell progenitors by fibroblast growth factor 2. Exp Cell Res 2003, 287(1):98-105.
[158] Laskowski A, Schmidt W, Dinkel K, Martinez-Sanchez M, Reymann KG: bFGF and EGF modulate trauma-induced proliferation and neurogenesis in juvenile organotypic hippocampal slice cultures. Brain Res 2005, 1037(1-2):78-89.
[159] Lachapelle F, Avellana-Adalid V, Nait-Oumesmar B, Baron-Van Evercooren A: Fibroblast growth factor-2 (FGF-2) and platelet-derived growth factor AB (PDGF AB) promote adult SVZ-derived oligodendrogenesis in vivo. Mol Cell Neurosci 2002, 20(3):390-403.
[160] Ciccolini F, Svendsen CN: Fibroblast growth factor 2 (FGF-2) promotes acquisition of epidermal growth factor (EGF) responsiveness in mouse striatal precursor cells: identification of neural precursors responding to both EGF and FGF-2. J Neurosci 1998, 18(19):7869-7880.
[161] Liu IH, Chen SJ, Ku HH, Kao CL, Tsai FT, Hsu WM, Lo CW, Kuo YH, Kuo CD, Lee CH, Chiou SH: Comparison of the proliferation and differentiation ability between adult rat retinal stem cells and cerebral cortex-derived neural stem cells. Ophthalmologica 2005, 219(3):171-176.
[162] Balasubramaniyan V, de Haas AH, Bakels R, Koper A, Boddeke HW, Copray JC: Functionally deficient neuronal differentiation of mouse embryonic neural stem cells in vitro. Neurosci Res 2004, 49(2):261-265.
[163] Ren W, Guo Q, Yang Y, Chen F: bFGF and heparin but not laminin are necessary factors in the mediums that affect NSCs differentiation into cholinergic neurons. Neurol Res 2006, 28(1):87-90.
[164] Barkho BZ, Song H, Aimone JB, Smrt RD, Kuwabara T, Nakashima K, Gage FH,Zhao X: Identification of astrocyte-expressed factors that modulate neural stem/progenitor cell differentiation. Stem Cells Dev 2006, 15(3):407-421.
[165] Mondal D, Pradhan L, LaRussa VF: Signal transduction pathways involved in the lineage-differentiation of NSCs: can the knowledge gained from blood be used in the brain? Cancer Invest 2004, 22(6):925-943.
[166] Taga T, Fukuda S: Role of IL-6 in the neural stem cell differentiation. Clin Rev Allergy Immunol 2005, 28(3):249-256.
[167] Pitman M, Emery B, Binder M, Wang S, Butzkueven H, Kilpatrick TJ: LIF receptor signaling modulates neural stem cell renewal. Mol Cell Neurosci 2004, 27(3):255-266.
[168] Oshima K, Teo DT, Senn P, Starlinger V, Heller S: LIF promotes neurogenesis and maintains neural precursors in cell populations derived from spiral ganglion stem cells. BMC Dev Biol 2007, 7:112.
[169] Koblar SA, Turnley AM, Classon BJ, Reid KL, Ware CB, Cheema SS, Murphy M, Bartlett PF: Neural precursor differentiation into astrocytes requires signaling through the leukemia inhibitory factor receptor. Proc Natl Acad Sci U S A 1998, 95(6):3178-3181.
[170] Emsley JG., Hagg T: Endogenous and exogenous ciliary neurotrophic factor enhances forebrain neurogenesis in adult mice. Exp Neurol 2003, 183(2):298-310.
[171] Shimazaki T, Shingo T, Weiss S: The ciliary neurotrophic factor/leukemia inhibitory factor/gp130 receptor complex operates in the maintenance of mammalian forebrain neural stem cells. J Neurosci 2001, 21(19):7642-7653.
[172] Sammons J, Ahmed N, El-Sheemy M, Hassan HT: The role of BMP-6, IL-6, and BMP-4 in mesenchymal stem cell-dependent bone development: effects on osteoblastic differentiation induced by parathyroid hormone and vitamin D(3). Stem Cells Dev 2004, 13(3):273-280.
[173] Jin G, Tan X, Tian M, Qin J, Zhu H, Huang Z, Xu H: The controlled differentiation of human neural stem cells into TH-immunoreactive (ir) neurons in vitro. Neurosci Lett 2005, 386(2):105-110.
[174] Dziewczapolski G, Lie DC, Ray J, Gage FH, Shults CW: Survival and differentiation of adult rat-derived neural progenitor cells transplanted to the striatum of hemiparkinsonian rats. Exp Neurol 2003, 183(2):653-664.
[175] Lee SH, Lumelsky N, Studer L, Auerbach JM, McKay RD: Efficient generation of midbrain and hindbrain neurons from mouse embryonic stem cells. Nat Biotechnol2000, 18(6):675-679.
[176] Studer L, Tabar V, McKay RD: Transplantation of expanded mesencephalic precursors leads to recovery in parkinsonian rats. Nat Neurosci 1998, 1(4):290-295.
[177] Sugaya K: Neuroreplacement therapy and stem cell biology under disease conditions. Cell Mol Life Sci 2003, 60(9):1891-1902.
[178] Salli U, Reddy AP, Salli N, Lu NZ, Kuo HC, Pau FK, Wolf DP, Bethea CL: Serotonin neurons derived from rhesus monkey embryonic stem cells: similarities to CNS serotonin neurons. Exp Neurol 2004, 188(2):351-364.
[179] Zhou J, Iacovitti L: Mechanisms governing the differentiation of a serotonergic phenotype in culture. Brain Res 2000, 877(1):37-46.
[180] Cowen DS: Serotonin and neuronal growth factors - a convergence of signaling pathways. J Neurochem 2007, 101(5):1161-1171.
[181] Xia Z, DePierre JW, Nassberger L: Tricyclic antidepressants inhibit IL-6, IL-1 beta and TNF-alpha release in human blood monocytes and IL-2 and interferon-gamma in T cells. Immunopharmacology 1996, 34(1):27-37.
[182] Konsman JP, Vigues S, Mackerlova L, Bristow A, Blomqvist A: Rat brain vascular distribution of interleukin-1 type-1 receptor immunoreactivity: relationship to patterns of inducible cyclooxygenase expression by peripheral inflammatory stimuli. J Comp Neurol 2004, 472(1):113-129.
[183] Williams JA, Shacter E: Regulation of macrophage cytokine production by prostaglandin E2. Distinct roles of cyclooxygenase-1 and -2. J Biol Chem 1997, 272(41):25693-25699.
[184] Ghezzi P, Sacco S, Agnello D, Marullo A, Caselli G, Bertini R: Lps induces IL-6 in the brain and in serum largely through TNF production. Cytokine 2000, 12(8):1205-1210.
[185] Geisterfer M, Richards CD, Gauldie J: Cytokines oncostatin M and interleukin 1 regulate the expression of the IL-6 receptor (gp80, gp130). Cytokine 1995, 7(6):503-509.
[186] Thabard W, Collette M, Mellerin MP, Puthier D, Barille S, Bataille R, Amiot M: IL-6 upregulates its own receptor on some human myeloma cell lines. Cytokine 2001, 14(6):352-356.
[187] Wang T, Wang BR, Zhao HZ, Kuang F, Duan XL, Ju G. Lipopolysaccharide up-regulates IL-6Rα expression in culturedleptomeningeal cells via activation of ERK1/2 pathway. Neurochemical Res 2008 Mar 21(Epub ahead of print)
[188] Dobrovolskaia MA, Vogel SN: Toll receptors, CD14, and macrophage activation and deactivation by LPS. Microbes Infect 2002, 4(9):903-914.
[189] Chakravarty S, Herkenham M: Toll-like receptor 4 on nonhematopoietic cells sustains CNS inflammation during endotoxemia, independent of systemic cytokines. J Neurosci 2005, 25(7):1788-1796.
[190] Armstrong L, Hughes O, Yung S, Hyslop L, Stewart R, Wappler I, Peters H, Walter T, Stojkovic P, Evans J, Stojkovic M, Lako M: The role of PI3K/AKT, MAPK/ERK and NFkappabeta signalling in the maintenance of human embryonic stem cell pluripotency and viability highlighted by transcriptional profiling and functional analysis. Hum Mol Genet 2006, 15(11):1894-1913.
[191] Campos LS, Leone DP, Relvas JB, Brakebusch C, Fassler R, Suter U, ffrench-Constant C: Beta1 integrins activate a MAPK signalling pathway in neural stem cells that contributes to their maintenance. Development 2004, 131(14):3433-3444.
[192] Hao Y, Creson T, Zhang L, Li P, Du F, Yuan P, Gould TD, Manji HK, Chen G: Mood stabilizer valproate promotes ERK pathway-dependent cortical neuronal growth and neurogenesis. J Neurosci 2004, 24(29):6590-6599.
[193] Bonni A, Sun Y, Nadal-Vicens M, Bhatt A, Frank DA, Rozovsky I, Stahl N, Yancopoulos GD, Greenberg ME: Regulation of gliogenesis in the central nervous system by the JAK-STAT signaling pathway. Science 1997, 278(5337):477-483.
[194] McKay R: Stem cells in the central nervous system. Science 1997, 276(5309):66-71.
[195] Takizawa T, Yanagisawa M, Ochiai W, Yasukawa K, Ishiguro T, Nakashima K, Taga T: Directly linked soluble IL-6 receptor-IL-6 fusion protein induces astrocyte differentiation from neuroepithelial cells via activation of STAT3. Cytokine 2001, 13(5):272-279.
[196] He F, Ge W, Martinowich K, Becker-Catania S, Coskun V, Zhu W, Wu H, Castro D, Guillemot F, Fan G, de Vellis J, Sun YE: A positive autoregulatory loop of Jak-STAT signaling controls the onset of astrogliogenesis. Nat Neurosci 2005, 8(5):616-625.
[197] Sun Y, Nadal-Vicens M, Misono S, Lin MZ, Zubiaga A, Hua X, Fan G, GreenbergME: Neurogenin promotes neurogenesis and inhibits glial differentiation by independent mechanisms. Cell 2001, 104(3):365-376.
[198] Yanagisawa M, Nakashima K, Arakawa H, Ikenaka K, Yoshida K, Kishimoto T, Hisatsune T, Taga T: Astrocyte differentiation of fetal neuroepithelial cells by interleukin-11 via activation of a common cytokine signal transducer, gp130, and a transcription factor, STAT3. J Neurochem 2000, 74(4):1498-1504.
[199] Erices A, Conget P, Rojas C, Minguell JJ: Gp130 activation by soluble interleukin-6 receptor/interleukin-6 enhances osteoblastic differentiation of human bone marrow-derived mesenchymal stem cells. Exp Cell Res 2002, 280(1):24-32.
[200] Grandoso L, Torrecilla M, Pineda J, Ugedo L: alpha(2)-Adrenoceptor involvement in the in vitro inhibitory effect of citalopram on a subpopulation of rat locus coeruleus neurons. Eur J Pharmacol 2005, 517(1-2):51-58.
[201] Laeng P, Pitts RL, Lemire AL, Drabik CE, Weiner A, Tang H, Thyagarajan R, Mallon BS, Altar CA: The mood stabilizer valproic acid stimulates GABA neurogenesis from rat forebrain stem cells. J Neurochem 2004, 91(1):238-251.
[202] Hashimoto R, Senatorov V, Kanai H, Leeds P, Chuang DM: Lithium stimulates progenitor proliferation in cultured brain neurons. Neuroscience 2003, 117(1):55-61.
[203] Madsen TM, Treschow A, Bengzon J, Bolwig TG, Lindvall O, Tingstrom A: Increased neurogenesis in a model of electroconvulsive therapy. Biol Psychiatry 2000, 47(12):1043-1049.
[204] Malberg JE, Eisch AJ, Nestler EJ, Duman RS: Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. J Neurosci 2000, 20(24):9104-9110.
[205] Manev H, Uz T, Smalheiser NR, Manev R: Antidepressants alter cell proliferation in the adult brain in vivo and in neural cultures in vitro. Eur J Pharmacol 2001, 411(1-2):67-70.
[206] Jacobs BL, Praag H, Gage FH: Adult brain neurogenesis and psychiatry: a novel theory of depression. Mol Psychiatry 2000, 5(3):262-269.
[207] Nibuya M, Morinobu S, Duman RS: Regulation of BDNF and trkB mRNA in rat brain by chronic electroconvulsive seizure and antidepressant drug treatments. J Neurosci 1995, 15(11):7539-7547.
[208] Nibuya M, Nestler EJ, Duman RS: Chronic antidepressant administration increases the expression of cAMP response element binding protein (CREB) in rathippocampus. J Neurosci 1996, 16(7):2365-2372.
[209] Thome J, Sakai N, Shin K, Steffen C, Zhang YJ, Impey S, Storm D, Duman RS: cAMP response element-mediated gene transcription is upregulated by chronic antidepressant treatment. J Neurosci 2000, 20(11):4030-4036.
[210] Finkbeiner S: CREB couples neurotrophin signals to survival messages. Neuron 2000, 25(1):11-14.
[211] Palmer TD, Takahashi J, Gage FH: The adult rat hippocampus contains primordial neural stem cells. Mol Cell Neurosci 1997, 8(6):389-404.
[212] Brezun JM, Daszuta A: Serotonin may stimulate granule cell proliferation in the adult hippocampus, as observed in rats grafted with foetal raphe neurons. Eur J Neurosci 2000, 12(1):391-396.
[213] Kubera M, Simbirtsev A, Mathison R, Maes M: Effects of repeated fluoxetine and citalopram administration on cytokine release in C57BL/6 mice. Psychiatry Res 2000, 96(3):255-266.
[214] Einat H, Yuan P, Gould TD, Li J, Du J, Zhang L, Manji HK, Chen G: The role of the extracellular signal-regulated kinase signaling pathway in mood modulation. J Neurosci 2003, 23(19):7311-7316.
[215] Yuan PX, Huang LD, Jiang YM, Gutkind JS, Manji HK, Chen G: The mood stabilizer valproic acid activates mitogen-activated protein kinases and promotes neurite growth. J Biol Chem 2001, 276(34):31674-31683.
[216] Sahin Kaya S, Mahmood A, Li Y, Yavuz E, Chopp M: Expression of nestin after traumatic brain injury in rat brain. Brain Res 1999, 840(1-2):153-157.
[217] Lang B, Liu HL, Liu R, Feng GD, Jiao XY, Ju G: Astrocytes in injured adult rat spinal cord may acquire the potential of neural stem cells. Neuroscience 2004, 128(4):775-783.
[218] Faulkner JR, Herrmann JE, Woo MJ, Tansey KE, Doan NB, Sofroniew MV: Reactive astrocytes protect tissue and preserve function after spinal cord injury. J Neurosci 2004, 24(9):2143-2155.
[219] Iseda T, Nishio T, Kawaguchi S, Yamanoto M, Kawasaki T, Wakisaka S: Spontaneous regeneration of the corticospinal tract after transection in young rats: a key role of reactive astrocytes in making favorable and unfavorable conditions for regeneration. Neuroscience 2004, 126(2):365-374.
[220] Chen J, Leong SY, Schachner M: Differential expression of cell fate determinants in neurons and glial cells of adult mouse spinal cord after compression injury. Eur JNeurosci 2005, 22(8):1895-1906.
[221] Frisen J, Johansson CB, Torok C, Risling M, Lendahl U: Rapid, widespread, and longlasting induction of nestin contributes to the generation of glial scar tissue after CNS injury. J Cell Biol 1995, 131(2):453-464.
[222] Song H, Stevens CF, Gage FH: Astroglia induce neurogenesis from adult neural stem cells. Nature 2002, 417(6884):39-44.