表达NgRs的活化巨噬细胞在大鼠脊髓损伤修复中的作用机制
|
摘要
一、研究背景
脊髓损伤后(Spinal cord injury,SCI)轴突难以有效再生是脊髓损伤研究的难点之一,这与脊髓损伤后周围环境中存在不利于轴突生长的抑制因子有关。
近年来,髓鞘相关抑制分子如Nogo-A、髓鞘相关糖蛋白(Myelin-associated glycoprotein,MAG)、少突胶质细胞髓鞘糖蛋白(Oligodendrocyte-myelin glycoprotein,OMgp)及Nogo-66受体(Nogo-66 receptors,NgRs)介导的信号转导途径的相继发现深化了人们对SCI轴突再生分子机制的认识,同时也找到了SCI治疗研究新的切入点,以Nogo或NgRs为靶点的治疗成为脊髓损伤研究新的热点。
然而,迄今为止,相关实验研究仍未取得突破性进展:单克隆抗体IN-1可以拮抗Nogo的抑制作用,但无法与另外两种抑制物MAG和OMgp结合;NgRs的竞争性短肽NEPI-40可对抗Nogo-66诱导的轴突生长抑制作用,但对除Nogo-66外的其他髓鞘抑制物不敏感。因此,找到另一种更有效清除髓鞘抑制因子的办法成为当务之急。
巨噬细胞是人体内的炎性细胞,在创伤修复过程中起着重要作用。目前,对巨噬细胞在中枢神经系统损伤修复中的作用,人们的认识并不一致:一种认为巨噬细胞对轴突生长有抑制作用;另一种则认为巨噬细胞对轴突的再生起到促进作用。既往观点认为,中枢神经系统的无菌性炎症反应是有害的,尤其对于SCI后的反应。然而,在整个机体组织的修复过程中,炎性反应贯穿始终,而炎性细胞中,巨噬细胞发挥了主要作用,它能清除坏死组织并分泌营养因子,在所有机体组织修复中起着重要作用。
近期研究显示,巨噬细胞在髓鞘碎片吞噬、促进轴突再生及再髓鞘化过程中发挥的作用可能超出我们的预期。1998年,Zeev-Brann报道成熟哺乳动物中枢神经系统损伤后的自我修复过程中发现了骨髓衍生炎性细胞;随后,2003年,Buss等发现巨噬细胞在局部的延迟浸润与脊髓挫伤后髓鞘碎片的持续存在密切相关,并且可导致轴突再髓鞘化过程受抑制。2007年,Samuel David等则进一步证实,巨噬细胞是否表达NgRs及其浸润与撤离过程关系到轴突再髓鞘化过程能否顺利进行,并进而影响脊髓神经细胞的生理机能恢复。
二、研究目的
分离、培养、鉴定大鼠脊髓损伤局部巨噬细胞,并对其形态、生长特点等生物学特性进行研究,观察其是否表达NgRs;研究原代神经干细胞(neural stem cells,NSCs)及嗅鞘细胞(Olfactory ensheathing cells, OECs)等的体外分离方法、细胞培养体系,探讨巨噬细胞、神经干细胞及嗅鞘细胞的移植应用可行性;将表达NgRs的巨噬细胞与神经干细胞联合移植到脊髓全横断损伤大鼠模型体内,并与嗅鞘细胞、神经干细胞等不同移植组比较,观察其对移植神经干细胞存活、分化、突触形成及大鼠脊髓神经功能恢复情况的影响,探讨表达NgRs的巨噬细胞在脊髓损伤修复中的可能作用机制,为进一步动物研究及临床应用提供实验和理论依据。
三、内容和方法
(一)用酶消化法分离获取大鼠脊髓损伤局部原代巨噬细胞,对其进行生物学鉴定,观察其细胞形态、生长特点,使用免疫荧光化学染色观察其NgRs表达情况;
(二)分离新生大鼠嗅球,解剖显微镜下选取嗅球最外二层进行酶解后培养,利用延迟差速贴壁法结合阿糖胞苷抑制剂法对嗅鞘细胞进行纯化,用免疫细胞化学方法鉴定不同时期嗅鞘细胞的纯度;
(三)无菌条件下分离鼠胚脑组织,使用含DNA酶的胰蛋白酶消化后制作神经干细胞单细胞悬液,DMEM/F12培养基悬浮培养,观察其细胞学特点与生长曲线,添加诱导剂后观察其分化情况;
(四)选取细胞活力旺盛的原代巨噬细胞、嗅鞘细胞及神经干细胞,调整细胞浓度,hoechst33342标记神经干细胞;将脊髓全横断模型大鼠分为4组,分别移植巨噬细胞和NSCs悬液、OECs和NSCs悬液、NSCs悬液、DMEM/F12培养液;观察术后各组
神经干细胞存活、分化、突触形成及大鼠BBB运动功能评分等各项指标。四、研究结果
(一)原代培养的巨噬细胞1小时后迅速贴壁生长,细胞形态呈圆形、椭圆形等,体积大,胞浆丰富,培养1～2周内细胞活动旺盛,免疫荧光化学染色显示CD68抗原阳性,多数细胞NgRs抗原阳性;
(二)原代培养5d的OECs胞体呈长梭形,多极状,立体感强,折光性好。8d后,胞体变大,突起变长,并逐渐相互交织成网。14d后细胞主要表现为双极、三极形态,贴壁第2、7d的细胞染色,P75阳性达到95%以上,随后阳性率逐步下降,第14d细胞染色阳性率降至90%。25d则仅为50%;
(三)原代培养的神经干细胞呈球团状悬浮生长,球体折光性好,边缘毛躁,细胞排列整齐,高倍镜下可见神经球周边毛刺状的细小突起,细胞生长速度较快。免疫细胞化学染色提示Nestin抗原阳性,添加血清诱导后,可分化成NF-200及GFAP抗原阳性细胞。
(四)表达NgRs的巨噬细胞与神经干细胞联合移植4W后,SCI大鼠BBB运动功能评分明显高于对照组、NSCs组及OECs、NSCs联合移植组,具有统计学差异(P<0.05),且随着时间延长差异更显著;同时,荧光显微镜下观察到该组hoechst33342标记神经干细胞荧光强度及密度也较其余三组高,该组免疫组织化学染色可观察到更多的NF-200阳性细胞及Synaptophysin抗体染色阳性细胞。
五、实验结论
成功地从脊髓损伤局部分离出表达NgRs抗原的巨噬细胞,对其细胞学特性及生物学特性获得一定了解,获得足够数量的NSCs及OECs,为实验研究提供了理想的移植材料;表达NgRs的巨噬细胞能改善脊髓轴突再生微环境,提高移植神经干细胞的生存率和神经元分化率,有利于神经细胞突起间突触的形成,进而促进损伤脊髓的神经功能恢复。其机制可能是巨噬细胞通过表达的NgRs介导胞内信号途径调节对髓鞘等坏死组织的吞噬作用,从而为神经再生创造条件。这为脊髓损伤的治疗研究提供了一个新的解决途径,也为进一步动物研究和临床应用奠定了可靠的实验基础和理论依据。
Back ground
Although the inhibitory environment of the CNS has been recognized one of the most difficulties for axonal regeneration, not until the past several decades have CNS myelin and related molecules become appreciated as primary blockades to CNS regeneration after injury and that’s why the clinical symptom occurs.
In recent several years, some molecules were discovered one after another such as Nogo-A, Myelin associated glycoprotein, Oligodendrocyte myelin glycoprotein and signal transduction pathway mediated by Nogo receptors which enhanced our understanding of mechanism for axonal regeneration in SCI. The treatments aimed at Nogo and Nogo receptors have became a new hot spot.
But until now, the outcomes of such research were not enough to overcome the difficulties. Monoclonal antibody IN-1 can block the axonal inhibitory effect of Nogo, but not for MAG and OMgp. NEPI-40, the antagonist of NgRs can only suppress the adverse effect of Nogo-66. It’s important to find another method to remove the myelin inhibitors.
Macrophage is one kind of inflammatory cell which plays a pivotal role for repair in trauma. Now, with regard to the role of macrophages in CNS repair there are two points of view. One kind of view thinks that macrophages can promote the axonal regeneration, another is the opposite. It was used to consider aseptic inflammation harmful in CNS, especially in SCI. In fact, the whole process of repair is accompanied with inflammation in human body. In the process, macrophages play major roles which could get rid of the necrotic tissues and secrete nutrition factors.
Recent research showed that macrophages could have more influence in phagocytosis of myelin pieces, promoting axonal regeneration and re-myelinization. In 1998, Zeev-Brann reported that bone marrow derived inflammatory cell appeared in repair of CNS injury and it was proved by Buss that delayed infiltration of macrophages in the injured region led to the persistent exist of myelin pieces which could inhibit re-myelinization of axon. In 2007, it was confirmed by Samuel David that whether macrophages expressed with NgRs and its infiltration process had close relationship with axonal re-myelinization, which have deep impact on physiologic function of neural cell. We expect to provide a new method for treatment of SCI and accumulate experimental and theoretical evidences for further animal study and clinical application.
Objective
To investigate the isolation, culture methods and evaluation of macrophages expressed with NgRs in vitro in preliminary and reveal the biological characteristics of the cells. To explore the separation, cultivation methods and practical potential of primary neural stem cells and olfactory ensheathing cells in vitro. To delivery the macrophages expressed with NgRs and NSCs to the wounds of SCI rat and compare the survival rate, cell differentiation, synapse formation and recovery of neurological function with other transplantation groups. To investigate the mechanism of the macrophages expressed with NgRs in recovery of SCI rat and to establish a foundation for further research in animal experiments and clinical applications.
Methods
1. Primary macrophages were harvested from injured spinal cord and digested with trypsin, and the morphological, biological characteristics and the NgRs antigen positive cells with methods of immunochemistry staining were observed.
2. Primary OECs were isolated from the olfactory bulb of new born rat and digested with trypsin, and purified with delaying differing rates of various cell types and method of Ara-C inhibition. The percent of P75 positive cells was calculated with methods of immunochemistry staining.
3. Embryonic brain of rats were chosen to isolate primary NSC with aseptic technique by trypsin digestion. The culture medium was added with nutrition factors in order to increase the amount of cells and the morphological characteristics, growth curve and cell differentiation were recorded.
4. Nine to ten days after models of rat spinal cord injury were established, primary macrophages, OECs and labled NSC were selected to deliver to the four groups of SCI rat with different methods. The data of survival rate, cell differentiation, synapse formation and recovery of neurological function in each group were surveyed.
Results
1. Most of the primary macrophages presented round and elliptic shape after adherence for one hour. The macrophages displayed with active metabolism could survive for about 3 weeks and be marked by CD68 antibody and NgR antibody for majority of the cells.
2. Primary OECs were successfully cultured and the body of OECs in the fifth day presented with two kinds of shapes:fusiform and multipolar. Their quality of profile was real and had good refraction. Eight days later, their body became larger and the increased process wove into net each other. Fourteen days later, majority of OECs showed themselves two morphological types:bipolar and tripolar. The percent of P75 positive cells decreased gradually from the beginning of the first week.
3. The suspended primary NSCs developed into mulberry-like cells with little process and expressed with nestin antigen. They could also express phenotypic NF-200 marker of neuron and GFAP marker of astrocyte after being induced to differentiation. Being marked by BrdU was adopted to examine the ability of renewing themselves.
4. From 4 to 10 weeks ,the BBB locomotion scores of all transplantion groups, especially the co-transplantation group of macrophages and NSCs, were improved significantly contrasting to that of the control group (P<0.05). Transplanted NSCs can survive for at least ten weeks and differentiated into neurons and astrocytes. Immunohistochemitry staining of NF-200 and synaptophysin showed the co-transplantion group of macrophages and NSCs had a higher percent of positive rate than that of the other three groups.
Conclusion
The macrophages presented with NgR antigen were isolated from the traumatic spinal cord tissues successfully and the morphological, biological characteristics were discovered. Enough OECs and NSCs were harvested and proved to be eligible resources for potential experimental application in research. Macrophages presented with NgRs antigen could alter the microenviroment and improve the survival and differentiation rate of NSCs grafts, thus promote the synapse formation and neurological recovery of SCI rat. Signal transduction pathway mediated by by Nogo receptors might be the key, which could conduct the process of phagocytosis in myelin pieces elimination and be beneficial for neural regeneration.
脊髓损伤后(Spinal cord injury,SCI)轴突难以有效再生是脊髓损伤研究的难点之一,这与脊髓损伤后周围环境中存在不利于轴突生长的抑制因子有关。
近年来,髓鞘相关抑制分子如Nogo-A、髓鞘相关糖蛋白(Myelin-associated glycoprotein,MAG)、少突胶质细胞髓鞘糖蛋白(Oligodendrocyte-myelin glycoprotein,OMgp)及Nogo-66受体(Nogo-66 receptors,NgRs)介导的信号转导途径的相继发现深化了人们对SCI轴突再生分子机制的认识,同时也找到了SCI治疗研究新的切入点,以Nogo或NgRs为靶点的治疗成为脊髓损伤研究新的热点。
然而,迄今为止,相关实验研究仍未取得突破性进展:单克隆抗体IN-1可以拮抗Nogo的抑制作用,但无法与另外两种抑制物MAG和OMgp结合;NgRs的竞争性短肽NEPI-40可对抗Nogo-66诱导的轴突生长抑制作用,但对除Nogo-66外的其他髓鞘抑制物不敏感。因此,找到另一种更有效清除髓鞘抑制因子的办法成为当务之急。
巨噬细胞是人体内的炎性细胞,在创伤修复过程中起着重要作用。目前,对巨噬细胞在中枢神经系统损伤修复中的作用,人们的认识并不一致:一种认为巨噬细胞对轴突生长有抑制作用;另一种则认为巨噬细胞对轴突的再生起到促进作用。既往观点认为,中枢神经系统的无菌性炎症反应是有害的,尤其对于SCI后的反应。然而,在整个机体组织的修复过程中,炎性反应贯穿始终,而炎性细胞中,巨噬细胞发挥了主要作用,它能清除坏死组织并分泌营养因子,在所有机体组织修复中起着重要作用。
近期研究显示,巨噬细胞在髓鞘碎片吞噬、促进轴突再生及再髓鞘化过程中发挥的作用可能超出我们的预期。1998年,Zeev-Brann报道成熟哺乳动物中枢神经系统损伤后的自我修复过程中发现了骨髓衍生炎性细胞;随后,2003年,Buss等发现巨噬细胞在局部的延迟浸润与脊髓挫伤后髓鞘碎片的持续存在密切相关,并且可导致轴突再髓鞘化过程受抑制。2007年,Samuel David等则进一步证实,巨噬细胞是否表达NgRs及其浸润与撤离过程关系到轴突再髓鞘化过程能否顺利进行,并进而影响脊髓神经细胞的生理机能恢复。
二、研究目的
分离、培养、鉴定大鼠脊髓损伤局部巨噬细胞,并对其形态、生长特点等生物学特性进行研究,观察其是否表达NgRs;研究原代神经干细胞(neural stem cells,NSCs)及嗅鞘细胞(Olfactory ensheathing cells, OECs)等的体外分离方法、细胞培养体系,探讨巨噬细胞、神经干细胞及嗅鞘细胞的移植应用可行性;将表达NgRs的巨噬细胞与神经干细胞联合移植到脊髓全横断损伤大鼠模型体内,并与嗅鞘细胞、神经干细胞等不同移植组比较,观察其对移植神经干细胞存活、分化、突触形成及大鼠脊髓神经功能恢复情况的影响,探讨表达NgRs的巨噬细胞在脊髓损伤修复中的可能作用机制,为进一步动物研究及临床应用提供实验和理论依据。
三、内容和方法
(一)用酶消化法分离获取大鼠脊髓损伤局部原代巨噬细胞,对其进行生物学鉴定,观察其细胞形态、生长特点,使用免疫荧光化学染色观察其NgRs表达情况;
(二)分离新生大鼠嗅球,解剖显微镜下选取嗅球最外二层进行酶解后培养,利用延迟差速贴壁法结合阿糖胞苷抑制剂法对嗅鞘细胞进行纯化,用免疫细胞化学方法鉴定不同时期嗅鞘细胞的纯度;
(三)无菌条件下分离鼠胚脑组织,使用含DNA酶的胰蛋白酶消化后制作神经干细胞单细胞悬液,DMEM/F12培养基悬浮培养,观察其细胞学特点与生长曲线,添加诱导剂后观察其分化情况;
(四)选取细胞活力旺盛的原代巨噬细胞、嗅鞘细胞及神经干细胞,调整细胞浓度,hoechst33342标记神经干细胞;将脊髓全横断模型大鼠分为4组,分别移植巨噬细胞和NSCs悬液、OECs和NSCs悬液、NSCs悬液、DMEM/F12培养液;观察术后各组
神经干细胞存活、分化、突触形成及大鼠BBB运动功能评分等各项指标。四、研究结果
(一)原代培养的巨噬细胞1小时后迅速贴壁生长,细胞形态呈圆形、椭圆形等,体积大,胞浆丰富,培养1～2周内细胞活动旺盛,免疫荧光化学染色显示CD68抗原阳性,多数细胞NgRs抗原阳性;
(二)原代培养5d的OECs胞体呈长梭形,多极状,立体感强,折光性好。8d后,胞体变大,突起变长,并逐渐相互交织成网。14d后细胞主要表现为双极、三极形态,贴壁第2、7d的细胞染色,P75阳性达到95%以上,随后阳性率逐步下降,第14d细胞染色阳性率降至90%。25d则仅为50%;
(三)原代培养的神经干细胞呈球团状悬浮生长,球体折光性好,边缘毛躁,细胞排列整齐,高倍镜下可见神经球周边毛刺状的细小突起,细胞生长速度较快。免疫细胞化学染色提示Nestin抗原阳性,添加血清诱导后,可分化成NF-200及GFAP抗原阳性细胞。
(四)表达NgRs的巨噬细胞与神经干细胞联合移植4W后,SCI大鼠BBB运动功能评分明显高于对照组、NSCs组及OECs、NSCs联合移植组,具有统计学差异(P<0.05),且随着时间延长差异更显著;同时,荧光显微镜下观察到该组hoechst33342标记神经干细胞荧光强度及密度也较其余三组高,该组免疫组织化学染色可观察到更多的NF-200阳性细胞及Synaptophysin抗体染色阳性细胞。
五、实验结论
成功地从脊髓损伤局部分离出表达NgRs抗原的巨噬细胞,对其细胞学特性及生物学特性获得一定了解,获得足够数量的NSCs及OECs,为实验研究提供了理想的移植材料;表达NgRs的巨噬细胞能改善脊髓轴突再生微环境,提高移植神经干细胞的生存率和神经元分化率,有利于神经细胞突起间突触的形成,进而促进损伤脊髓的神经功能恢复。其机制可能是巨噬细胞通过表达的NgRs介导胞内信号途径调节对髓鞘等坏死组织的吞噬作用,从而为神经再生创造条件。这为脊髓损伤的治疗研究提供了一个新的解决途径,也为进一步动物研究和临床应用奠定了可靠的实验基础和理论依据。
Back ground
Although the inhibitory environment of the CNS has been recognized one of the most difficulties for axonal regeneration, not until the past several decades have CNS myelin and related molecules become appreciated as primary blockades to CNS regeneration after injury and that’s why the clinical symptom occurs.
In recent several years, some molecules were discovered one after another such as Nogo-A, Myelin associated glycoprotein, Oligodendrocyte myelin glycoprotein and signal transduction pathway mediated by Nogo receptors which enhanced our understanding of mechanism for axonal regeneration in SCI. The treatments aimed at Nogo and Nogo receptors have became a new hot spot.
But until now, the outcomes of such research were not enough to overcome the difficulties. Monoclonal antibody IN-1 can block the axonal inhibitory effect of Nogo, but not for MAG and OMgp. NEPI-40, the antagonist of NgRs can only suppress the adverse effect of Nogo-66. It’s important to find another method to remove the myelin inhibitors.
Macrophage is one kind of inflammatory cell which plays a pivotal role for repair in trauma. Now, with regard to the role of macrophages in CNS repair there are two points of view. One kind of view thinks that macrophages can promote the axonal regeneration, another is the opposite. It was used to consider aseptic inflammation harmful in CNS, especially in SCI. In fact, the whole process of repair is accompanied with inflammation in human body. In the process, macrophages play major roles which could get rid of the necrotic tissues and secrete nutrition factors.
Recent research showed that macrophages could have more influence in phagocytosis of myelin pieces, promoting axonal regeneration and re-myelinization. In 1998, Zeev-Brann reported that bone marrow derived inflammatory cell appeared in repair of CNS injury and it was proved by Buss that delayed infiltration of macrophages in the injured region led to the persistent exist of myelin pieces which could inhibit re-myelinization of axon. In 2007, it was confirmed by Samuel David that whether macrophages expressed with NgRs and its infiltration process had close relationship with axonal re-myelinization, which have deep impact on physiologic function of neural cell. We expect to provide a new method for treatment of SCI and accumulate experimental and theoretical evidences for further animal study and clinical application.
Objective
To investigate the isolation, culture methods and evaluation of macrophages expressed with NgRs in vitro in preliminary and reveal the biological characteristics of the cells. To explore the separation, cultivation methods and practical potential of primary neural stem cells and olfactory ensheathing cells in vitro. To delivery the macrophages expressed with NgRs and NSCs to the wounds of SCI rat and compare the survival rate, cell differentiation, synapse formation and recovery of neurological function with other transplantation groups. To investigate the mechanism of the macrophages expressed with NgRs in recovery of SCI rat and to establish a foundation for further research in animal experiments and clinical applications.
Methods
1. Primary macrophages were harvested from injured spinal cord and digested with trypsin, and the morphological, biological characteristics and the NgRs antigen positive cells with methods of immunochemistry staining were observed.
2. Primary OECs were isolated from the olfactory bulb of new born rat and digested with trypsin, and purified with delaying differing rates of various cell types and method of Ara-C inhibition. The percent of P75 positive cells was calculated with methods of immunochemistry staining.
3. Embryonic brain of rats were chosen to isolate primary NSC with aseptic technique by trypsin digestion. The culture medium was added with nutrition factors in order to increase the amount of cells and the morphological characteristics, growth curve and cell differentiation were recorded.
4. Nine to ten days after models of rat spinal cord injury were established, primary macrophages, OECs and labled NSC were selected to deliver to the four groups of SCI rat with different methods. The data of survival rate, cell differentiation, synapse formation and recovery of neurological function in each group were surveyed.
Results
1. Most of the primary macrophages presented round and elliptic shape after adherence for one hour. The macrophages displayed with active metabolism could survive for about 3 weeks and be marked by CD68 antibody and NgR antibody for majority of the cells.
2. Primary OECs were successfully cultured and the body of OECs in the fifth day presented with two kinds of shapes:fusiform and multipolar. Their quality of profile was real and had good refraction. Eight days later, their body became larger and the increased process wove into net each other. Fourteen days later, majority of OECs showed themselves two morphological types:bipolar and tripolar. The percent of P75 positive cells decreased gradually from the beginning of the first week.
3. The suspended primary NSCs developed into mulberry-like cells with little process and expressed with nestin antigen. They could also express phenotypic NF-200 marker of neuron and GFAP marker of astrocyte after being induced to differentiation. Being marked by BrdU was adopted to examine the ability of renewing themselves.
4. From 4 to 10 weeks ,the BBB locomotion scores of all transplantion groups, especially the co-transplantation group of macrophages and NSCs, were improved significantly contrasting to that of the control group (P<0.05). Transplanted NSCs can survive for at least ten weeks and differentiated into neurons and astrocytes. Immunohistochemitry staining of NF-200 and synaptophysin showed the co-transplantion group of macrophages and NSCs had a higher percent of positive rate than that of the other three groups.
Conclusion
The macrophages presented with NgR antigen were isolated from the traumatic spinal cord tissues successfully and the morphological, biological characteristics were discovered. Enough OECs and NSCs were harvested and proved to be eligible resources for potential experimental application in research. Macrophages presented with NgRs antigen could alter the microenviroment and improve the survival and differentiation rate of NSCs grafts, thus promote the synapse formation and neurological recovery of SCI rat. Signal transduction pathway mediated by by Nogo receptors might be the key, which could conduct the process of phagocytosis in myelin pieces elimination and be beneficial for neural regeneration.
引文
1. McGee AW, Strittmatter SM. The Nogo-66 receptor: focusing myelin inhibition of axon regeneration. Trends Neurosci, 2003, 26: 193-198.
2. Prinjha R, Moore SE, Vinson M, et al. Inhibitor of neurite outgrowth in humans. Nature, 2000, 403: 383-384.
3. Bareeyre F.M.Neuronal repair and replacement in spinal cord injury.J Neurol Sci.2008(265):63-72
4. Chen MS, Huber AB, van der Haar ME ,et al. Nogo-A is a myelin-associated neurite outgrowth inhibitor and an antigen for monoclonal antibody IN-1.Nature, 2000, 403: 434-439.
5. GrandPre T, Nakamura F, Vartanian T, et al. Identification of the Nogo inhibitor of axon regeneration as a Reticulon protein. Nature, 2000, 403: 439-444.
6. Huber AB., Weinmann O, Br?samle C, et al. Patterns of Nogo mRNA and Protein Expression in the Developing and Adult Rat and After CNS Lesions. J. Neurosci, 2002, 22: 3553 - 3567.
7. Wang X, Chun SJ, Treloar H, et al. Localization of Nogo-A and Nogo-66 Receptor Proteins at Sites of Axon-Myelin and Synaptic Contact. J. Neurosci, 2002, 22: 5505 - 5515.
8. Simonen M, Pedersen V. Systemic deletion of the myelin-associated outgrowth inhibitor Nogo-A improves regenerative and plastic responses after spinal cord injury. Neuron, 2003,38: 201-11
9. Mukhopadhhyay G ,Doherty P ,Walsh FS ,et al. A novel role of myelin-associated glycoprotein as an inhibitor of axonal regeneration . Neuron ,1994,13:757-767
10. Wang k.C, Koprivica V, Kim JA, et al. Oligodendrocyte-myelin glycoprotein is a Nogo receptor ligand that inhibits neurite outgrowth. Nature, 2002, 417: 941-4.
11. Habib AA, Marton LS, Allwardt B, et al. Expression of the oligodendrocyte-myelin glycoprotein by neurons in the mouse central nervous system. J Neurochem, 1998, 70: 1704-1711.
12. Fournier AE, GrandPre T, and Strittmatter SM. Identification of a receptor mediating Nogo-66 inhibition of axonal regeneration. Nature, 2001, 409: 341-346.
13. Fournier AE, Gould GC, Liu BP, et al.Truncated Soluble Nogo Receptor Binds Nogo-66 and Blocks Inhibition of Axon Growth by Myelin. J. Neurosci, 2002, 22: 8876 - 8883.
14. Wang KC, Kim JA, Sivasankaran R,et al. P75 interacts with the Nogo receptor as a co-receptor for Nogo, MAG and OMgp. Nature, 2002, 420: 74-8.
15. Wong ST, Henley JR, Kanning KC, et al. A p75(NTR) and Nogo receptor complex mediates repulsive signaling by myelin-associated glycoprotein. Nat Neurosci, 2002,5: 1302-1308.
16. M. Nikolic. The role of Rho GTPases and associated kinases in regulating neurite outgrowth. Int. J. Biochem. Cell Biol, 2002, 34:731–745.
17. Dergham P, Ellezam B, Essagian C, et al.Rho Signaling Pathway Targeted to Promote Spinal CordRepair. J. Neurosci, 2002,22: 6570 - 6577.
18. David S, Lacroix S .Molecular approaches to spinal cord repair. Annu Rev Neurosci, 2003, 26: 411-40
19. Fouad K, Volker D,Schwab M.E. Improving axonal growth and functional recovery after experimental spinal cord injury by neutralizing myelin associated inhibitors. Brain Res Rev, 2001,36:204-212
20. Emerick AJ, Neafsey EJ. Functional reorganization of the motor cortex in adult rats after cortical lesion and treatment with monoclonal antibody IN-1. J-Neurosci, 2003,23: 4826-30
21. Horner P.J,Gage F.H. Regenerating the damaged central nervous system. Nature, 2000,407:963–970.
22. Cui Q, Cho KS. Synergistic effect of Nogo-neutralizing antibody IN-1 and ciliary neurotrophic factor on axonal regeneration in adult rodent visual systems. J-Neurotrauma, 2004 ,21: 617-25
23. GrandPre T, Li S, Strittmatter SM. Nogo-66 receptor antagonist peptide promotes axonal regeneration. Nature, 2002,417:568-573
24. Li S; Strittmatter SM. Delayed systemic Nogo-66 receptor antagonist promotes recovery from spinal cord injury. J-Neurosci, 2003,23: 4219-27
25. Sicotte M, Tsatas O, Jeong SY, et al. Immunization with myelin or recombinant Nogo-66/MAG in alum promotes axon regeneration and sprouting after corticospinal tract lesions in the spinal cord.Mol Cell Neurosci, 2003, 23: 251-63.
26. Xu G, Nie DY, Chen JT, et al. Recombinant DNA encoding multiple domains related to inhibition of neurite outgrowth:a potential strategy for axonal regeneration. J. neuroche,2004,91:1018-1023
27. Ogawa T, Sawamoto K, Miyata T, et al. Transp lantation of in vitro expanded fetal neural p rogenitor cells results in neurogenesis and functional recovery after sp inal cord injury in adult rats. JNeurosci Res,2002,69 (6) : 925– 933.
28. Mitsui T, Kakizaki H. Immortalized neural stem cells transp lanted into the injured sp inal cord p romote recovery of voiding function in the rat. J Urol,2003,10 (170) : 1421 - 1425.
29. Li Y, Field PM, Raisman G. Repair of adult rat corticosp inal tract by transp lants of olfactory ensheathing cells. Science,1997,277: 2000– 2002
30. Fouad K, Volker D,Schwab M.E. Improving axonal growth and functional recovery after experimental spinal cord injury by neutralizing myelin associated inhibitors. Brain Res Rev, 2001,36:204-212
31. GrandPre T, Li S, Strittmatter SM. Nogo-66 receptor antagonist peptide promotes axonal regeneration. Nature, 2002,417:568-573
32. Y CG,Jimenez O,Marcillo AE,et al.Beneficial effects of modest systemic hypothermia on locomotor function and histopathological damage following contusion-induced spinal cord injury in rats. J.Neurosurg,2000,93(1suppl):85-93
33. Sicard RE.Differential inflammatory and immunological responses in tissue regeneration and repair. M.Ann N Y Acad Sci.2002,961:368-371
34. Mantovani,-A; Sozzani,-S; Locati,-M.et al. Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes.Trends-Immunol. 2002,23(11): 549-55
35. Zeev-Brann AB,Lazarov-Spiegler O,Brenner T,et al.Differential effects of central and peripheral nerves on macrophages and microglia.Glia 1998,23:181-190
36. Buss A,Schwab ME.Sequential loss of myelin protein during wallerian degeneration in the rat spinal cord.Glia,2003,42:424-432
37. Masaaki I,Masahiko W, Kaori S, et al. Delayed accumulation of activated macrophages and inhibition of remyelination after spinal cord injury in an adult rodent model. J Neurosurg Spine 2008,8(1):58-66
38. Fry EJ,Ho C, David S.A role for Nogo receptor in macrophage clearance from injured peripheral nerve. Neuron,2007,53(5):649-662.
1. Shuman SL, Bresnahan JC, Beauie MS. Apoptosis of microglial and oligodendrocytes after spinal cord contusion in rats. J Neurosci Res.1997,50:798-808
2. Lazar DA, Ellegala DB, Avellina AM,et al. Modulation of macrophage and micraglial responses to axonal injury in the peripheral and central nervous systems. Neurosurgery,1999,45(3):593-600
3. Sicard RE.Differential inflammatory and immunological responses in tissue regeneration and repair. M.Ann N Y Acad Sci.2002,961:368-371.
4. Lazarov-Spiegler O, Sclomon AS, Zeev-Brann AB, et al. Transplantation of activated macrophages overcomes central nervous system regrowth failure. Faseb J,1996,10:1296-1302
5. Zeev-Brann AB,Lazarov-Spiegler O,Brenner T,et al.Differential effects of central and peripheral nerves on macrophages and microglia.Glia 1998,23:181-190
6. Buss A,Schwab ME.Sequential loss of myelin protein during wallerian degeneration in the rat spinal cord.Glia,2003,42:424-432:
7. Masaaki I,Masahiko W, Kaori S, et al. Delayed accumulation of activated macrophages andinhibition of remyelination after spinal cord injury in an adult rodent model. J Neurosurg Spine 2008,8(1):58-66
8. Fry EJ,Ho C, David S.A role for Nogo receptor in macrophage clearance from injured peripheral nerve. Neuron,2007,53(5):649-662.)
1. Rossi F,Cattaneo E. Opinion: neural stem cell therapy for neurological diseases: dreams and reality. Nat Rev Neurosci,2002,3:401– 409
2. HuberAB,SchwabME. Nogo - A,a potent inhibitor of neurite outgrowth and regeneration. Biol Chem,2000,381: 407– 419
3. Lacroix S,TuszynskiMH. Neurotrophic factors and gene therapy in spinal cord injury. Neurorehabil Neural Repair,2000,14: 265- 275
4. McKerracher L. Spinal cord repair: strategies to p romote axon regeneration. Neurobiol Dis,2001,8: 11– 18
5. BungeMB, Pearse DD. Transplantation strategies to p romote repair of the injured spinal cord. J Rehabil ResDev,2003,40: 55- 62
6.魏开斌,刘爱华,孙卫山等.成年大鼠嗅球成鞘细胞的原代培养及形态学研究.中国矫形外科,2004,12(20):1561-1564.
7. Barnett SC, Hutchins AM, Noble M. Purification of olfactory nerve ensheathing cells from the olfactory bulb. Dev Biol. 1993,155(2):337-50.
8. Nash HH, Borke RC, Anders JJ. New method of purification for establishing primary cultures of ensheathing cells from the adult olfactory bulb. Glia. 2001,34(2):81-7.
9. Ramon-Cueto A,Nieto-Sampedro M. Regeneration into the spinal cord of transected dorsal root axons is promoted by ensheathing glia transplants. Exp Neurol. 1994,127(2):232-44
10. Franceschini IA,Barnett SC. Low affinity NGF - receptor and E-N-CAM expression define two types of olfactory nerve ensheathing cells that share a common lineage. Dev Biol,1996,173: 327– 343
11. van den PolAN,Santarelli JG. Olfactory ensheathing cells: time lapse imaging of cellular interactions,axonal support,rapid morphologic shifts,and mitosis. J Comp Neurol,2003,458: 175 -194
12. Sonigra RJ, Brighton PC, Jacoby J, et al. Adult rat olfactory nerve ensheathing cells are effective p romoters of adult central nervous system neurite outgrowth in coculture. Glia,1999 ,25:256– 269
13. Au E, Roskams AJ. Olfactory ensheathing cells of the laminap ropria in vivo and in vitro. Glia,2003,41: 224– 236
14. Mirsky R,Jessen KR. The neurobiology of Schwann cells. Brain Pathol. 1999,9: 293– 311
15. Ramon-Cueto A,Valverde F. Olfactory bulb ensheathing glia: a unique cell type with axonal growthpromoting p roperties. Glia,1995,14: 163– 173
16. AuWW, Treloar HB, Greer CA. Sublaminar organization of the mouse olfactory bulb nerve layer. J Comp Neurol,2002,446: 68-80
17. Li Y, Field PM, Raisman G. Repair of adult rat corticosp inal tract by transplants of olfactory ensheathing cells. Science,1997,277: 2000– 2002
18. Li Y,Sauve Y,Li D,et al. Transp lanted olfactory ensheathing cells p romote regeneration of cut adult rat op tic nerve axons. J Neurosci,2003,23: 7783–7788
19. Mirsky R,Jessen KR,Brennan A,et al. Schwann cells as regulators of nerve development. J Physiol Paris,2002,96: 17– 24
20. Guntinas - LichiusO,Wewetzer K,Tomov TL,et al. Transp lantation of olfactory mucosa minimizes axonal branching and p romotes the recovery of vibrissae motor performance after facial nerve repair in rats. J Neurosci,2002,22: 7121– 7131
21. Schwob JE. Neural regeneration and the peripheral olfactory system. Anat Rec,2002,269: 33– 49
22. Holbrook EH , Szumowski KE , Schwob JE. An immunochemical , ultrastructural , and developmental characterization of the horizontal basal cells of rat olfactory epithelium. J Comp Neurol,1995,363: 129– 146
23. Ramon-CuetoA,AvilaJ. Olfactory ensheathing glia: properties and function. Brain Res Bull. 1998 ,46(3):175-87. Review.
24. Guntinas-Lichius O,Wewetzer K,Tomov TL,et al. Transplantation of olfactory mucosa minimizes axonal branching and promotes the recovery of vibrissae motor performance after facial nerve repair in rats. J Neurosci. 2002,22(16):7121-31.
25. Martin LV, Weston S, West AK, et al. Nerve growth factor promotes olfactory axonal elongation. Neuroreport. 2002,13(5):621-5.
26. Ramon-Cueto A,Cordero MI,Santos-Benito FF, et al . Functional recovery of paraplegic rats and motor axon regeneration in their spinal cords by olfactory ensheathing glia. Neuron. 2000,25(2):425-35.
27. Li Y, Field PM. Raisman G. Repair of adult rat corticospinal tract by transplants of olfactory ensheathing cells. Science. 1997,277(5334):2000-2.
28. Bartolomei JC, Greer CA. Olfactory ensheathing cells: bridging the gap in spinal cord injury. Neurosurgery,2000,47: 1057-1069
29. Takami T,OudegaM,BatesML,et al. Schwann cell but not olfactory ensheathing glia transplants imp rove hindlimb locomotor performance in the moderately contused adult rat thoracic spinal cord. J Neurosci,2002,22: 6670 - 6681
30. Santos - Benito FF, Ramon - Cueto A. Olfactory ensheathing glia transp lantation: a therapy to promote repair in the mammalian central nervous system. Anat Rec B New Anat,2003,271: 77-85
31. Lakatos A, Smith PM, Barnett SC, et al. Meningeal cells enhance limited CNS remyelination by transplanted olfactory ensheathing cells. Brain,2003,126: 598 - 609
32. Barnett SC, Riddell JS. Olfactory ensheathing cells (OECs) and the treatment of CNS injury: advantages and possible caveats. J Anat,2004,204: 57 - 67
33. H. Burkitt. Wheater’s Functional Histology: a Text and colour Atlas. Churchill Livingstone,New York,1995. 23 - 25
34. Venstum KA. Extracellular matrix: role of extracellular matrix molecules and their receptor in the nerve system. FASEB J,1993,7: 996 - 1003
35. Feltri I. Conditional disrup tion of 1 integrin in Schwann cells impedes interaction with axon. J Cell Biol,2002,156: 199 - 209
36. Sun Y, J in K, Xie L, et al. VEGF - induced neuroprotection,neurogenesis,and angiogenesis after focal cerebral ischemia. J Clin Invest, 2003, 111: 1843 - 1851
37. ShearerMC,Fawcett JW. The astrocyte /meningeal cell interface a barrier to successful nerve regeneration? Cell Tissue Res,2001,305: 267 - 273
38. Franzen R, Martin D, Daloze A, et al. Grafts of meningeal fibroblasts in adult rat spinal cord lesion p romote axonal regrowth.Neuroreport,1999,10: 1551– 1556
1. Becker D,Sadowsky CL,Mcdonald JW. Restoring function after spinal cord injury. Neurology,2003,9 (1) : 11-13
2. Amar AP,LevyML.Pathogenesis and pharmacological strategies for mitigating secondary damage in acute sp inal cord injury. Neurosurgery,1999,44 (5) : 1027 - 1039.
3. Yick LW,Wu W,So KF,et al. Chondroitinase ABC promotes axonal regeneration of Clark’s neurons after sp inal cord injury. Neuroreport,2000,11 (5) : 1063 - 1067.
4. Alexander GR,George MS. Therapeutic interventions following mammalian spinal cord injury. Arch Neurol,2001,58 ( 5 ) :721 - 726.
5. Morrison SJ,Shah NM,Anderson DJ. Regulatory mechanisms in stem cell biology. Cell,1997,88 (3) : 287 - 298.
6. McDonald JW,Liu XZ,Qu Y,et al. Transplanted embryonic stem cells survive,differentiate and promote recovery in injured rat spinal cord,Nat Med,2000(6):358-340
7. Himes BT,Liu Y,Solowska JM,et al. Transplants of cells genetically modified to express neurotrophin-3 rescue axotomized Clarke’s nucleus neurons after spinal cord hemisection in adult rats,J.Neurosci Res,2001(65):549-564.
8.蔡培强,汤逊,林月秋.脊髓损伤的基因治疗实验研究,伤残医学杂志,2005,13(1):60-62
9. Alberto MS,Anders B . Immortalized neural progenitor cells for CNS gene transfer and repair,Trends Neurosci,1997(20): 530-538
10. Lundberg C,Martinez-Serrano A,Cattaneo E,et al. Survival,integration,and differentiation ofneural stem cell lines after transplantation to the adult rat striatum, Exp Neurol,1997(145):342-360
11. Morrison SJ,Shah NM,Anderson DJ,et al.Regulatory mechanisms in stem cell biology,Cell,1997(88)287-298
12. Carpenter MK,Cui Xia,Hu Zhong-yi,et al.In vitro expansion of a Multipotent population of human progenitor cells,Exp.Neurol,1999(158):265-278.
13. Svendsen CN,Borg MG,Armstrong RJE,et al. A new method for the rapid and long term growth of human neural precursor cells,J.Neurosci,1998(85):141-152.
14. Gage FH. Mammalian neural stem cell. Science,2000,287(5457) : 1433 - 1441.
15. CarpenterMK, Cui X, Hu ZY, et al. In vitro expansion of a multipotent population of human neural p rogenitor cells. Exp Neurol,1999,158 (2) : 265 - 278.
16. Fricker RA,CarpenterMK,Winkler C,et al. Site2specificmigration and neuronal differentiation of human neural p rogenitor cells after transp lantation in adult rat brain. J Neurosci,1999,19(4) : 5992 - 6005.
17. Vescovi AL, Parati EA, Gritti A, et al. Isolation and cloning of multipotential stem cells from the embryonic human CNS and establishment of transp lantable human neural stem cell lines by epigenetic stimulation. Exp Neurol,1999,156 (1) : 71 - 83.
18. Flax JD,Aurora S,Yang C,et al. Engraftable human neural stem cells respond to developmental cues,replace neurons,and express foreign genes. Nature Biotech,1998,16 (11) : 1033 - 1039.
19. Svendsen CN,Caldwell MA,Ostenfeld T. Human neural stem cells: isolation,expansion and transp lantation. Brain Pathol,1999,9 (3) : 499 - 513.
20. Uchida N,Buck D,He D,et al. Direct isolation of human central nervous system stem cells. Proc NatlAcad SciUSA,2000,97(26) : 14720 - 14725.
21. Kukekov V,Laywell E,Suslov O,et al. Multipotent stem progenitor cells with similar p roperties arise from two neurogenic regions of the adult human brain. Exp Neurol,1999,156 (2) :333 - 344.
22. Roy NS,Benraiss A,Wang S,et al. Promoter targeted selection and isolation of neural progenitor cells from the adult human ventricular zone. J Neurosci Res,2000,59 (3) : 321 - 331.
23. Akiyama Y,Honmou O,Kato T,et al. Transp lantation of clonal neural p recursor cells derived from adult human brain establishes functional peripheralmyelin in the rat spinal cord . Exp Neurol,2001,167 (1) : 27 - 39.
24. Arsenijevic Y,Villemure JG Brunet JF,et al. Isolation ofmultipotent neural p recursors residing in the cortex of the adult human brain. Exp Neurol,2001,170 (1) : 48 - 62.
25. Quinn SM,WaltersWM,VescoviAL,et al. Lineage restriction of neuroepithelial precursor cells from fetal human sp inal cord . J Neurosci Res,1999,57 (5) : 590 - 602.
26. Johansson CB,Momma S,Clarke DL,et al. Identification of a neural stem cell in the adult mammalian central nervous system . Cell,1999,96 (1) : 25 - 34.
27. Eriksson P,Perfilieva E,Bjork Eriksson J,et al. Neurogenesis in the adult human hippocampus. Nature Med,1998,4 ( 11 ) :1313 - 1317.
28. Villa A,Snyder EY,VescoviA,et al. Establishment and p roperties of a growth factor dependent, perpetual neural stem cell line from the human CNS. Exp Neurol,2000,161 (1) : 67 - 84.
29. Park KI, Liu SX, Flax JD, et al. Transplanted of neural progenitor and stem cells: developmental insights may suggest new therapies for sp inal cord and other CNS dysfunction . J Neurotrauma,1999,16 (8) : 675 - 687.
30. Ogawa T, Sawamoto K, Miyata T, et al. Transp lantation of in vitro expanded fetal neural progenitor cells results in neurogenesis and functional recovery after spinal cord injury in adult rats. JNeurosci Res,2002,69 (6) : 925 - 933.
31. Mitsui T, Kakizaki H. Immortalized neural stem cells transp lanted into the injured spinal cord promote recovery of voiding function in the rat. J Urol,2003,10 (170) : 1421 - 1425.
32. Mcdonald JW,Liu XZ,Qu Y,et al,Transplanted embryonic stem cells survive,differentiate and promote recovery in injured rat spinal cord. NatMed,1999,5 (12) : 1410 - 1412.
1. Prinjha R, Moore SE, Vinson M, et al. Inhibitor of neurite outgrowth in humans. Nature, 2000, 403: 383-384
2. Fouad K, Volker D,Schwab M.E. Improving axonal growth and functional recovery after experimental spinal cord injury by neutralizing myelin associated inhibitors. Brain Res Rev, 2001,36:204-212
3. GrandPre T, Li S, Strittmatter SM. Nogo-66 receptor antagonist peptide promotes axonal regeneration. Nature, 2002,417:568-573
4. Y CG,Jimenez O,Marcillo AE,et al.Beneficial effects of modest systemic hypothermia on locomotorfunction and histopathological damage following contusion-induced spinal cord injury in rats. J.Neurosurg,2000,93(1suppl):85-93
5. Sicard RE.Differential inflammatory and immunological responses in tissue regeneration and repair. M.Ann N Y Acad Sci.2002,961:368-371
6. Zeev-Brann AB,Lazarov-Spiegler O,Brenner T,et al.Differential effects of central and peripheral nerves on macrophages and microglia.Glia 1998,23:181-190
7. Buss A,Schwab ME.Sequential loss of myelin protein during wallerian degeneration in the rat spinal cord.Glia,2003,42:424-432
8. Fry EJ,Ho C, David S.A role for Nogo receptor in macrophage clearance from injured peripheral nerve. Neuron,2007,53(5):649-662.
9. McGee AW , Strittmatter SM.The Nogo-66 receptor : focusing myelin inhibition of axon regeneration.Trends Neurosci,2003,26:193-198
10. Ying Z, Roy RR, Edgerton VR,et al. Exercise restores levels of neurotrophins and synaptic plasticity following spinal cord injury. Exp Neurol, June 1, 2005,193(2): 411-419
11. Raisman G. Olfactory ensheathing cells and repair of brain and spinal cord injuries. Cloning Stem Cells, 2004, 6(4): 364-8
12. Reynolds BA,Weiss A.Generation of neurons and astrocytes from isolated cells of adult mammalian central nervous system.Science,1992,255:1707-1709
13. Lakatos A,Franklin RJ,Bamett SC.Olfactory ensheathing cells and Schwann cells differ in their in vitro interactions with astrocytes .Glia,2000,32(3):214~225
14. Venstum KA Extracellular matrix role of extracellular matrix molecules and their receptor in the nerve system FASEB J,1993,7:993-1003
15. Feltri I Conditional disruption of I integrin in Schwann cells impedes interaction with axon J Cell Biol,2002,156:199-209
16. Schwab ME. Repairing the injured spinal cord Science,2002,255:1029-1031
17. Cao QL, Zhang YP,Howard RM,et al. Pluripotent stem cells engrafted into the normal or lesioned adult rat spinal cord are restricted to a glial lineage. Exp Neurol, 2001, 167:48-58
18. Cao QL, Howard RM,Dennison JB,et al. Differentiation of engrafted neuronal-restricted precursor cells is inhibited in the traumatically injured spinal cord.Exp Neurol,2002,177:349-359
19.李巍,李成仁,蔡文琴,等.胎牛血清对人胚胎神经干细胞分化的影响.第三军医大学学报,2003,25:4-6
20. Gaiano DW,Goodman RR,Fraser RA,et al.Neural stem and progenitor cells:a strategy for gene therapy and brain repair.Neurosurgery,1998,42:858-867
21. Dunning MD,Lakatos A,Loizou L,et al.Superparamagnetic iron oxide-labeled schwann cels and olfactory ensheathing cells can be traced in vivo by magnetic resonance imaging and retain functional properties after transplantation into the CNS.J Neurosci,2004,24:9799-9810
22. Chung RS,Woodhouse A,Fung S,et al.Olfactory ensheathing cells promote neurite sprouting of injured axons invitro by direct cellular contact and sectetion of soluble factors. Cell Mol Life Sci,2004,61:1238-1245
23. Barone FC,Hillegass LM,Tzimas MN,et a1.Time-related changes in myeloperoxidase activity and leukotriene B4 receptor binding reflect leukocyte influx in cerebral focal stroke.Mol Cell Neuropathol,1995,24:13-30.
24. Lazarov Spiegler O,Solomon AS,Ben Zeev-Brann A,et a1.Transplantation of activated macrophages overcomes centralnervous system regrowth failure.FASEB J,1996,10:1296-1302.
25. Rapalino O,Lazarov Spiegler O,Agranov I,Velan G,et a1.Implantation of stimulated macrophages leads to partial recovery of paraplegic rats.Nature Med。1998,4:814-882.
26. Prewitt CM,Niesman IR,Kane CJ,et a1.Activated macrophage/microglial cells can promote the regeneration of sensoryaxons into the injured spinal cord.Exp Neurol,1997,148(2):433-443.
1. Fawcett J.Repair of spinal cord injuries:where we are, and where we are going.Spinal Cord,2002,40(12):615-623.
2. Spillmann AA,Bandtlow CE,Lottspeich F,et a1.Identificationand characterization of a bovine neurite growth inhibitor(bNI-220) .J Biol Chem,1998,273(30):19283-19293.
3. Grandpre T,Nakamura F,Vartanian T,et a1.Identification ofthe Nogo inhibitor of axon regeneration as a reticulon protein.Nature,2001,409(6768):E439-444.
4. Grandper T. Li S.Nogo-66 receptor antagonist peptide promotes axonal regeneration.Nature,2002,417(6888):547-551.
5. Ng CE,Tang BL.Nogos and the Nogo-66 receptor:factors in-hibiting CNS neuron regeneration .J Neurosci Res,2002,67(5):559-565.
6. Fournier AE,Grandpre T.Strittmatter SM.Identification of areceptor mediating Nogo-66 inhibition of axonal regeneration.Nature,2001,409(6818):E34I-346.
7. Wang KC,Kim JA,Sivasankaran R,et a1.P75 interacts with the Nogo receptor as a co-receptor for Nogo,MAG and OMgp.Nature,2002,420(6911):74-78.
8. Schnell L,Schwan ME.Axonal regeneration in the rat spinal cord produced by an antibody against myelin associated neurite growth inhibitors.Nature,1990,343(6255):269-272.
9. Raineteau O,Fouad K,Noth P,et a1.Functional switch between motor tracts in the presence of the mAb IN-1 in the adult rat.Proc Natl Acad Sci USA,2001,98(12):6929-6934.
10. Fiedler M ,Hom C, Bandtlow C,et a1.An engineered IN-1 fragment with improved affinity for the Nogo:a axonal growth inhibitor permits immunochemical detection and shows enhanced neutralizing activity .Protein Eng,2002,1 5(1 1):931-941.
11. ukhopadhyay G,Doherty P,Walsh FS,et a1.A novel role for myelin-associated glycopmtein as an inhibitor of axonal regeneration.Neuron,1994,13(3):757-767.
12. Li M,Shibata A,Li C,et a1.Myelin-associated glycoproteininhibits neurite axon growth and canses growth cone collapse.J Neurosci Res,1996,46(4):404-414.
13. Schwegler G,Schwab ME,Kapfhammer JP.Increased collateralsprouting of primary afferents in the myelin-free spinal cord .J Neurosci,1995,15(4):2756-2767.
14. Vanek P,Thallmair M,Schwab ME,et a1.Increased lision induced sprouting of corticospinal fibres in the myelin freerat spinal cord.Eur J Neurosci,1998,10(1):45-56.
15. Bedi KS,Winter J,Berry M,et a1.Adult rat dorsal root ganglion neurons extend neurites on predegenerated but not onnormal peripheral nerves in vitro.Eur J Neurosci,1992,4(3):193-200.
16. Trapp BD.Myelin associated glycoprotein,location and ptential function.Ann N Y Acad Sci,1990,605:29-43.
17. Erb M ,Steck AJ,Nave KA,et a1.Differential expression of L and S-MAG upon cAMP stimulated differentiation in oligodendroglial cells .J Neurosci Res,2003,7 1(3):326-337.
18. Vyas AA, Patel HV, Fromhoh SE,et a1.Gangliosides arefunctional nerve cell ligands for myelin assoc iatedglycoprotein(MAG),an inhibitor of nerve regeneration.ProcNatl Acad Sci USA,2002,99(12):8412-8417.
19. Cai D,Deng K,Mellado W ,et a1.Arginase 1 and polyamines act downstream from cyclic AMP in overcoming inhibitionof axonal growth MAG and myelin in vitro.Neuron,2002,35(4):711-719.
20. Wang k.C, Koprivica V, Kim JA, et al. Oligodendrocyte-myelin glycoprotein is a Nogo receptor ligand that inhibits neurite outgrowth. Nature, 2002, 417: 941-4.
21. Habib AA, Marton LS, Allwardt B, et al. Expression of the oligodendrocyte-myelin glycoprotein by neurons in the mouse central nervous system. J Neurochem, 1998, 70: 1704-1711
22. Davies SJA,Goucher DR,Doller C,et a1.Robust regenerationof adult sensory axons in degenerating white matter of theadult rat spinal cord.J Neurosci,1999,19(14):5810-5822.
23. Tang X,Davies JE,Davies SJ,et a1.Changes in distribution,cell associations,and protein expression levels of NG2,neurocan,phosphacan,brevican,versican V2,and tenascin-C during acute to chronic maturation of spinal cord scar tissue.J Neulosci Res,2003,71(3):427-444.
24. Monnier PP, Sierra A, Schwab JM, et a1.The Rho/ROCKpathway mediates neurite growth inhibitory activity associated with the chondroitin sufate pmteoglycans of the CNS glialscar.Mol Cell Neurosci,2003,22(3):3 19-330.
25. Mon LD,Asher RA,Fawcett JW,et a1.Limited growth ofsevered CNS axons after treatment of adult rat brain with hyalumnidase.J Neurosci Res,2003,71(1):23-37.
26. Bradbury EJ,Mon LD,Popat RJ,et a1.Chondroitinase ABC promotes regeneration and functional recovery following cordinjury.Nature,2002,4l6(6881):636-640.
27. Smith-Thomas LC,Stevens J,Fok-Seang J,et a1.Increased axon regeneration in astrocytes grown in the presence of pmteoglycansynthesis inhibitors.J Cell Sci,1995(108):1307-1315.
28. Tatagiba M,Brosamle C,Schwanh ME.Regeneration of injured axons in the adult mammalian central nervous system.Neurosurgery,1997,40:541—547.
29. Cheng H, Cao Y. Olson L. Spinal coed repair in adult paraplegic rats partial restoration of hind limb function . Science, 1996, 273: 510-514.
30. Levi, Allan D O; Dancausse, Hector; Li, Xiuming;et al。Peripheral nerve grafts promoting centralnervous system regeneration after spinal cord injury in the primate. Journal Of Neurosurgery ,Volume 96, Issue 2, Supplement, March 2002, Pages 197-205.
31. Xu XM, Zhang SX, Li H, ED AL. Regrowth of axons into the distal spinal cord. Exp, Neurol, 1997 ,148: 502-522.
32. Nash, H.H., Borke,R.C., Anders,J. J. (2002). Ensheathing Cells and Methylprednisolone Promote Axonal Regeneration and Functional Recovery the Lesioned Adult Rat Spinal Cord. J. Neurosci. 22: 7111-7120
33. Mark.H.Tuszynski, Norbert Weidner, Melissa McCormack, et al, Grafts of genetically modified Schwann cells to the spinal cord: Survival,Axon growth and Myelination. Cell Transplantation. Volume 7, Issue 2, 4 March 1998, p187-196.
34. Li Y, Field PM, Raisman G, Repair of adult rat corticospinal tract by transplants of olfactory ensheathing cells. Science, 1997.277:2000-2002.
35. Nash,H.H., Borke, R.C.,Anders, J. J. (2002). Ensheathing Cells and Methylprednisolone Promote Axonal Regeneration and Functional Recovery in the Lesioned Adult Rat Spinal Cord. J. Neurosci. 2001,22: 7111-7120.
36. Lu, J., Feron, F., Mackay-Sim, A., Waite, P. M. E.. Olfactory ensheathing cells promote locomotor recovery after delayed transplantation into transected spinal cord. Brain 2002,125: 14-21.
37. Zheng M,Kuffler DP,Guidance of regenerating motor axons in vivo by gradients of diffusible perpheral nerve-derived factors.J Neurobiol,2000,42:2212-2219.
38. Diener DS. Bregman BS. Fetal spinal cord transplants support the development of target reaching and coordinated postural, adjustments after neonatal cervical cord injury. J Neurosci ,1998,18,763-778.
39. J.V. Coumans, T.T. Lin, H.N. Dai, L. MacArthur, M. McAtee, C. Nash and B.S. Bregman, Axonal regeneration and functional recovery after complete spinal cord transection in rats by delayed treatment with transplants and neurotrophins. J. Neurosci. 21 (2001), pp. 9334–9344.
40.胥少汀,郭世绂。脊髓损伤基础与临床,第二版,人民卫生出版社,2002,p439。
41. P. Lu, L.L. Jones, E.Y. Snyder,et al. Neural stem cells constitutively secrete neurotrophic factors andpromote extensive host axonal growth after spinal cord injury. Experimental Neurology 181 (2003) 115–129.
42. Yang D. Teng, Erin B. Lavik, Xianlu Qu.et al. Functional recovery following traumatic spinal cord injury mediated by a unique polymer scaffold seeded with neural stem cells. Proc. Natl. Acad. Sci. USA, Vol. 99, Issue 5, 3024-3029, March 5, 2002
43. Akiyama Y, Honmou O, Kato T, et al. Transplantation of clonal neural precursor cells derived fromadult human brain established functional peripheral myelin in the rat spinal cord .EXP Neurol, 2001,167,29-39.
44. Liu Y, Himes BT, Solowska J, et al. intraspinal delivery of neurotrophin-3 using neural stem cell genetically modified by Recombinant Retrovirus. EXP Neurology volume 158 Issue 1, July 1999.P9-22.
45. Lovosky JM, The epidemiology of spinal cord injury. In: Narayan RK, ED. Neutotrauma. 1st ed. New York; McGraw Hill, 1996.1049-1058.
46. Martin E. Schwab。Repairing the Injured Spinal Cord,Science,Volume 295,8 February, 2002,Pages 1029-1031.
47. Armin Blesch, Paul Lu and Mark H. Tuszynski. Neurotrophic factors, gene therapy, and neural stem cells for spinal cord repair. Brain Research Bulletin ,Volume 57, issue 6 , April 2002 , Pages 833-838.
48. Hideyuki Okano, Yuto Ogawa, Masaya Nakamura,et al. Transplantation of neural stem cells into the spinal cord after injury . Seminars in Cell & Developmental Biology ,Volume 14, Issue 3 , June 2003, Pages 191-198 ,Making and Repairing the Mammalian Brain
49. Mark H. Tuszynski , Ray Grill, Leonard L, NT-3 gene delivery elicits growth of chronically injured corticospinal axons and modestly improves functional deficits after chronic scar resection. Experimental Neurology, Volume 181, Issue 1 , May 2003, Pages 47-56.
50. Mi-Yoon Chang, Hyeon Son, Yong-Sung Lee. Neurons and astrocytes secrete factors that cause stem cells to differentiate into neurons and astrocytes, respectively, Molecular and Cellular Neuroscience, Article in Press, Corrected Proof - Note to users
51. P. Lu, L.L. Jones, K.I. Park, E.Y. Snyder and M.H. Tuszynski , Neural stem cells secrete BDNF and GDNF, and promote axonal growth after spinal cord injury. Soc. Neurosci. Abstr 26 (2000), pp. 124–125.
52. Mark H. Tuszynski , Ray Grill, Leonard L, NT-3 gene delivery elicits growth of chronically injured corticospinal axons and modestly improves functional deficits after chronic scar resection. Experimental Neurology, Volume 181, Issue 1 , May 2003, Pages 47-56.
53. Lijun Zhou, Brian J. Baumgartner, Sandra J. Hill-Felberg .Neurotrophin-3 Expressed In Situ Induces Axonal Plasticity in the Adult Injured Spinal Cord . The Journal of Neuroscience, February 15, 2003, 23(4):1424.
54. Lijun Zhou, Brian J. Baumgartner. Neurotrophin-3 Expressed In Situ Induces Axonal Plasticity in the Adult Injured Spinal Cord. The Journal of Neuroscience, February 15, 2003, 23(4):1424
55. Armin Blesch, Paul Lu and Mark H. Tuszynski. Neurotrophic factors, gene therapy, and neural stemcells. for spinal cord repair .Brain Research Bulletin.Volume 57,Issue 6, April 2002, Pages 833-838
56. A Blesch, J, Conner and MH Tuszynski, Modulation of neuronal survival and axonal growth in vivo by tetracycline-regulated neurotrophin expression. Gene Ther 8(2001) pp, 954-960.
2. Prinjha R, Moore SE, Vinson M, et al. Inhibitor of neurite outgrowth in humans. Nature, 2000, 403: 383-384.
3. Bareeyre F.M.Neuronal repair and replacement in spinal cord injury.J Neurol Sci.2008(265):63-72
4. Chen MS, Huber AB, van der Haar ME ,et al. Nogo-A is a myelin-associated neurite outgrowth inhibitor and an antigen for monoclonal antibody IN-1.Nature, 2000, 403: 434-439.
5. GrandPre T, Nakamura F, Vartanian T, et al. Identification of the Nogo inhibitor of axon regeneration as a Reticulon protein. Nature, 2000, 403: 439-444.
6. Huber AB., Weinmann O, Br?samle C, et al. Patterns of Nogo mRNA and Protein Expression in the Developing and Adult Rat and After CNS Lesions. J. Neurosci, 2002, 22: 3553 - 3567.
7. Wang X, Chun SJ, Treloar H, et al. Localization of Nogo-A and Nogo-66 Receptor Proteins at Sites of Axon-Myelin and Synaptic Contact. J. Neurosci, 2002, 22: 5505 - 5515.
8. Simonen M, Pedersen V. Systemic deletion of the myelin-associated outgrowth inhibitor Nogo-A improves regenerative and plastic responses after spinal cord injury. Neuron, 2003,38: 201-11
9. Mukhopadhhyay G ,Doherty P ,Walsh FS ,et al. A novel role of myelin-associated glycoprotein as an inhibitor of axonal regeneration . Neuron ,1994,13:757-767
10. Wang k.C, Koprivica V, Kim JA, et al. Oligodendrocyte-myelin glycoprotein is a Nogo receptor ligand that inhibits neurite outgrowth. Nature, 2002, 417: 941-4.
11. Habib AA, Marton LS, Allwardt B, et al. Expression of the oligodendrocyte-myelin glycoprotein by neurons in the mouse central nervous system. J Neurochem, 1998, 70: 1704-1711.
12. Fournier AE, GrandPre T, and Strittmatter SM. Identification of a receptor mediating Nogo-66 inhibition of axonal regeneration. Nature, 2001, 409: 341-346.
13. Fournier AE, Gould GC, Liu BP, et al.Truncated Soluble Nogo Receptor Binds Nogo-66 and Blocks Inhibition of Axon Growth by Myelin. J. Neurosci, 2002, 22: 8876 - 8883.
14. Wang KC, Kim JA, Sivasankaran R,et al. P75 interacts with the Nogo receptor as a co-receptor for Nogo, MAG and OMgp. Nature, 2002, 420: 74-8.
15. Wong ST, Henley JR, Kanning KC, et al. A p75(NTR) and Nogo receptor complex mediates repulsive signaling by myelin-associated glycoprotein. Nat Neurosci, 2002,5: 1302-1308.
16. M. Nikolic. The role of Rho GTPases and associated kinases in regulating neurite outgrowth. Int. J. Biochem. Cell Biol, 2002, 34:731–745.
17. Dergham P, Ellezam B, Essagian C, et al.Rho Signaling Pathway Targeted to Promote Spinal CordRepair. J. Neurosci, 2002,22: 6570 - 6577.
18. David S, Lacroix S .Molecular approaches to spinal cord repair. Annu Rev Neurosci, 2003, 26: 411-40
19. Fouad K, Volker D,Schwab M.E. Improving axonal growth and functional recovery after experimental spinal cord injury by neutralizing myelin associated inhibitors. Brain Res Rev, 2001,36:204-212
20. Emerick AJ, Neafsey EJ. Functional reorganization of the motor cortex in adult rats after cortical lesion and treatment with monoclonal antibody IN-1. J-Neurosci, 2003,23: 4826-30
21. Horner P.J,Gage F.H. Regenerating the damaged central nervous system. Nature, 2000,407:963–970.
22. Cui Q, Cho KS. Synergistic effect of Nogo-neutralizing antibody IN-1 and ciliary neurotrophic factor on axonal regeneration in adult rodent visual systems. J-Neurotrauma, 2004 ,21: 617-25
23. GrandPre T, Li S, Strittmatter SM. Nogo-66 receptor antagonist peptide promotes axonal regeneration. Nature, 2002,417:568-573
24. Li S; Strittmatter SM. Delayed systemic Nogo-66 receptor antagonist promotes recovery from spinal cord injury. J-Neurosci, 2003,23: 4219-27
25. Sicotte M, Tsatas O, Jeong SY, et al. Immunization with myelin or recombinant Nogo-66/MAG in alum promotes axon regeneration and sprouting after corticospinal tract lesions in the spinal cord.Mol Cell Neurosci, 2003, 23: 251-63.
26. Xu G, Nie DY, Chen JT, et al. Recombinant DNA encoding multiple domains related to inhibition of neurite outgrowth:a potential strategy for axonal regeneration. J. neuroche,2004,91:1018-1023
27. Ogawa T, Sawamoto K, Miyata T, et al. Transp lantation of in vitro expanded fetal neural p rogenitor cells results in neurogenesis and functional recovery after sp inal cord injury in adult rats. JNeurosci Res,2002,69 (6) : 925– 933.
28. Mitsui T, Kakizaki H. Immortalized neural stem cells transp lanted into the injured sp inal cord p romote recovery of voiding function in the rat. J Urol,2003,10 (170) : 1421 - 1425.
29. Li Y, Field PM, Raisman G. Repair of adult rat corticosp inal tract by transp lants of olfactory ensheathing cells. Science,1997,277: 2000– 2002
30. Fouad K, Volker D,Schwab M.E. Improving axonal growth and functional recovery after experimental spinal cord injury by neutralizing myelin associated inhibitors. Brain Res Rev, 2001,36:204-212
31. GrandPre T, Li S, Strittmatter SM. Nogo-66 receptor antagonist peptide promotes axonal regeneration. Nature, 2002,417:568-573
32. Y CG,Jimenez O,Marcillo AE,et al.Beneficial effects of modest systemic hypothermia on locomotor function and histopathological damage following contusion-induced spinal cord injury in rats. J.Neurosurg,2000,93(1suppl):85-93
33. Sicard RE.Differential inflammatory and immunological responses in tissue regeneration and repair. M.Ann N Y Acad Sci.2002,961:368-371
34. Mantovani,-A; Sozzani,-S; Locati,-M.et al. Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes.Trends-Immunol. 2002,23(11): 549-55
35. Zeev-Brann AB,Lazarov-Spiegler O,Brenner T,et al.Differential effects of central and peripheral nerves on macrophages and microglia.Glia 1998,23:181-190
36. Buss A,Schwab ME.Sequential loss of myelin protein during wallerian degeneration in the rat spinal cord.Glia,2003,42:424-432
37. Masaaki I,Masahiko W, Kaori S, et al. Delayed accumulation of activated macrophages and inhibition of remyelination after spinal cord injury in an adult rodent model. J Neurosurg Spine 2008,8(1):58-66
38. Fry EJ,Ho C, David S.A role for Nogo receptor in macrophage clearance from injured peripheral nerve. Neuron,2007,53(5):649-662.
1. Shuman SL, Bresnahan JC, Beauie MS. Apoptosis of microglial and oligodendrocytes after spinal cord contusion in rats. J Neurosci Res.1997,50:798-808
2. Lazar DA, Ellegala DB, Avellina AM,et al. Modulation of macrophage and micraglial responses to axonal injury in the peripheral and central nervous systems. Neurosurgery,1999,45(3):593-600
3. Sicard RE.Differential inflammatory and immunological responses in tissue regeneration and repair. M.Ann N Y Acad Sci.2002,961:368-371.
4. Lazarov-Spiegler O, Sclomon AS, Zeev-Brann AB, et al. Transplantation of activated macrophages overcomes central nervous system regrowth failure. Faseb J,1996,10:1296-1302
5. Zeev-Brann AB,Lazarov-Spiegler O,Brenner T,et al.Differential effects of central and peripheral nerves on macrophages and microglia.Glia 1998,23:181-190
6. Buss A,Schwab ME.Sequential loss of myelin protein during wallerian degeneration in the rat spinal cord.Glia,2003,42:424-432:
7. Masaaki I,Masahiko W, Kaori S, et al. Delayed accumulation of activated macrophages andinhibition of remyelination after spinal cord injury in an adult rodent model. J Neurosurg Spine 2008,8(1):58-66
8. Fry EJ,Ho C, David S.A role for Nogo receptor in macrophage clearance from injured peripheral nerve. Neuron,2007,53(5):649-662.)
1. Rossi F,Cattaneo E. Opinion: neural stem cell therapy for neurological diseases: dreams and reality. Nat Rev Neurosci,2002,3:401– 409
2. HuberAB,SchwabME. Nogo - A,a potent inhibitor of neurite outgrowth and regeneration. Biol Chem,2000,381: 407– 419
3. Lacroix S,TuszynskiMH. Neurotrophic factors and gene therapy in spinal cord injury. Neurorehabil Neural Repair,2000,14: 265- 275
4. McKerracher L. Spinal cord repair: strategies to p romote axon regeneration. Neurobiol Dis,2001,8: 11– 18
5. BungeMB, Pearse DD. Transplantation strategies to p romote repair of the injured spinal cord. J Rehabil ResDev,2003,40: 55- 62
6.魏开斌,刘爱华,孙卫山等.成年大鼠嗅球成鞘细胞的原代培养及形态学研究.中国矫形外科,2004,12(20):1561-1564.
7. Barnett SC, Hutchins AM, Noble M. Purification of olfactory nerve ensheathing cells from the olfactory bulb. Dev Biol. 1993,155(2):337-50.
8. Nash HH, Borke RC, Anders JJ. New method of purification for establishing primary cultures of ensheathing cells from the adult olfactory bulb. Glia. 2001,34(2):81-7.
9. Ramon-Cueto A,Nieto-Sampedro M. Regeneration into the spinal cord of transected dorsal root axons is promoted by ensheathing glia transplants. Exp Neurol. 1994,127(2):232-44
10. Franceschini IA,Barnett SC. Low affinity NGF - receptor and E-N-CAM expression define two types of olfactory nerve ensheathing cells that share a common lineage. Dev Biol,1996,173: 327– 343
11. van den PolAN,Santarelli JG. Olfactory ensheathing cells: time lapse imaging of cellular interactions,axonal support,rapid morphologic shifts,and mitosis. J Comp Neurol,2003,458: 175 -194
12. Sonigra RJ, Brighton PC, Jacoby J, et al. Adult rat olfactory nerve ensheathing cells are effective p romoters of adult central nervous system neurite outgrowth in coculture. Glia,1999 ,25:256– 269
13. Au E, Roskams AJ. Olfactory ensheathing cells of the laminap ropria in vivo and in vitro. Glia,2003,41: 224– 236
14. Mirsky R,Jessen KR. The neurobiology of Schwann cells. Brain Pathol. 1999,9: 293– 311
15. Ramon-Cueto A,Valverde F. Olfactory bulb ensheathing glia: a unique cell type with axonal growthpromoting p roperties. Glia,1995,14: 163– 173
16. AuWW, Treloar HB, Greer CA. Sublaminar organization of the mouse olfactory bulb nerve layer. J Comp Neurol,2002,446: 68-80
17. Li Y, Field PM, Raisman G. Repair of adult rat corticosp inal tract by transplants of olfactory ensheathing cells. Science,1997,277: 2000– 2002
18. Li Y,Sauve Y,Li D,et al. Transp lanted olfactory ensheathing cells p romote regeneration of cut adult rat op tic nerve axons. J Neurosci,2003,23: 7783–7788
19. Mirsky R,Jessen KR,Brennan A,et al. Schwann cells as regulators of nerve development. J Physiol Paris,2002,96: 17– 24
20. Guntinas - LichiusO,Wewetzer K,Tomov TL,et al. Transp lantation of olfactory mucosa minimizes axonal branching and p romotes the recovery of vibrissae motor performance after facial nerve repair in rats. J Neurosci,2002,22: 7121– 7131
21. Schwob JE. Neural regeneration and the peripheral olfactory system. Anat Rec,2002,269: 33– 49
22. Holbrook EH , Szumowski KE , Schwob JE. An immunochemical , ultrastructural , and developmental characterization of the horizontal basal cells of rat olfactory epithelium. J Comp Neurol,1995,363: 129– 146
23. Ramon-CuetoA,AvilaJ. Olfactory ensheathing glia: properties and function. Brain Res Bull. 1998 ,46(3):175-87. Review.
24. Guntinas-Lichius O,Wewetzer K,Tomov TL,et al. Transplantation of olfactory mucosa minimizes axonal branching and promotes the recovery of vibrissae motor performance after facial nerve repair in rats. J Neurosci. 2002,22(16):7121-31.
25. Martin LV, Weston S, West AK, et al. Nerve growth factor promotes olfactory axonal elongation. Neuroreport. 2002,13(5):621-5.
26. Ramon-Cueto A,Cordero MI,Santos-Benito FF, et al . Functional recovery of paraplegic rats and motor axon regeneration in their spinal cords by olfactory ensheathing glia. Neuron. 2000,25(2):425-35.
27. Li Y, Field PM. Raisman G. Repair of adult rat corticospinal tract by transplants of olfactory ensheathing cells. Science. 1997,277(5334):2000-2.
28. Bartolomei JC, Greer CA. Olfactory ensheathing cells: bridging the gap in spinal cord injury. Neurosurgery,2000,47: 1057-1069
29. Takami T,OudegaM,BatesML,et al. Schwann cell but not olfactory ensheathing glia transplants imp rove hindlimb locomotor performance in the moderately contused adult rat thoracic spinal cord. J Neurosci,2002,22: 6670 - 6681
30. Santos - Benito FF, Ramon - Cueto A. Olfactory ensheathing glia transp lantation: a therapy to promote repair in the mammalian central nervous system. Anat Rec B New Anat,2003,271: 77-85
31. Lakatos A, Smith PM, Barnett SC, et al. Meningeal cells enhance limited CNS remyelination by transplanted olfactory ensheathing cells. Brain,2003,126: 598 - 609
32. Barnett SC, Riddell JS. Olfactory ensheathing cells (OECs) and the treatment of CNS injury: advantages and possible caveats. J Anat,2004,204: 57 - 67
33. H. Burkitt. Wheater’s Functional Histology: a Text and colour Atlas. Churchill Livingstone,New York,1995. 23 - 25
34. Venstum KA. Extracellular matrix: role of extracellular matrix molecules and their receptor in the nerve system. FASEB J,1993,7: 996 - 1003
35. Feltri I. Conditional disrup tion of 1 integrin in Schwann cells impedes interaction with axon. J Cell Biol,2002,156: 199 - 209
36. Sun Y, J in K, Xie L, et al. VEGF - induced neuroprotection,neurogenesis,and angiogenesis after focal cerebral ischemia. J Clin Invest, 2003, 111: 1843 - 1851
37. ShearerMC,Fawcett JW. The astrocyte /meningeal cell interface a barrier to successful nerve regeneration? Cell Tissue Res,2001,305: 267 - 273
38. Franzen R, Martin D, Daloze A, et al. Grafts of meningeal fibroblasts in adult rat spinal cord lesion p romote axonal regrowth.Neuroreport,1999,10: 1551– 1556
1. Becker D,Sadowsky CL,Mcdonald JW. Restoring function after spinal cord injury. Neurology,2003,9 (1) : 11-13
2. Amar AP,LevyML.Pathogenesis and pharmacological strategies for mitigating secondary damage in acute sp inal cord injury. Neurosurgery,1999,44 (5) : 1027 - 1039.
3. Yick LW,Wu W,So KF,et al. Chondroitinase ABC promotes axonal regeneration of Clark’s neurons after sp inal cord injury. Neuroreport,2000,11 (5) : 1063 - 1067.
4. Alexander GR,George MS. Therapeutic interventions following mammalian spinal cord injury. Arch Neurol,2001,58 ( 5 ) :721 - 726.
5. Morrison SJ,Shah NM,Anderson DJ. Regulatory mechanisms in stem cell biology. Cell,1997,88 (3) : 287 - 298.
6. McDonald JW,Liu XZ,Qu Y,et al. Transplanted embryonic stem cells survive,differentiate and promote recovery in injured rat spinal cord,Nat Med,2000(6):358-340
7. Himes BT,Liu Y,Solowska JM,et al. Transplants of cells genetically modified to express neurotrophin-3 rescue axotomized Clarke’s nucleus neurons after spinal cord hemisection in adult rats,J.Neurosci Res,2001(65):549-564.
8.蔡培强,汤逊,林月秋.脊髓损伤的基因治疗实验研究,伤残医学杂志,2005,13(1):60-62
9. Alberto MS,Anders B . Immortalized neural progenitor cells for CNS gene transfer and repair,Trends Neurosci,1997(20): 530-538
10. Lundberg C,Martinez-Serrano A,Cattaneo E,et al. Survival,integration,and differentiation ofneural stem cell lines after transplantation to the adult rat striatum, Exp Neurol,1997(145):342-360
11. Morrison SJ,Shah NM,Anderson DJ,et al.Regulatory mechanisms in stem cell biology,Cell,1997(88)287-298
12. Carpenter MK,Cui Xia,Hu Zhong-yi,et al.In vitro expansion of a Multipotent population of human progenitor cells,Exp.Neurol,1999(158):265-278.
13. Svendsen CN,Borg MG,Armstrong RJE,et al. A new method for the rapid and long term growth of human neural precursor cells,J.Neurosci,1998(85):141-152.
14. Gage FH. Mammalian neural stem cell. Science,2000,287(5457) : 1433 - 1441.
15. CarpenterMK, Cui X, Hu ZY, et al. In vitro expansion of a multipotent population of human neural p rogenitor cells. Exp Neurol,1999,158 (2) : 265 - 278.
16. Fricker RA,CarpenterMK,Winkler C,et al. Site2specificmigration and neuronal differentiation of human neural p rogenitor cells after transp lantation in adult rat brain. J Neurosci,1999,19(4) : 5992 - 6005.
17. Vescovi AL, Parati EA, Gritti A, et al. Isolation and cloning of multipotential stem cells from the embryonic human CNS and establishment of transp lantable human neural stem cell lines by epigenetic stimulation. Exp Neurol,1999,156 (1) : 71 - 83.
18. Flax JD,Aurora S,Yang C,et al. Engraftable human neural stem cells respond to developmental cues,replace neurons,and express foreign genes. Nature Biotech,1998,16 (11) : 1033 - 1039.
19. Svendsen CN,Caldwell MA,Ostenfeld T. Human neural stem cells: isolation,expansion and transp lantation. Brain Pathol,1999,9 (3) : 499 - 513.
20. Uchida N,Buck D,He D,et al. Direct isolation of human central nervous system stem cells. Proc NatlAcad SciUSA,2000,97(26) : 14720 - 14725.
21. Kukekov V,Laywell E,Suslov O,et al. Multipotent stem progenitor cells with similar p roperties arise from two neurogenic regions of the adult human brain. Exp Neurol,1999,156 (2) :333 - 344.
22. Roy NS,Benraiss A,Wang S,et al. Promoter targeted selection and isolation of neural progenitor cells from the adult human ventricular zone. J Neurosci Res,2000,59 (3) : 321 - 331.
23. Akiyama Y,Honmou O,Kato T,et al. Transp lantation of clonal neural p recursor cells derived from adult human brain establishes functional peripheralmyelin in the rat spinal cord . Exp Neurol,2001,167 (1) : 27 - 39.
24. Arsenijevic Y,Villemure JG Brunet JF,et al. Isolation ofmultipotent neural p recursors residing in the cortex of the adult human brain. Exp Neurol,2001,170 (1) : 48 - 62.
25. Quinn SM,WaltersWM,VescoviAL,et al. Lineage restriction of neuroepithelial precursor cells from fetal human sp inal cord . J Neurosci Res,1999,57 (5) : 590 - 602.
26. Johansson CB,Momma S,Clarke DL,et al. Identification of a neural stem cell in the adult mammalian central nervous system . Cell,1999,96 (1) : 25 - 34.
27. Eriksson P,Perfilieva E,Bjork Eriksson J,et al. Neurogenesis in the adult human hippocampus. Nature Med,1998,4 ( 11 ) :1313 - 1317.
28. Villa A,Snyder EY,VescoviA,et al. Establishment and p roperties of a growth factor dependent, perpetual neural stem cell line from the human CNS. Exp Neurol,2000,161 (1) : 67 - 84.
29. Park KI, Liu SX, Flax JD, et al. Transplanted of neural progenitor and stem cells: developmental insights may suggest new therapies for sp inal cord and other CNS dysfunction . J Neurotrauma,1999,16 (8) : 675 - 687.
30. Ogawa T, Sawamoto K, Miyata T, et al. Transp lantation of in vitro expanded fetal neural progenitor cells results in neurogenesis and functional recovery after spinal cord injury in adult rats. JNeurosci Res,2002,69 (6) : 925 - 933.
31. Mitsui T, Kakizaki H. Immortalized neural stem cells transp lanted into the injured spinal cord promote recovery of voiding function in the rat. J Urol,2003,10 (170) : 1421 - 1425.
32. Mcdonald JW,Liu XZ,Qu Y,et al,Transplanted embryonic stem cells survive,differentiate and promote recovery in injured rat spinal cord. NatMed,1999,5 (12) : 1410 - 1412.
1. Prinjha R, Moore SE, Vinson M, et al. Inhibitor of neurite outgrowth in humans. Nature, 2000, 403: 383-384
2. Fouad K, Volker D,Schwab M.E. Improving axonal growth and functional recovery after experimental spinal cord injury by neutralizing myelin associated inhibitors. Brain Res Rev, 2001,36:204-212
3. GrandPre T, Li S, Strittmatter SM. Nogo-66 receptor antagonist peptide promotes axonal regeneration. Nature, 2002,417:568-573
4. Y CG,Jimenez O,Marcillo AE,et al.Beneficial effects of modest systemic hypothermia on locomotorfunction and histopathological damage following contusion-induced spinal cord injury in rats. J.Neurosurg,2000,93(1suppl):85-93
5. Sicard RE.Differential inflammatory and immunological responses in tissue regeneration and repair. M.Ann N Y Acad Sci.2002,961:368-371
6. Zeev-Brann AB,Lazarov-Spiegler O,Brenner T,et al.Differential effects of central and peripheral nerves on macrophages and microglia.Glia 1998,23:181-190
7. Buss A,Schwab ME.Sequential loss of myelin protein during wallerian degeneration in the rat spinal cord.Glia,2003,42:424-432
8. Fry EJ,Ho C, David S.A role for Nogo receptor in macrophage clearance from injured peripheral nerve. Neuron,2007,53(5):649-662.
9. McGee AW , Strittmatter SM.The Nogo-66 receptor : focusing myelin inhibition of axon regeneration.Trends Neurosci,2003,26:193-198
10. Ying Z, Roy RR, Edgerton VR,et al. Exercise restores levels of neurotrophins and synaptic plasticity following spinal cord injury. Exp Neurol, June 1, 2005,193(2): 411-419
11. Raisman G. Olfactory ensheathing cells and repair of brain and spinal cord injuries. Cloning Stem Cells, 2004, 6(4): 364-8
12. Reynolds BA,Weiss A.Generation of neurons and astrocytes from isolated cells of adult mammalian central nervous system.Science,1992,255:1707-1709
13. Lakatos A,Franklin RJ,Bamett SC.Olfactory ensheathing cells and Schwann cells differ in their in vitro interactions with astrocytes .Glia,2000,32(3):214~225
14. Venstum KA Extracellular matrix role of extracellular matrix molecules and their receptor in the nerve system FASEB J,1993,7:993-1003
15. Feltri I Conditional disruption of I integrin in Schwann cells impedes interaction with axon J Cell Biol,2002,156:199-209
16. Schwab ME. Repairing the injured spinal cord Science,2002,255:1029-1031
17. Cao QL, Zhang YP,Howard RM,et al. Pluripotent stem cells engrafted into the normal or lesioned adult rat spinal cord are restricted to a glial lineage. Exp Neurol, 2001, 167:48-58
18. Cao QL, Howard RM,Dennison JB,et al. Differentiation of engrafted neuronal-restricted precursor cells is inhibited in the traumatically injured spinal cord.Exp Neurol,2002,177:349-359
19.李巍,李成仁,蔡文琴,等.胎牛血清对人胚胎神经干细胞分化的影响.第三军医大学学报,2003,25:4-6
20. Gaiano DW,Goodman RR,Fraser RA,et al.Neural stem and progenitor cells:a strategy for gene therapy and brain repair.Neurosurgery,1998,42:858-867
21. Dunning MD,Lakatos A,Loizou L,et al.Superparamagnetic iron oxide-labeled schwann cels and olfactory ensheathing cells can be traced in vivo by magnetic resonance imaging and retain functional properties after transplantation into the CNS.J Neurosci,2004,24:9799-9810
22. Chung RS,Woodhouse A,Fung S,et al.Olfactory ensheathing cells promote neurite sprouting of injured axons invitro by direct cellular contact and sectetion of soluble factors. Cell Mol Life Sci,2004,61:1238-1245
23. Barone FC,Hillegass LM,Tzimas MN,et a1.Time-related changes in myeloperoxidase activity and leukotriene B4 receptor binding reflect leukocyte influx in cerebral focal stroke.Mol Cell Neuropathol,1995,24:13-30.
24. Lazarov Spiegler O,Solomon AS,Ben Zeev-Brann A,et a1.Transplantation of activated macrophages overcomes centralnervous system regrowth failure.FASEB J,1996,10:1296-1302.
25. Rapalino O,Lazarov Spiegler O,Agranov I,Velan G,et a1.Implantation of stimulated macrophages leads to partial recovery of paraplegic rats.Nature Med。1998,4:814-882.
26. Prewitt CM,Niesman IR,Kane CJ,et a1.Activated macrophage/microglial cells can promote the regeneration of sensoryaxons into the injured spinal cord.Exp Neurol,1997,148(2):433-443.
1. Fawcett J.Repair of spinal cord injuries:where we are, and where we are going.Spinal Cord,2002,40(12):615-623.
2. Spillmann AA,Bandtlow CE,Lottspeich F,et a1.Identificationand characterization of a bovine neurite growth inhibitor(bNI-220) .J Biol Chem,1998,273(30):19283-19293.
3. Grandpre T,Nakamura F,Vartanian T,et a1.Identification ofthe Nogo inhibitor of axon regeneration as a reticulon protein.Nature,2001,409(6768):E439-444.
4. Grandper T. Li S.Nogo-66 receptor antagonist peptide promotes axonal regeneration.Nature,2002,417(6888):547-551.
5. Ng CE,Tang BL.Nogos and the Nogo-66 receptor:factors in-hibiting CNS neuron regeneration .J Neurosci Res,2002,67(5):559-565.
6. Fournier AE,Grandpre T.Strittmatter SM.Identification of areceptor mediating Nogo-66 inhibition of axonal regeneration.Nature,2001,409(6818):E34I-346.
7. Wang KC,Kim JA,Sivasankaran R,et a1.P75 interacts with the Nogo receptor as a co-receptor for Nogo,MAG and OMgp.Nature,2002,420(6911):74-78.
8. Schnell L,Schwan ME.Axonal regeneration in the rat spinal cord produced by an antibody against myelin associated neurite growth inhibitors.Nature,1990,343(6255):269-272.
9. Raineteau O,Fouad K,Noth P,et a1.Functional switch between motor tracts in the presence of the mAb IN-1 in the adult rat.Proc Natl Acad Sci USA,2001,98(12):6929-6934.
10. Fiedler M ,Hom C, Bandtlow C,et a1.An engineered IN-1 fragment with improved affinity for the Nogo:a axonal growth inhibitor permits immunochemical detection and shows enhanced neutralizing activity .Protein Eng,2002,1 5(1 1):931-941.
11. ukhopadhyay G,Doherty P,Walsh FS,et a1.A novel role for myelin-associated glycopmtein as an inhibitor of axonal regeneration.Neuron,1994,13(3):757-767.
12. Li M,Shibata A,Li C,et a1.Myelin-associated glycoproteininhibits neurite axon growth and canses growth cone collapse.J Neurosci Res,1996,46(4):404-414.
13. Schwegler G,Schwab ME,Kapfhammer JP.Increased collateralsprouting of primary afferents in the myelin-free spinal cord .J Neurosci,1995,15(4):2756-2767.
14. Vanek P,Thallmair M,Schwab ME,et a1.Increased lision induced sprouting of corticospinal fibres in the myelin freerat spinal cord.Eur J Neurosci,1998,10(1):45-56.
15. Bedi KS,Winter J,Berry M,et a1.Adult rat dorsal root ganglion neurons extend neurites on predegenerated but not onnormal peripheral nerves in vitro.Eur J Neurosci,1992,4(3):193-200.
16. Trapp BD.Myelin associated glycoprotein,location and ptential function.Ann N Y Acad Sci,1990,605:29-43.
17. Erb M ,Steck AJ,Nave KA,et a1.Differential expression of L and S-MAG upon cAMP stimulated differentiation in oligodendroglial cells .J Neurosci Res,2003,7 1(3):326-337.
18. Vyas AA, Patel HV, Fromhoh SE,et a1.Gangliosides arefunctional nerve cell ligands for myelin assoc iatedglycoprotein(MAG),an inhibitor of nerve regeneration.ProcNatl Acad Sci USA,2002,99(12):8412-8417.
19. Cai D,Deng K,Mellado W ,et a1.Arginase 1 and polyamines act downstream from cyclic AMP in overcoming inhibitionof axonal growth MAG and myelin in vitro.Neuron,2002,35(4):711-719.
20. Wang k.C, Koprivica V, Kim JA, et al. Oligodendrocyte-myelin glycoprotein is a Nogo receptor ligand that inhibits neurite outgrowth. Nature, 2002, 417: 941-4.
21. Habib AA, Marton LS, Allwardt B, et al. Expression of the oligodendrocyte-myelin glycoprotein by neurons in the mouse central nervous system. J Neurochem, 1998, 70: 1704-1711
22. Davies SJA,Goucher DR,Doller C,et a1.Robust regenerationof adult sensory axons in degenerating white matter of theadult rat spinal cord.J Neurosci,1999,19(14):5810-5822.
23. Tang X,Davies JE,Davies SJ,et a1.Changes in distribution,cell associations,and protein expression levels of NG2,neurocan,phosphacan,brevican,versican V2,and tenascin-C during acute to chronic maturation of spinal cord scar tissue.J Neulosci Res,2003,71(3):427-444.
24. Monnier PP, Sierra A, Schwab JM, et a1.The Rho/ROCKpathway mediates neurite growth inhibitory activity associated with the chondroitin sufate pmteoglycans of the CNS glialscar.Mol Cell Neurosci,2003,22(3):3 19-330.
25. Mon LD,Asher RA,Fawcett JW,et a1.Limited growth ofsevered CNS axons after treatment of adult rat brain with hyalumnidase.J Neurosci Res,2003,71(1):23-37.
26. Bradbury EJ,Mon LD,Popat RJ,et a1.Chondroitinase ABC promotes regeneration and functional recovery following cordinjury.Nature,2002,4l6(6881):636-640.
27. Smith-Thomas LC,Stevens J,Fok-Seang J,et a1.Increased axon regeneration in astrocytes grown in the presence of pmteoglycansynthesis inhibitors.J Cell Sci,1995(108):1307-1315.
28. Tatagiba M,Brosamle C,Schwanh ME.Regeneration of injured axons in the adult mammalian central nervous system.Neurosurgery,1997,40:541—547.
29. Cheng H, Cao Y. Olson L. Spinal coed repair in adult paraplegic rats partial restoration of hind limb function . Science, 1996, 273: 510-514.
30. Levi, Allan D O; Dancausse, Hector; Li, Xiuming;et al。Peripheral nerve grafts promoting centralnervous system regeneration after spinal cord injury in the primate. Journal Of Neurosurgery ,Volume 96, Issue 2, Supplement, March 2002, Pages 197-205.
31. Xu XM, Zhang SX, Li H, ED AL. Regrowth of axons into the distal spinal cord. Exp, Neurol, 1997 ,148: 502-522.
32. Nash, H.H., Borke,R.C., Anders,J. J. (2002). Ensheathing Cells and Methylprednisolone Promote Axonal Regeneration and Functional Recovery the Lesioned Adult Rat Spinal Cord. J. Neurosci. 22: 7111-7120
33. Mark.H.Tuszynski, Norbert Weidner, Melissa McCormack, et al, Grafts of genetically modified Schwann cells to the spinal cord: Survival,Axon growth and Myelination. Cell Transplantation. Volume 7, Issue 2, 4 March 1998, p187-196.
34. Li Y, Field PM, Raisman G, Repair of adult rat corticospinal tract by transplants of olfactory ensheathing cells. Science, 1997.277:2000-2002.
35. Nash,H.H., Borke, R.C.,Anders, J. J. (2002). Ensheathing Cells and Methylprednisolone Promote Axonal Regeneration and Functional Recovery in the Lesioned Adult Rat Spinal Cord. J. Neurosci. 2001,22: 7111-7120.
36. Lu, J., Feron, F., Mackay-Sim, A., Waite, P. M. E.. Olfactory ensheathing cells promote locomotor recovery after delayed transplantation into transected spinal cord. Brain 2002,125: 14-21.
37. Zheng M,Kuffler DP,Guidance of regenerating motor axons in vivo by gradients of diffusible perpheral nerve-derived factors.J Neurobiol,2000,42:2212-2219.
38. Diener DS. Bregman BS. Fetal spinal cord transplants support the development of target reaching and coordinated postural, adjustments after neonatal cervical cord injury. J Neurosci ,1998,18,763-778.
39. J.V. Coumans, T.T. Lin, H.N. Dai, L. MacArthur, M. McAtee, C. Nash and B.S. Bregman, Axonal regeneration and functional recovery after complete spinal cord transection in rats by delayed treatment with transplants and neurotrophins. J. Neurosci. 21 (2001), pp. 9334–9344.
40.胥少汀,郭世绂。脊髓损伤基础与临床,第二版,人民卫生出版社,2002,p439。
41. P. Lu, L.L. Jones, E.Y. Snyder,et al. Neural stem cells constitutively secrete neurotrophic factors andpromote extensive host axonal growth after spinal cord injury. Experimental Neurology 181 (2003) 115–129.
42. Yang D. Teng, Erin B. Lavik, Xianlu Qu.et al. Functional recovery following traumatic spinal cord injury mediated by a unique polymer scaffold seeded with neural stem cells. Proc. Natl. Acad. Sci. USA, Vol. 99, Issue 5, 3024-3029, March 5, 2002
43. Akiyama Y, Honmou O, Kato T, et al. Transplantation of clonal neural precursor cells derived fromadult human brain established functional peripheral myelin in the rat spinal cord .EXP Neurol, 2001,167,29-39.
44. Liu Y, Himes BT, Solowska J, et al. intraspinal delivery of neurotrophin-3 using neural stem cell genetically modified by Recombinant Retrovirus. EXP Neurology volume 158 Issue 1, July 1999.P9-22.
45. Lovosky JM, The epidemiology of spinal cord injury. In: Narayan RK, ED. Neutotrauma. 1st ed. New York; McGraw Hill, 1996.1049-1058.
46. Martin E. Schwab。Repairing the Injured Spinal Cord,Science,Volume 295,8 February, 2002,Pages 1029-1031.
47. Armin Blesch, Paul Lu and Mark H. Tuszynski. Neurotrophic factors, gene therapy, and neural stem cells for spinal cord repair. Brain Research Bulletin ,Volume 57, issue 6 , April 2002 , Pages 833-838.
48. Hideyuki Okano, Yuto Ogawa, Masaya Nakamura,et al. Transplantation of neural stem cells into the spinal cord after injury . Seminars in Cell & Developmental Biology ,Volume 14, Issue 3 , June 2003, Pages 191-198 ,Making and Repairing the Mammalian Brain
49. Mark H. Tuszynski , Ray Grill, Leonard L, NT-3 gene delivery elicits growth of chronically injured corticospinal axons and modestly improves functional deficits after chronic scar resection. Experimental Neurology, Volume 181, Issue 1 , May 2003, Pages 47-56.
50. Mi-Yoon Chang, Hyeon Son, Yong-Sung Lee. Neurons and astrocytes secrete factors that cause stem cells to differentiate into neurons and astrocytes, respectively, Molecular and Cellular Neuroscience, Article in Press, Corrected Proof - Note to users
51. P. Lu, L.L. Jones, K.I. Park, E.Y. Snyder and M.H. Tuszynski , Neural stem cells secrete BDNF and GDNF, and promote axonal growth after spinal cord injury. Soc. Neurosci. Abstr 26 (2000), pp. 124–125.
52. Mark H. Tuszynski , Ray Grill, Leonard L, NT-3 gene delivery elicits growth of chronically injured corticospinal axons and modestly improves functional deficits after chronic scar resection. Experimental Neurology, Volume 181, Issue 1 , May 2003, Pages 47-56.
53. Lijun Zhou, Brian J. Baumgartner, Sandra J. Hill-Felberg .Neurotrophin-3 Expressed In Situ Induces Axonal Plasticity in the Adult Injured Spinal Cord . The Journal of Neuroscience, February 15, 2003, 23(4):1424.
54. Lijun Zhou, Brian J. Baumgartner. Neurotrophin-3 Expressed In Situ Induces Axonal Plasticity in the Adult Injured Spinal Cord. The Journal of Neuroscience, February 15, 2003, 23(4):1424
55. Armin Blesch, Paul Lu and Mark H. Tuszynski. Neurotrophic factors, gene therapy, and neural stemcells. for spinal cord repair .Brain Research Bulletin.Volume 57,Issue 6, April 2002, Pages 833-838
56. A Blesch, J, Conner and MH Tuszynski, Modulation of neuronal survival and axonal growth in vivo by tetracycline-regulated neurotrophin expression. Gene Ther 8(2001) pp, 954-960.