神经营养因子-3基因修饰的雪旺细胞对神经缺损的研究
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摘要
周围神经损伤临床疗效常常不能令人满意。近年来,雪旺细胞(Schwann cells,SCs)对神经系统的作用开始引起学者们的重视。Rathbone等在实验研究中发现:SCs是周围神经基因治疗理想的受体细胞,在周围神经系统神经损伤后,SCs对再生轴突具有诱向作用,并有较强的维持神经元存活,促进轴突的生长、神经再生的作用。并通过自分泌多种神经营养因子(neurotrophic factors NTs)维持存活,神经营养因子能促进发育中的交感和感觉神经细胞的分化和成熟,维持交感神经元正常功能,促进该神经元突起的长出,并诱导突起向神经纤维生长。特别是神经营养因子(neurotrophic factor 3 NT-3),能够维持肌梭、肌腱和皮肤传入感觉神经元的存活,增加运动神经元再生,促进神经肌突触的成熟,增加再生轴突的数量和长度,防止神经损伤后肌肉萎缩。在周围神经损伤再生过程中有非常重要作用。但NT-3在体内不稳定,极易被稀释或降解失活,吸收率不高,在临床应用上效能较低。SCs有时效局限。本实验为了提高NT-3和雪旺细胞促进神经再生的活性、减少局限性,将NT-3基因转入雪旺细胞,观察其表达。为了初步探讨其作用,故设计本实验。
首先我们培养、分离、纯化雪旺细胞。先将出生后3d的Wistar大鼠坐骨神经,经双酶消化后的剩余组织块采用植块法培养雪旺细胞,混悬于DMEM培养液中,接种于培养瓶中,置于培养箱。3d后首次换液,以后7d换液1次。细胞80%融合时,双差速贴壁法G-418(geneticin)纯化雪旺细胞。然后再培养24h。相差显微镜下观察计数,绘制各自的增殖曲线。在不同时间对雪旺细胞进行流式细胞分析、免疫组化S-100蛋白染色鉴定、四氮唑盐(MTT)比色法测定细胞的生长增殖情况。结果发现:胰酶和胶原酶混合消化后的雪旺细胞活细胞率为
94.6±3.4%,经免疫组化S-100法鉴定纯化后的雪旺细胞纯度为95.6±2.5%。差异有非常显著性意义(P<0.01)。说明周围神经中存在大量雪旺细胞,这些细胞能在体外进行分离培养,能获取量大纯度高、活力良好的雪旺细胞。胰酶和胶原酶混合消化结合差速贴壁法和G418纯化,可得到较高纯度和较多数量的雪旺细胞。这是一种简便有效的雪旺细胞培养、纯化的方法。
在第二部分,我们先将NT-3质粒提取、鉴定和纯化;采用阳离子脂质体介入法,将脂质体转染酶介导的NT-3转染至已培养好的雪旺细胞,转染后的雪旺细胞经G418筛选,获得成功转染NT-3基因的SCs克隆。观察NT-3蛋白的表达,镜下测定转染率,收集不同阶段的无血清培养液,通过免疫组化和RT-PCR结果测定样本中NT-3含量。采用免疫组化和逆转录酶-多聚酶链反应(RT-PCR)方法进行鉴定,并对RT-PCR产物测序,进一步证实NT-3的存在;用限制性内切酶酶切质粒后琼脂糖电泳鉴定;ELISA双抗体夹心法检测NT-3的表达;经过G418的多次筛选,并经Gimsa染色、免疫组化S-100法鉴定SCs的纯度。结果显示:经Gimsa染色、免疫组化S-100法鉴定SCs的纯度达95%以上。转染后雪旺细胞最突出的表现是胞体多呈长梭形,胞浆丰富,核卵圆形,可见到丰富的粗面内质网、线粒体和发育良好的高尔基体。ELISA双抗体夹心法测定转染后不同时期的NT-3的浓度:1周开始表达,2周后表达增加,4周后明显增加,差异有非常显著性意义(P<0.01)。所以,NT-3基因可转入培养的SCs并高效表达。SCs作为受体细胞,易于获取并能在体外大量培养繁殖;能较长时间表达所携带基因而不衰减,并能稳定大量地表达。
为了进一步探讨神经营养因子3基因修饰的雪旺细胞对周围神经再生修复的影响,从转基因角度探讨治疗周围神经损伤的有效方法,我们在第三部分设计NT-3基因修饰的雪旺细胞修复大鼠坐骨神经缺损观察其对促进神经再生的影响。我们选用96只SD大鼠,于右侧梨状肌下缘以远8mm切断并切除远断端10mm长的神经干保持10mm的缺损,制成坐骨神经缺损模型,应用NT-3基因修饰的雪旺细胞结合细胞外基质凝胶及生物可降解聚乳酸聚羟基乙酸共聚物管(PLGA)构建的神经移植复合体,修复大鼠坐骨神经的缺损。将坐骨神经切断缺损模型大鼠按桥接物的不同随机分为4组,每组24只。A组:细胞外基质凝胶PLGA管桥接组;B组:雪旺细胞-细胞外基质凝胶PLGA管桥接组;C组:NT-3基因-细胞外基质凝胶PLGA管桥接组;D组:NT-3基因修饰的雪旺细胞-细胞外基质凝胶PLGA管桥接组。术后1周、4周、8周、12周进行运动神经传导速度、轴突数、髓鞘的厚度、神经纤维的直径、神经组织面积的百分比和坐骨神经功能指数(sciatic nerve functional index SFI)等检测,发现D组均优于B、C组,B、C组均优于A组(P<0.01),而B、C组相比无明显差异(P>0.05)。因此,转染NT-3基因的雪旺细胞移植于损伤的周围神经,有促进神经生长、髓鞘再生的作用,使局部释放的NT-3加快轴突再生速度以促进周围神经再生,减缓失神经支配肌肉的萎缩,能弥补单纯细胞移植、神经营养因子含量的不足。
综合我们的试验,结合参阅文献,我们认为:(1)胰酶和胶原酶混合消化结合差速贴壁法和G418纯化,可得到较高纯度和较多数量的雪旺细胞。这是一种简便有效的雪旺细胞培养、纯化的方法。(2)NT-3基因可转入培养的SCs并高效表达。SCs作为受体细胞,易于获取并能在体外大量培养繁殖;能较长时间表达所携带基因而不衰减,并能稳定大量地表达。(3)转染NT-3基因的雪旺细胞移植于损伤的周围神经,有促进神经生长、髓鞘再生的作用,能弥补单纯细胞移植、神经营养因子含量的不足。因此,利用外源性神经营养因子促进周围神经再生成为周围神经损伤修复的一个重要课题。雪旺细胞是周围神经损伤后神经再生所需营养物质的重要来源。我们的实验研究将为修复周围神经损伤的基因治疗提供前提条件。
The results of the treatment to these patients with peripheral nerve injury are rarely satisfactory . Scientists these days begin to take more attention to the affection of Schwann cells peripheral nerve regeneration . Rothbone MP and his colleagus found that Schwann cells are perfect asreceptor cells and effective techniques of treating peripheral nerve regeneration in gene. Schwann cells can increase neurotrophic factors whice and has protective effects on peripheral nerve injury . Schwann cells can promote neuronal and nerve regeneration after peripheral nerve injury . Neurotrophic factors can facilitate nerve regeneration and protect neuronal survival . Especialy neurotrophic factor 3 NT-3 could facilitate nerve regeneration and increase neuronal survival and the sensory recovery , facilitate nerve-muscle relation and protect denervated skeletai muscle and motor end-plate. But NT-3 is not steady and soluble easily , the clinical effection is much lower . Therefore , the relation of Schwann cells and neurotrophic factors is the base peripheral nerve regeneration . Earlier investigation manifested that Schwann cells have a powerful attraction to the regenerating fibre of peripheral nerve after sciatic nerve, and also can enhance neuronal survival and prompt axonal growth. The project is mainly to explore this mechanisms preliminary . The purpose of this experimental study is to culture adult Schwann cells and modify them genetically by human NT-3 genes to increase the formation and promote neuronal and nerve regeneration .
Firstly , Schwann cells were cultured、separated and purified with post-digestion tissue blot and time-speed difference stick . The sciatic nerves of 10 four to three-days-old Wistar rats were harvested and removed . After separating Schwann cells with typsin and collagenase , purified cell with G-418 . The purified Schwann cells were were identified through the phase contrast microscope and S-100 immunocytochemical stain every two days . Flow cytometries were carried out respectively . The prolife rating function of these SCs was assessed by MTT assay .We found that The purity of SCs was 95.6±2.5% by S-100 immunohistochemistry . The flow cytomery were significantly higher than the control group . The results have statistical significance (P<0.01 ). It is said that there are a large of Schwann cells in the peripheral nerve . Schwann cells can were separated and purified in extracellular . Asreceptor cells, SCs can be obtained easily and also can be cultured and reproduced massively in vitro . they can be transduced to secrete augmented levels and express the transgene for a prolonged time .This is a good methods of culturing and purifying Schwann cells . It is a simple , availability , worth spreading way to obtain and purify the schwann cells by the upper .
Sencondly , Neurotrophic factor-3 is separated , purified and measured . The NT-3 cDNA gene was transfected into cultured Schwann cells by using cationic liposome . Plasmids expressing NT-3 genes were transfected to SC with lipofectamine,. The Schwann cells with NT-3 cDNA gene was examined by RT-PCR and immunoreactivity methods. The primary culture and purification of Schwann cells wasestablished and the efficiency of transfection of NT-3 was determined by reverse transcriptase polymerase chain reaction(RT PCT) , Gimsa and immunoreactivity methods. The result of RT-PCR was examined. Schwann cells with NT-3 gene were successfully selected by G418. NT-3 could be expressed in transfected Schwann cells for a long time, the ratio of transfection could be to 40%. Compared with nontranduced Schwann cells group, the levels of NT-3 began increasing after two weeks of gene transfer,and were increased obviously after four weeks . The results have statistical significance (P<0.01). Therefore, Schwann cells can be obtained easily and also can be cultured and reproduced massively in vitro ; they can be transduced to secrete augmented levels of NT-3 and express the transgene for a prolonged time . It was shown that NT-3 genes could efficiently promote Schwann cells by transfected into directly SCs in vivo ,
Thirtly , in order to investigate the effective treatment of peripheral nerve injury with NT-3 gene modified Schwann cells,to explore the feasibility of the treatment by means of gene transfection . The nerve grafts was constructed by schwann cells modified with NT-3 harvesting from ex vitro , combined with extracellular gel and biodegradable polyCDL-lactide-co-glycolide (PLGA) conduit. The sciatic nerve was bridged by the grafts. The sciatic nerve transected model were made and sutured end to end with epineurium. Seventy-two adult rats were divided into 4 groups randomly,with 24 in each. Group A:extraceellular matrix gel and PLGA conduits, Group B:Schwwann cells,extraceellular matrix gel and PLGA conduits, Group C:NT-3 gene , extraceellular matrix gel and PLGA conduits .Group D: :NT-3 modified Schwwann cells , extraceellular matrix gel and PLGA conduits . Motor nerve conduction velocity(MNCV) and were investigated on 4 week,8week and 12 week potoperatively. Compared with group A and B、C,there was higher rates in group B、C in MNCV, the number and thickness of axon,the diameter of nerve fiber,the percentage of the nerve tissue area, survival rate of motoneuron in the ventral horn in spinal cord and sciatic nerve functional index SFI. But there is no singniificant difference in group B、C. there was higher rates in group D than B、C. Therefore , NT-3 gene modified Schwann cells could be used in the treatment of peripheral nerve injury. It can accelerate the growth of axis-cylinder, defer the atrophy of muscles. Schwann cells gene transfer techniques can promote nerve and axon regeneration, make up the shortage of the lower content in simple schwann cells and neurotrophic factors .
Composite our experiment and literatures before, we can conclude that first Schwann cells can were separated and purified in extracellular . Asreceptor cells, SCs can be obtained easily and also can be cultured and reproduced massively in vitro . they can be transduced to secrete augmented levels and express the transgene for a prolonged time .This is a good methods of culturing and purifying Schwann cells . It is a simple , availability , worth spreading way to obtain and purify the schwann cells by the upper . Secondly , Schwann cells can be obtained easily and also can be cultured and reproduced massively in vitro ; they can be transduced to secrete augmented levels of neurotrophic factor -3 and express the transgene for a prolonged time . Thirtly, Schwann cells by neurotrophic factor -3modified genes transfer techniques can promote nerve and axon regeneration, make up the shortage of the lower content in simple schwann cells and neurotrophic factors . So , it is a important study for neurotrophic factors stimulate peripheral nerve regeneration .Schwann cells are source of accelerating peripheral nerve regeneration . Our investigation could provides a reliable animal model to study on gene treatment of peripheral nerve injury . The results provided with elementary theory for the genes treatment of neuotrophic factors .
首先我们培养、分离、纯化雪旺细胞。先将出生后3d的Wistar大鼠坐骨神经,经双酶消化后的剩余组织块采用植块法培养雪旺细胞,混悬于DMEM培养液中,接种于培养瓶中,置于培养箱。3d后首次换液,以后7d换液1次。细胞80%融合时,双差速贴壁法G-418(geneticin)纯化雪旺细胞。然后再培养24h。相差显微镜下观察计数,绘制各自的增殖曲线。在不同时间对雪旺细胞进行流式细胞分析、免疫组化S-100蛋白染色鉴定、四氮唑盐(MTT)比色法测定细胞的生长增殖情况。结果发现:胰酶和胶原酶混合消化后的雪旺细胞活细胞率为
94.6±3.4%,经免疫组化S-100法鉴定纯化后的雪旺细胞纯度为95.6±2.5%。差异有非常显著性意义(P<0.01)。说明周围神经中存在大量雪旺细胞,这些细胞能在体外进行分离培养,能获取量大纯度高、活力良好的雪旺细胞。胰酶和胶原酶混合消化结合差速贴壁法和G418纯化,可得到较高纯度和较多数量的雪旺细胞。这是一种简便有效的雪旺细胞培养、纯化的方法。
在第二部分,我们先将NT-3质粒提取、鉴定和纯化;采用阳离子脂质体介入法,将脂质体转染酶介导的NT-3转染至已培养好的雪旺细胞,转染后的雪旺细胞经G418筛选,获得成功转染NT-3基因的SCs克隆。观察NT-3蛋白的表达,镜下测定转染率,收集不同阶段的无血清培养液,通过免疫组化和RT-PCR结果测定样本中NT-3含量。采用免疫组化和逆转录酶-多聚酶链反应(RT-PCR)方法进行鉴定,并对RT-PCR产物测序,进一步证实NT-3的存在;用限制性内切酶酶切质粒后琼脂糖电泳鉴定;ELISA双抗体夹心法检测NT-3的表达;经过G418的多次筛选,并经Gimsa染色、免疫组化S-100法鉴定SCs的纯度。结果显示:经Gimsa染色、免疫组化S-100法鉴定SCs的纯度达95%以上。转染后雪旺细胞最突出的表现是胞体多呈长梭形,胞浆丰富,核卵圆形,可见到丰富的粗面内质网、线粒体和发育良好的高尔基体。ELISA双抗体夹心法测定转染后不同时期的NT-3的浓度:1周开始表达,2周后表达增加,4周后明显增加,差异有非常显著性意义(P<0.01)。所以,NT-3基因可转入培养的SCs并高效表达。SCs作为受体细胞,易于获取并能在体外大量培养繁殖;能较长时间表达所携带基因而不衰减,并能稳定大量地表达。
为了进一步探讨神经营养因子3基因修饰的雪旺细胞对周围神经再生修复的影响,从转基因角度探讨治疗周围神经损伤的有效方法,我们在第三部分设计NT-3基因修饰的雪旺细胞修复大鼠坐骨神经缺损观察其对促进神经再生的影响。我们选用96只SD大鼠,于右侧梨状肌下缘以远8mm切断并切除远断端10mm长的神经干保持10mm的缺损,制成坐骨神经缺损模型,应用NT-3基因修饰的雪旺细胞结合细胞外基质凝胶及生物可降解聚乳酸聚羟基乙酸共聚物管(PLGA)构建的神经移植复合体,修复大鼠坐骨神经的缺损。将坐骨神经切断缺损模型大鼠按桥接物的不同随机分为4组,每组24只。A组:细胞外基质凝胶PLGA管桥接组;B组:雪旺细胞-细胞外基质凝胶PLGA管桥接组;C组:NT-3基因-细胞外基质凝胶PLGA管桥接组;D组:NT-3基因修饰的雪旺细胞-细胞外基质凝胶PLGA管桥接组。术后1周、4周、8周、12周进行运动神经传导速度、轴突数、髓鞘的厚度、神经纤维的直径、神经组织面积的百分比和坐骨神经功能指数(sciatic nerve functional index SFI)等检测,发现D组均优于B、C组,B、C组均优于A组(P<0.01),而B、C组相比无明显差异(P>0.05)。因此,转染NT-3基因的雪旺细胞移植于损伤的周围神经,有促进神经生长、髓鞘再生的作用,使局部释放的NT-3加快轴突再生速度以促进周围神经再生,减缓失神经支配肌肉的萎缩,能弥补单纯细胞移植、神经营养因子含量的不足。
综合我们的试验,结合参阅文献,我们认为:(1)胰酶和胶原酶混合消化结合差速贴壁法和G418纯化,可得到较高纯度和较多数量的雪旺细胞。这是一种简便有效的雪旺细胞培养、纯化的方法。(2)NT-3基因可转入培养的SCs并高效表达。SCs作为受体细胞,易于获取并能在体外大量培养繁殖;能较长时间表达所携带基因而不衰减,并能稳定大量地表达。(3)转染NT-3基因的雪旺细胞移植于损伤的周围神经,有促进神经生长、髓鞘再生的作用,能弥补单纯细胞移植、神经营养因子含量的不足。因此,利用外源性神经营养因子促进周围神经再生成为周围神经损伤修复的一个重要课题。雪旺细胞是周围神经损伤后神经再生所需营养物质的重要来源。我们的实验研究将为修复周围神经损伤的基因治疗提供前提条件。
The results of the treatment to these patients with peripheral nerve injury are rarely satisfactory . Scientists these days begin to take more attention to the affection of Schwann cells peripheral nerve regeneration . Rothbone MP and his colleagus found that Schwann cells are perfect asreceptor cells and effective techniques of treating peripheral nerve regeneration in gene. Schwann cells can increase neurotrophic factors whice and has protective effects on peripheral nerve injury . Schwann cells can promote neuronal and nerve regeneration after peripheral nerve injury . Neurotrophic factors can facilitate nerve regeneration and protect neuronal survival . Especialy neurotrophic factor 3 NT-3 could facilitate nerve regeneration and increase neuronal survival and the sensory recovery , facilitate nerve-muscle relation and protect denervated skeletai muscle and motor end-plate. But NT-3 is not steady and soluble easily , the clinical effection is much lower . Therefore , the relation of Schwann cells and neurotrophic factors is the base peripheral nerve regeneration . Earlier investigation manifested that Schwann cells have a powerful attraction to the regenerating fibre of peripheral nerve after sciatic nerve, and also can enhance neuronal survival and prompt axonal growth. The project is mainly to explore this mechanisms preliminary . The purpose of this experimental study is to culture adult Schwann cells and modify them genetically by human NT-3 genes to increase the formation and promote neuronal and nerve regeneration .
Firstly , Schwann cells were cultured、separated and purified with post-digestion tissue blot and time-speed difference stick . The sciatic nerves of 10 four to three-days-old Wistar rats were harvested and removed . After separating Schwann cells with typsin and collagenase , purified cell with G-418 . The purified Schwann cells were were identified through the phase contrast microscope and S-100 immunocytochemical stain every two days . Flow cytometries were carried out respectively . The prolife rating function of these SCs was assessed by MTT assay .We found that The purity of SCs was 95.6±2.5% by S-100 immunohistochemistry . The flow cytomery were significantly higher than the control group . The results have statistical significance (P<0.01 ). It is said that there are a large of Schwann cells in the peripheral nerve . Schwann cells can were separated and purified in extracellular . Asreceptor cells, SCs can be obtained easily and also can be cultured and reproduced massively in vitro . they can be transduced to secrete augmented levels and express the transgene for a prolonged time .This is a good methods of culturing and purifying Schwann cells . It is a simple , availability , worth spreading way to obtain and purify the schwann cells by the upper .
Sencondly , Neurotrophic factor-3 is separated , purified and measured . The NT-3 cDNA gene was transfected into cultured Schwann cells by using cationic liposome . Plasmids expressing NT-3 genes were transfected to SC with lipofectamine,. The Schwann cells with NT-3 cDNA gene was examined by RT-PCR and immunoreactivity methods. The primary culture and purification of Schwann cells wasestablished and the efficiency of transfection of NT-3 was determined by reverse transcriptase polymerase chain reaction(RT PCT) , Gimsa and immunoreactivity methods. The result of RT-PCR was examined. Schwann cells with NT-3 gene were successfully selected by G418. NT-3 could be expressed in transfected Schwann cells for a long time, the ratio of transfection could be to 40%. Compared with nontranduced Schwann cells group, the levels of NT-3 began increasing after two weeks of gene transfer,and were increased obviously after four weeks . The results have statistical significance (P<0.01). Therefore, Schwann cells can be obtained easily and also can be cultured and reproduced massively in vitro ; they can be transduced to secrete augmented levels of NT-3 and express the transgene for a prolonged time . It was shown that NT-3 genes could efficiently promote Schwann cells by transfected into directly SCs in vivo ,
Thirtly , in order to investigate the effective treatment of peripheral nerve injury with NT-3 gene modified Schwann cells,to explore the feasibility of the treatment by means of gene transfection . The nerve grafts was constructed by schwann cells modified with NT-3 harvesting from ex vitro , combined with extracellular gel and biodegradable polyCDL-lactide-co-glycolide (PLGA) conduit. The sciatic nerve was bridged by the grafts. The sciatic nerve transected model were made and sutured end to end with epineurium. Seventy-two adult rats were divided into 4 groups randomly,with 24 in each. Group A:extraceellular matrix gel and PLGA conduits, Group B:Schwwann cells,extraceellular matrix gel and PLGA conduits, Group C:NT-3 gene , extraceellular matrix gel and PLGA conduits .Group D: :NT-3 modified Schwwann cells , extraceellular matrix gel and PLGA conduits . Motor nerve conduction velocity(MNCV) and were investigated on 4 week,8week and 12 week potoperatively. Compared with group A and B、C,there was higher rates in group B、C in MNCV, the number and thickness of axon,the diameter of nerve fiber,the percentage of the nerve tissue area, survival rate of motoneuron in the ventral horn in spinal cord and sciatic nerve functional index SFI. But there is no singniificant difference in group B、C. there was higher rates in group D than B、C. Therefore , NT-3 gene modified Schwann cells could be used in the treatment of peripheral nerve injury. It can accelerate the growth of axis-cylinder, defer the atrophy of muscles. Schwann cells gene transfer techniques can promote nerve and axon regeneration, make up the shortage of the lower content in simple schwann cells and neurotrophic factors .
Composite our experiment and literatures before, we can conclude that first Schwann cells can were separated and purified in extracellular . Asreceptor cells, SCs can be obtained easily and also can be cultured and reproduced massively in vitro . they can be transduced to secrete augmented levels and express the transgene for a prolonged time .This is a good methods of culturing and purifying Schwann cells . It is a simple , availability , worth spreading way to obtain and purify the schwann cells by the upper . Secondly , Schwann cells can be obtained easily and also can be cultured and reproduced massively in vitro ; they can be transduced to secrete augmented levels of neurotrophic factor -3 and express the transgene for a prolonged time . Thirtly, Schwann cells by neurotrophic factor -3modified genes transfer techniques can promote nerve and axon regeneration, make up the shortage of the lower content in simple schwann cells and neurotrophic factors . So , it is a important study for neurotrophic factors stimulate peripheral nerve regeneration .Schwann cells are source of accelerating peripheral nerve regeneration . Our investigation could provides a reliable animal model to study on gene treatment of peripheral nerve injury . The results provided with elementary theory for the genes treatment of neuotrophic factors .
引文
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41 Blasing H, Hendrix S, Paus R. Pro-inflammatory cytokines upregulate the skin immunoreactivity for NGF, NT-3, NT-4 and their receptor, p75NTR in vivo: a preliminary report.Arch Dermatol Res. 2005,96(12):580-4.
42 Butowt R, von Bartheld CS.A nterograde axonal transport of BDNF and NT-3 by retinal ganglion cells: roles of neurotrophin receptors.Mol Cell Neurosci. 2005 ,29(1):11-25.
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16 Blasing H, Hendrix S, Paus R. Pro-inflammatory cytokines upregulate the skin immunoreactivity for NGF, NT-3, NT-4 and their receptor, p75NTR in vivo: a preliminary report.Arch Dermatol Res. 2005,96(12):580-4.
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