SDF-1α在颅脑创伤后促进血管新生的作用
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摘要
背景
颅脑创伤(Traumatic brain injury, TBI)是已成为全世界的一个公共卫生问题。全世界每年有大约1000万患者因颅脑创伤住院或死亡,大约有5700万人因1次或更多次的颅脑创伤住过院。虽然对颅脑创伤后的病理生理机制的研究有了很大的进展,对颅脑创伤后治疗的动物学实验也取得了可喜的成果,但目前仍缺乏临床上有效地治疗颅脑创伤的策略。以往的研究较多的关注颅脑创伤后的神经再生,对创伤后血管新生的关注较少。但颅脑创伤后的血管新生与神经新生二者相辅相成,互相促进和制约。血管和神经作为一个整体—“血管神经单元”越来越受到神经科学研究人员的关注,促进创伤后组织血管的新生成为颅脑创伤治疗的一个新的方向。
目的
研究颅脑创伤后外源性给予重组人基质细胞衍生因子-1α(rhSDF-1α)对创伤脑组织局部CD34、CXCR4基因和蛋白质表达以及血管新生的影响。
研究颅脑创伤后通过给予SDF-1α中和性抗体拮抗SDF-1/CXCR4轴对创伤脑组织局部CD34、CXCR4基因和蛋白质表达以及血管新生的影响。
通过对rhSDF-1α和SDF-1α中和性抗体干预后大鼠神经功能恢复的评估研究血管新生和神经功能恢复之间的相关性。
方法
健康青年Wistar大鼠用液压打击仪成功制备颅脑创伤大鼠模型后,将颅脑创伤大鼠随机分为rhSDF-1α干预组、SDF-1α中和抗体干预组、生理盐水对照组。创伤后30分钟,rhSDF-1α干预组大鼠接受立体定向脑组织局部注射rhSDF-1α4μ8/4μ1,SDF-1α中和抗体干预组大鼠接受立体定向脑组织局部注射SDF-1α中和性抗体4μg/4μ1,对照组大鼠接受立体定向脑组织局部注射生理盐水4μ1。
分别在创伤前、创伤后1、3、7、14、21天用改良神经功能评分(mNSS)对大鼠进行神经功能评分,创伤后14天开始用Morris水迷宫对大鼠进行空间学习记忆能力进行评估。
取3个干预组动物创伤后14天的脑组织用组织学染色方法评估创伤脑组织CD34+的微血管密度和CD34/CXCR4双阳性的微血管的数量以了解SDF-1/CXCR4轴在血管新生过程中的作用,用qRT-PCR和Western-blot检测创伤脑组织局部的CD34和CXCR4mRNA和蛋白质的表达以进一步明确SDF-1/CXCR4轴在血管新生过程中的作用并分析大鼠神经功能改善与创伤脑组织血管新生的相关性。
结果
流式细胞仪分析结果显示不同干预对大鼠脑创伤后外周血CD34+干祖细胞数量无明显影响。
组织学染色发现rhSDF-1α干预组大鼠损伤脑组织局部的微血管密度(MVD)和CD34/CXCR4双阳性微血管的数目较生理盐水对照组显著增加,结果有统计学差异(P<0.05)。与之相反,SDF-1α中和抗体干预组大鼠损伤脑组织局部MVD和CD34/CXCR4双阳性微血管的数目较生理盐水对照组减少(P<0.05)。
qRT-PCR和Western blot结果显示rhSDF-1α干预大鼠损伤脑组织局部CD34和CXCR4mRNA和蛋白质的表达较生理盐水对照组增加,而SDF-1α中和抗体干预大鼠脑组织局部CD34和CXCR4mRNA和蛋白质的表达较生理盐水对照组显著降低(P<0.05)。
mNSS评分显示伤前大鼠的mNSS均较低,3组动物的评分无统计学差异。损伤后1天,3组动物的mNSS均较高,说明液压打击导致了大鼠神经功能障碍,在后续的实验时间内,3组大鼠的mNSS评分均呈逐渐降低趋势,提示大鼠脑创伤后有一个神经功能恢复过程。在治疗后的14天和21天,rhSDF-1α干预组的大鼠的神经功能恢复明显优于SDF-1α中和性抗体处理组(P<0.01)和生理盐水对照组(P<0.05)。SDF-1α中和性抗体治疗组大鼠的mNSS在液压打击后的1-14天与生理盐水干预组相比无明显差异(P>0.05),但是在打击后21天,其mNSS评分高于生理盐水对照组(P<0.05)。Spearman秩相关分析发现TBI后14天微血管密度的增加与mNSS呈负相关。
Morris水迷宫试验显示在试验的开始阶段,三组大鼠的潜伏期均较长,但是在后续的空间记忆能力试验中,潜伏期较前明显变短(P<0.001)。这提示通过试验建立了大鼠的空间记忆。SDF-1α中和抗体干预组动物的潜伏期长于生理盐水对照组大鼠,差异具有统计学意义(P<0.05)。rhSDF-1α干预组大鼠的潜伏期短于生理盐水对照组大鼠,差异具有统计学意义(P<0.05)。探索试验结果显示rhSDF-1α干预组大鼠在目标象限的游泳时间明显大于生理盐水对照组大鼠,差异具有统计学意义(P<0.05)。SDF-1α中和抗体干预组动物在目标象限的游泳时间与生理盐水对照组相比明显减少(P<0.05)。通过对三组动物游泳速度的统计分析发现,三组动物的游泳速度并无明显统计学差异,提示空间学习记忆能力障碍与动物的肢体功能障碍无关。
结论
颅脑创伤后脑组织局部给予rhSDF-1α可以通过SDF-1/CXCR4轴促进CD34+细胞向损伤部位的迁移,提高局部CD34、CXCR4的表达,促进损伤脑组织的血管新生,改善神经功能。
应用SDF-1α中和性抗体拮抗SDF-1/CXCR4轴,则减弱了CD34+细胞向损伤部位的迁移,降低了局部CD34、CXCR4的表达,抑制了损伤脑组织的血管新生,使神经功能恶化。
SDF-1/CXCR4轴可能是颅脑创伤治疗的一个新的靶点。
Background
Traumatic brain injury (TBI) is one of the most important global public health problem. About100million people around the world are hospitalized or dead of TBI, and more than570million people world wide have been hospitalized with one or more TBI[1]. Despite the research progression of pathophysiological mechanism after TBI and the treatment strategies on TBI animal models, the effective clinical therapy is still limited. The previous research of TBI therapies focused more on the neurogenesis, but less on the angiogenesis after the initial injury. The angiogenesis and neurogenesis after TBI are co-regulated. Neurovascular niche, a unit that include neuron and microvessel draw more and more researchers' attention. The angiogenesis promoting strategies after TBI may be a promising field for TBI treatment.
Objective
To evaluated the angiogenesis and also the local brain tissue expression of CD34、 CXCR4mRNA and protein after rhSDF-1α treatment in TBI animal model.
To evaluated the angiogenesis and also the local brain tissue expression of CD34、 CXCR4mRNA and protein after SDF-1α neutralizing antibody treatment in TBI animal model.
To evaluate the correlation of angiogenesis and neurological outcome in different treatment groups.
Methods
Youth male Wistar rats received fluid percussion and were divided into3groups, the rhSDF-1α treated group, the SDF-1α neutralizing antibody treated group and the normal saline treated group.30minutes after TBI, the rhSDF-1α group received stereotactic cortical injection of rhSDF-1α4μg/4μl, the SDF-1α neutralizing antibody group received stereotactic cortical injection of SDF-1α neutralizing antibody4μg/4μl, the controlled group received stereotactic cortical injection of normal saline4μl.
Modified neurological severity score (mNSS) was used to evaluate the neurological functional outcome before trauma and1,3,7,14and21days post trauma. The Morris water maze was used to evaluate the special learning memory deficit14days after injury. Flow cytometry was used to analyze the peripheral CD34+cells1,3,7,14days after injury. The brain tissues were harvest from the3groups14days post injury for histological and molecular biological assessment. The immunochemistry and immunofluorescence staining were used to assess the CD34positive microvessel density (MVD) and CD34/CXCR4double positive microvessels. Quantitative real time polymerase chain reaction (qRT-PCR) and western blot were used to assess the mRNA and protein expression of CD34and CXCR4. The role of SDF-1/CXCR4axis in angiogenesis was evaluated and the correlation of angiogenesis and neurological outcome was also assessed.
Results
No significant differences of the number of peripheral blood CD34+cells were observed among the three different treated groups by flow cytometry analysis. The histology staining results showed that the MVD and CD34/CXCR4double positive mivrovessels of the rhSDF-1α treated group increased significantly, whereas, decreased in the SDF-1α neutralizing antibody treated group compared with that of normal saline treated group (P<0.05). The results of qRT-PCR and western blot demonstrated that the expression of mRNA and protein of CD34and CXCR4in injured tissue increased compared to that of normal saline treated animals, however, in SDF-1α neutralizing antibody treated animals, the mRNA and protein expression of CD34and CXCR4decreased compared to that of normal saline treated animals (P <0.05). All of the3group animals displayed low mNSS before injury, but high mNSS lday post injury. The mNSS result indicated that the fluid percussion induced neurological dysfunction to the rats. The mNSS decreased dramatically in the subsequent evaluation days, demonstrating that there was a neurological recovery process after injury. The neurological outcome of rhSDF-1α treated group was better that of SDF-1α neutralizing antibody treated group (P<0.01) or normal saline treated group (P<0.05)14and21days after injury. The mNSS of SDF-la neutralizing antibody treated group had no significant difference compared to that of normal saline treated animals in14days after injury (P>0.05). However, the mNSS of neutralizing antibody treated group was worse than that of normal saline treated animals (P<0.05). The Morris water maze (MWM) was used to assess the special learning memory ability after injury. The latency of the3groups animals were similar at the beginning of the test, but decreased in the subsequent special acquisition test (P<0.001) This indicated that the special learning memory was established. The rhSDF-1α treated animals had shorter latency compared to that of normal saline treated group, whereas, the SDF-1α antibody treated group had longer latency compared to that of normal saline treated group (P<0.05). In the probe trial, the rhSDF-1α treated animals spend more time in the target quadrant, in the contrary, the SDF-1α neutralizing antibody treated animals spend less time in the target quadrant compared to that of the normal saline treated animals (P<0.05). The swimming speed of the3groups rats had no significant differences demonstrated that the special learning deficit was not due to the injury induced limb impairment. The Spearman rank correlation coefficient test showed that there was a significant negative correlation between mNSS and MVD14days after TBI in the3differently treated groups.
Conclusion
Local distribution of rhSDF-1α after TBI could enhance the migration of CD34+cells to the injured site, increase the expression of mRNA and protein of CD34and CXCR4, promote angiogenesis, ameliorate neurological outcome via SDF-1/CXCR4axis.
Local distribution of SDF-1α neutralizing antibody after TBI could suppress the migration of CD34+cells to the injured site, decrease the expression of mRNA and protein of CD34and CXCR4, inhibit angiogenesis, exacerbate neurological outcome via blocking SDF-1/CXCR4axis.
SDF-1/CXCR4axis may be a new promising therapeutic target for TBI.
颅脑创伤(Traumatic brain injury, TBI)是已成为全世界的一个公共卫生问题。全世界每年有大约1000万患者因颅脑创伤住院或死亡,大约有5700万人因1次或更多次的颅脑创伤住过院。虽然对颅脑创伤后的病理生理机制的研究有了很大的进展,对颅脑创伤后治疗的动物学实验也取得了可喜的成果,但目前仍缺乏临床上有效地治疗颅脑创伤的策略。以往的研究较多的关注颅脑创伤后的神经再生,对创伤后血管新生的关注较少。但颅脑创伤后的血管新生与神经新生二者相辅相成,互相促进和制约。血管和神经作为一个整体—“血管神经单元”越来越受到神经科学研究人员的关注,促进创伤后组织血管的新生成为颅脑创伤治疗的一个新的方向。
目的
研究颅脑创伤后外源性给予重组人基质细胞衍生因子-1α(rhSDF-1α)对创伤脑组织局部CD34、CXCR4基因和蛋白质表达以及血管新生的影响。
研究颅脑创伤后通过给予SDF-1α中和性抗体拮抗SDF-1/CXCR4轴对创伤脑组织局部CD34、CXCR4基因和蛋白质表达以及血管新生的影响。
通过对rhSDF-1α和SDF-1α中和性抗体干预后大鼠神经功能恢复的评估研究血管新生和神经功能恢复之间的相关性。
方法
健康青年Wistar大鼠用液压打击仪成功制备颅脑创伤大鼠模型后,将颅脑创伤大鼠随机分为rhSDF-1α干预组、SDF-1α中和抗体干预组、生理盐水对照组。创伤后30分钟,rhSDF-1α干预组大鼠接受立体定向脑组织局部注射rhSDF-1α4μ8/4μ1,SDF-1α中和抗体干预组大鼠接受立体定向脑组织局部注射SDF-1α中和性抗体4μg/4μ1,对照组大鼠接受立体定向脑组织局部注射生理盐水4μ1。
分别在创伤前、创伤后1、3、7、14、21天用改良神经功能评分(mNSS)对大鼠进行神经功能评分,创伤后14天开始用Morris水迷宫对大鼠进行空间学习记忆能力进行评估。
取3个干预组动物创伤后14天的脑组织用组织学染色方法评估创伤脑组织CD34+的微血管密度和CD34/CXCR4双阳性的微血管的数量以了解SDF-1/CXCR4轴在血管新生过程中的作用,用qRT-PCR和Western-blot检测创伤脑组织局部的CD34和CXCR4mRNA和蛋白质的表达以进一步明确SDF-1/CXCR4轴在血管新生过程中的作用并分析大鼠神经功能改善与创伤脑组织血管新生的相关性。
结果
流式细胞仪分析结果显示不同干预对大鼠脑创伤后外周血CD34+干祖细胞数量无明显影响。
组织学染色发现rhSDF-1α干预组大鼠损伤脑组织局部的微血管密度(MVD)和CD34/CXCR4双阳性微血管的数目较生理盐水对照组显著增加,结果有统计学差异(P<0.05)。与之相反,SDF-1α中和抗体干预组大鼠损伤脑组织局部MVD和CD34/CXCR4双阳性微血管的数目较生理盐水对照组减少(P<0.05)。
qRT-PCR和Western blot结果显示rhSDF-1α干预大鼠损伤脑组织局部CD34和CXCR4mRNA和蛋白质的表达较生理盐水对照组增加,而SDF-1α中和抗体干预大鼠脑组织局部CD34和CXCR4mRNA和蛋白质的表达较生理盐水对照组显著降低(P<0.05)。
mNSS评分显示伤前大鼠的mNSS均较低,3组动物的评分无统计学差异。损伤后1天,3组动物的mNSS均较高,说明液压打击导致了大鼠神经功能障碍,在后续的实验时间内,3组大鼠的mNSS评分均呈逐渐降低趋势,提示大鼠脑创伤后有一个神经功能恢复过程。在治疗后的14天和21天,rhSDF-1α干预组的大鼠的神经功能恢复明显优于SDF-1α中和性抗体处理组(P<0.01)和生理盐水对照组(P<0.05)。SDF-1α中和性抗体治疗组大鼠的mNSS在液压打击后的1-14天与生理盐水干预组相比无明显差异(P>0.05),但是在打击后21天,其mNSS评分高于生理盐水对照组(P<0.05)。Spearman秩相关分析发现TBI后14天微血管密度的增加与mNSS呈负相关。
Morris水迷宫试验显示在试验的开始阶段,三组大鼠的潜伏期均较长,但是在后续的空间记忆能力试验中,潜伏期较前明显变短(P<0.001)。这提示通过试验建立了大鼠的空间记忆。SDF-1α中和抗体干预组动物的潜伏期长于生理盐水对照组大鼠,差异具有统计学意义(P<0.05)。rhSDF-1α干预组大鼠的潜伏期短于生理盐水对照组大鼠,差异具有统计学意义(P<0.05)。探索试验结果显示rhSDF-1α干预组大鼠在目标象限的游泳时间明显大于生理盐水对照组大鼠,差异具有统计学意义(P<0.05)。SDF-1α中和抗体干预组动物在目标象限的游泳时间与生理盐水对照组相比明显减少(P<0.05)。通过对三组动物游泳速度的统计分析发现,三组动物的游泳速度并无明显统计学差异,提示空间学习记忆能力障碍与动物的肢体功能障碍无关。
结论
颅脑创伤后脑组织局部给予rhSDF-1α可以通过SDF-1/CXCR4轴促进CD34+细胞向损伤部位的迁移,提高局部CD34、CXCR4的表达,促进损伤脑组织的血管新生,改善神经功能。
应用SDF-1α中和性抗体拮抗SDF-1/CXCR4轴,则减弱了CD34+细胞向损伤部位的迁移,降低了局部CD34、CXCR4的表达,抑制了损伤脑组织的血管新生,使神经功能恶化。
SDF-1/CXCR4轴可能是颅脑创伤治疗的一个新的靶点。
Background
Traumatic brain injury (TBI) is one of the most important global public health problem. About100million people around the world are hospitalized or dead of TBI, and more than570million people world wide have been hospitalized with one or more TBI[1]. Despite the research progression of pathophysiological mechanism after TBI and the treatment strategies on TBI animal models, the effective clinical therapy is still limited. The previous research of TBI therapies focused more on the neurogenesis, but less on the angiogenesis after the initial injury. The angiogenesis and neurogenesis after TBI are co-regulated. Neurovascular niche, a unit that include neuron and microvessel draw more and more researchers' attention. The angiogenesis promoting strategies after TBI may be a promising field for TBI treatment.
Objective
To evaluated the angiogenesis and also the local brain tissue expression of CD34、 CXCR4mRNA and protein after rhSDF-1α treatment in TBI animal model.
To evaluated the angiogenesis and also the local brain tissue expression of CD34、 CXCR4mRNA and protein after SDF-1α neutralizing antibody treatment in TBI animal model.
To evaluate the correlation of angiogenesis and neurological outcome in different treatment groups.
Methods
Youth male Wistar rats received fluid percussion and were divided into3groups, the rhSDF-1α treated group, the SDF-1α neutralizing antibody treated group and the normal saline treated group.30minutes after TBI, the rhSDF-1α group received stereotactic cortical injection of rhSDF-1α4μg/4μl, the SDF-1α neutralizing antibody group received stereotactic cortical injection of SDF-1α neutralizing antibody4μg/4μl, the controlled group received stereotactic cortical injection of normal saline4μl.
Modified neurological severity score (mNSS) was used to evaluate the neurological functional outcome before trauma and1,3,7,14and21days post trauma. The Morris water maze was used to evaluate the special learning memory deficit14days after injury. Flow cytometry was used to analyze the peripheral CD34+cells1,3,7,14days after injury. The brain tissues were harvest from the3groups14days post injury for histological and molecular biological assessment. The immunochemistry and immunofluorescence staining were used to assess the CD34positive microvessel density (MVD) and CD34/CXCR4double positive microvessels. Quantitative real time polymerase chain reaction (qRT-PCR) and western blot were used to assess the mRNA and protein expression of CD34and CXCR4. The role of SDF-1/CXCR4axis in angiogenesis was evaluated and the correlation of angiogenesis and neurological outcome was also assessed.
Results
No significant differences of the number of peripheral blood CD34+cells were observed among the three different treated groups by flow cytometry analysis. The histology staining results showed that the MVD and CD34/CXCR4double positive mivrovessels of the rhSDF-1α treated group increased significantly, whereas, decreased in the SDF-1α neutralizing antibody treated group compared with that of normal saline treated group (P<0.05). The results of qRT-PCR and western blot demonstrated that the expression of mRNA and protein of CD34and CXCR4in injured tissue increased compared to that of normal saline treated animals, however, in SDF-1α neutralizing antibody treated animals, the mRNA and protein expression of CD34and CXCR4decreased compared to that of normal saline treated animals (P <0.05). All of the3group animals displayed low mNSS before injury, but high mNSS lday post injury. The mNSS result indicated that the fluid percussion induced neurological dysfunction to the rats. The mNSS decreased dramatically in the subsequent evaluation days, demonstrating that there was a neurological recovery process after injury. The neurological outcome of rhSDF-1α treated group was better that of SDF-1α neutralizing antibody treated group (P<0.01) or normal saline treated group (P<0.05)14and21days after injury. The mNSS of SDF-la neutralizing antibody treated group had no significant difference compared to that of normal saline treated animals in14days after injury (P>0.05). However, the mNSS of neutralizing antibody treated group was worse than that of normal saline treated animals (P<0.05). The Morris water maze (MWM) was used to assess the special learning memory ability after injury. The latency of the3groups animals were similar at the beginning of the test, but decreased in the subsequent special acquisition test (P<0.001) This indicated that the special learning memory was established. The rhSDF-1α treated animals had shorter latency compared to that of normal saline treated group, whereas, the SDF-1α antibody treated group had longer latency compared to that of normal saline treated group (P<0.05). In the probe trial, the rhSDF-1α treated animals spend more time in the target quadrant, in the contrary, the SDF-1α neutralizing antibody treated animals spend less time in the target quadrant compared to that of the normal saline treated animals (P<0.05). The swimming speed of the3groups rats had no significant differences demonstrated that the special learning deficit was not due to the injury induced limb impairment. The Spearman rank correlation coefficient test showed that there was a significant negative correlation between mNSS and MVD14days after TBI in the3differently treated groups.
Conclusion
Local distribution of rhSDF-1α after TBI could enhance the migration of CD34+cells to the injured site, increase the expression of mRNA and protein of CD34and CXCR4, promote angiogenesis, ameliorate neurological outcome via SDF-1/CXCR4axis.
Local distribution of SDF-1α neutralizing antibody after TBI could suppress the migration of CD34+cells to the injured site, decrease the expression of mRNA and protein of CD34and CXCR4, inhibit angiogenesis, exacerbate neurological outcome via blocking SDF-1/CXCR4axis.
SDF-1/CXCR4axis may be a new promising therapeutic target for TBI.
引文
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