骨髓间充质干细胞治疗脊髓损伤的临床初步研究
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摘要
目的脊髓损伤(SCI)严重威胁人类健康,给家庭和社会带来沉重负担。对SCI的治疗包括外科手术、药物治疗以及康复训练等,但均作用有限。近年来,干细胞的临床应用给SCI的治疗带来了新希望,其相关研究备受关注。研究表明,骨髓间充质干细胞(MSCs)对SCI患者造成的神经功能缺失具有治疗作用,而自体MSCs有取材方便、无免疫排斥反应、不存在伦理道德问题等优点,已成为了研究的热点。但临床尚缺乏足够资料证实其疗效。本文首次报道采用自体MSCs经根动脉和蛛网膜下腔移植法治疗SCI患者,观察比较研究2种治疗方法的近期治疗效果以及治疗安全性。
方法选择经CT或MRI确诊并行手术或非手术治疗、暴力引起的、病程1月～2年、年龄15岁～60岁之间、无昏迷及其他并发症、能至少接受标准康复治疗一月、自愿并签署知情同意书的SCI患者26例,其中16例除做标准康复治疗外,接受干细胞移植治疗(8例为经根动脉途径移植治疗组,简称根动脉组;8例为经蛛网膜下腔途径移植治疗组,简称蛛网膜下腔组),10例为只做标准康复治疗的对照组病例。所有受试者标准康复治疗时间为一月,感觉、运动功能评定采用美国脊柱损伤协会(ASIA)与国际脊髓学会(ISCoS)制定的脊髓损伤神经学分类国际标准(第六版,2006)进行评定。两组在年龄、性别、病程、损伤程度等方面无统计学差异(均p>0.05),具有可比性。根动脉组与蛛网膜下腔组在标准康复治疗的基础上给予自体MSCs移植治疗,经髂骨穿刺采集自体骨髓,分离提取后经根动脉或蛛网膜下腔注入;对照组仅给予常规标准的康复治疗。根动脉组与蛛网膜下腔组于移植术前和后一月、对照组于标准康复治疗前和后一月进行运动与感觉神经功能评分、日常生活活动能力(ADL)评定。由两名非参与治疗的且经过专业训练的医师进行评估。
结果1)、神经功能评分变化:治疗后一月和治疗前相比,根动脉组患者浅感觉、深感觉及运动功能评分有改善,统计学处理后差异有显著性(均p<0.01);蛛网膜下腔组患者运动功能评分有改善,统计学处理后差异有显著性(p<0.01);对照组患者浅感觉评分有所改善,统计学处理后差异有显著性(p<0.05)。
2)、日常生活活动能力(ADL)评分:治疗后一月与治疗前相比,根动脉组与蛛网膜下腔组患者的ADL评分均提高,差异有统计学意义(均p<0.05);对照组ADL评分统计学差异没有显著性(P>0.05)。
3)、不同治疗途径的治疗效果比较:治疗后一月将根动脉组、蛛网膜下腔组与对照组之间的治疗效果进行比较,根动脉组和蛛网膜下腔组的浅深感觉、运动功能评分统计学处理差异没有显著性(均P>0.05);三组ADL评分统计学差异没有显著性(P>0.05);根动脉组与蛛网膜下腔组之间进行比较,浅深感觉、运动功能、ADL评分统计学差异也没有显著性(P>0.05)。
4)、不良反应:有1例经蛛网膜下腔治疗患者发生了术后的发热,原因不明,肌肉注射地塞米松后缓解,无复发。根动脉组患者未有任何不良反应出现。
结论自体MSCs经根动脉或蛛网膜下腔移植治疗SCI,术后一月患者的浅深感觉、运动功能及ADL评分有所改善,未有严重副反应发生,其中经根动脉途径移植治疗SCI为首次报道。临床初步研究表明:自体MSCs移植治疗SCI有一定的近期临床疗效,操作简便,安全可行,值得做大样本双盲多中心的进一步临床研究与探索。
目的初步观察自体骨髓间充质干细胞(MSCs)移植治疗脑神经损伤的临床效果和存在的问题。
方法选取自愿并签署知情同意书的2例脑神经损伤患者(脑梗塞患者1例,脑干挫裂伤患者1例),首先抽取自体骨髓细胞悬液,在体外经过分离提取后,制成骨髓间充质干细胞悬液,经L4-5注入蛛网膜下腔,分离后剩余的血液立即经静脉回输给患者,术后常规标准康复治疗。采取手法肌力检查(MMT)进行肌力评定分级,日常生活活动能力(ADL)评定采用Barthel指数评分,偏瘫分级采用Brunnstrom偏瘫运动分级标准。
结果脑梗塞患者(病例1)自体移植MSCs术后1月功能评定无明显变化。脑干挫裂伤患者(病例2)自体移植MSCs术后1月ADL评分提高10分,Brunnstrom偏瘫分级右下肢提升1级;术后3月ADL评分提高15分,右上肢肌力提升1级,Brunnstrom偏瘫分级右侧手指与上肢分别提升了1级。
结论自体MSCs移植治疗脑神经损伤有一定的效果,本报告病例2的肌力评定、ADL评分、Brunnstrom偏瘫分级有所改善,治疗后无副反应发生。但是否真正为MSCs治疗所起的作用,还有待对比研究证实;对MSCs移植的时机、途径、个体差异、效果等还需更深入的研究与探讨。
Objective SCI is not only a threat to human health, but also brings heavy burden for family and society. The main therapies for SCI are surgery, drugs, rehabilitation training and so on, but their effects are limited currently . In recent years, stem cells therapy for SCI brings a light for SCI and it attracts more attention. Some studies have indicated that MSCs have a therapeutic effect on neurological deficit caused by SCI, meanwhile autologous MSCs without immunity rejection and ethic problem are more available therefore, it has become a focused research field. However, adequate clinical data of its effects are still lack.In this study we first report the autologous marrow mesenchymal stem cells transplantation through root artery and subarachnoid spaceto treat patients with SCI, and through observation we investigate the short-term curative effect and the safety of the two therapies.
METHODS 26 SCI patients were enrolled in this study. They were diagnosed by CT or MRI and received surgical or conservative treatment, caused by violence, within 1-month to 2-year of SCI onset, age between 15 years to 60 years, with no coma or other complications, being able to get at least 1-month of standard rehabilitation, and were informed and had signed the informed consent document. Among the 26 enrolled patients, 16 received the stem cells transplantation as well as standard rehabilitation training (8 cases are the transplantation group through abbreviated as subarachnoid space group; another 8 are the transplantation group through root artery abbreviated as root artery group), and 10 patients were control group with standard rehabilitation therapy. The duration of standard rehabilitation treatment for all the enrolled patients was one month. Sensory and motor function assessments adopted the American Spinal Injury Association (ASIA) classification and degree of SCI were evaluated by International Standards for Neurological Classification of Spinal Cord Injury (Sixth Edition, 2006). There were no differences of age, duration of disease, degree of injury between the two groups (p>0.05). Both subarachnoid space group and root artery group were given autologous marrow mesenchymal stem cells transplantation therapy on the basis of comprehensive rehabilitation treatment. The autologous marrow was collected from iliac bone marrow puncture and injected through subarachnoid space and root artery after separation and extraction. The control group was given only conventional rehabilitation treatment. Both groups were received assessment of motor and sensory function and assessment of activities of daily living (ADL) on admission and one
month after transplantation respectively; the control group received those assessments on admission and one month after rehabilitation treatment. The study was evaluated independently by two professional doctors who were not involved in the treatment.
RESULTS 1)Change of neurological function scores: compared with admission,the root artery group had improvement in superficial, deep sensory and motor function scores in one month after transplantation, and there was a significant difference(p<0.01); The subarachnoid space group only had improvement in motor function scores, and there was a significant difference(p<0.01); The control group had improvement in superficial sensory function scores in one month after treatment, and there was a significant difference(p<0.05).
2) Activities of daily living (ADL) score: The ADL scores of stem cells therapy group were all improved between on admission and one month after transplantation , and there was a significant difference (p<0.05); The ADL scores of control group had no significant difference (P>0.05).
3) Comparisons on effect of different therapies: one month after treatment , to compare the different effects of subarachnoid space group, root artery group and control group, scores of superficial and deep sensory as well as motor functions patients in subarachnoid space group and root artery group looked like a better results than that of control group, but no significant difference (P>0.05); on ADL scores, patients in the three groups were nearly the same, and there was no significant difference (P>0.05); Compared between the two transplantation groups, patients had no significant difference on scores of superficial and deep sensory as well as motor functions(P>0.05).
4) The adverse effects of stem cells transplantation: 1 patient got fever after transplantation through subarachnoid space, and the cause was unclear. The symptom relieved after giving intramuscular dexamethasone and there was no recurrence. No adverse effect was found in root artery group.
CONCLUSION Using autologous MSCs transplantation through subarachnoid space and root artery to treat patients with SCI which was first reported, one month after operation the superficial and deep sensory, motor function as well as ADL scores of patients were improved, and there is no serious side effect. Autologous marrow stem cells transplantation has some short-term clinical effects for patients with SCI, and can be easily operated, it is safe and feasible, however, large sample, double-blind, multi-center clinical trials are further needed for evidence based medicine .
Objective To explore the efficacy and clinical problems of autologous transplantation of marrow mesenchymal stem cells (MSCs) for treating patients with cranial nerve damage.
METHODS 2 patients with cranial nerve damage treated by autologous transplantation of marrow mesenchymal stem cells were enrolled, who was volunteered and had signed the informed consent document. One was suffering from cerebral infarction,and the other was brainstem contusion and laceration. At first, extract autologous marrow cells suspension, and after isolation, make it as MSCs suspension; inject it into subarachnoid space through L4-5. The rest isolated blood was transfused back to patients through vein immediately. After operation, patients received conventional rehabilitation treatment. The grade of muscle strength was evaluated by MMT, ADL was assessed by Barthel, and hemiparalysis grade was evaluated by standard Brunnstrom stage.
RESULTS The patient with cerebral infarction (case one) had no apparent change in functional evaluation one month after transplanting autologous MSCs. At the same time, one month after transplanting autologous MSCs the ADL score of the patient with brainstem contusion and laceration (case two) raised 10 points and Brunnstrom stage of right lower extremity raised 1 grade; in 3 month after operation, his ADL score raised 15 points, the muscle strength of right upper extremity increased 1 grade, and Brunnstrom stage of right upper extremity also raised 1 grade.
CONCLUSION Autologous transplantation of marrow mesenchymal stem cells could be an effective method to treat patients with cranial nerve damage. The manual muscle, scores of ADL and Brunnstrom stage of the patient in case two of this report were equally improved, but it still needs to be identified whether the functional improvement was actually gotten from the stem cells therapy. Further studies are needed to explore the timing, paths, individual differences, clinical effects and so on of MSCs transplantation.
方法选择经CT或MRI确诊并行手术或非手术治疗、暴力引起的、病程1月～2年、年龄15岁～60岁之间、无昏迷及其他并发症、能至少接受标准康复治疗一月、自愿并签署知情同意书的SCI患者26例,其中16例除做标准康复治疗外,接受干细胞移植治疗(8例为经根动脉途径移植治疗组,简称根动脉组;8例为经蛛网膜下腔途径移植治疗组,简称蛛网膜下腔组),10例为只做标准康复治疗的对照组病例。所有受试者标准康复治疗时间为一月,感觉、运动功能评定采用美国脊柱损伤协会(ASIA)与国际脊髓学会(ISCoS)制定的脊髓损伤神经学分类国际标准(第六版,2006)进行评定。两组在年龄、性别、病程、损伤程度等方面无统计学差异(均p>0.05),具有可比性。根动脉组与蛛网膜下腔组在标准康复治疗的基础上给予自体MSCs移植治疗,经髂骨穿刺采集自体骨髓,分离提取后经根动脉或蛛网膜下腔注入;对照组仅给予常规标准的康复治疗。根动脉组与蛛网膜下腔组于移植术前和后一月、对照组于标准康复治疗前和后一月进行运动与感觉神经功能评分、日常生活活动能力(ADL)评定。由两名非参与治疗的且经过专业训练的医师进行评估。
结果1)、神经功能评分变化:治疗后一月和治疗前相比,根动脉组患者浅感觉、深感觉及运动功能评分有改善,统计学处理后差异有显著性(均p<0.01);蛛网膜下腔组患者运动功能评分有改善,统计学处理后差异有显著性(p<0.01);对照组患者浅感觉评分有所改善,统计学处理后差异有显著性(p<0.05)。
2)、日常生活活动能力(ADL)评分:治疗后一月与治疗前相比,根动脉组与蛛网膜下腔组患者的ADL评分均提高,差异有统计学意义(均p<0.05);对照组ADL评分统计学差异没有显著性(P>0.05)。
3)、不同治疗途径的治疗效果比较:治疗后一月将根动脉组、蛛网膜下腔组与对照组之间的治疗效果进行比较,根动脉组和蛛网膜下腔组的浅深感觉、运动功能评分统计学处理差异没有显著性(均P>0.05);三组ADL评分统计学差异没有显著性(P>0.05);根动脉组与蛛网膜下腔组之间进行比较,浅深感觉、运动功能、ADL评分统计学差异也没有显著性(P>0.05)。
4)、不良反应:有1例经蛛网膜下腔治疗患者发生了术后的发热,原因不明,肌肉注射地塞米松后缓解,无复发。根动脉组患者未有任何不良反应出现。
结论自体MSCs经根动脉或蛛网膜下腔移植治疗SCI,术后一月患者的浅深感觉、运动功能及ADL评分有所改善,未有严重副反应发生,其中经根动脉途径移植治疗SCI为首次报道。临床初步研究表明:自体MSCs移植治疗SCI有一定的近期临床疗效,操作简便,安全可行,值得做大样本双盲多中心的进一步临床研究与探索。
目的初步观察自体骨髓间充质干细胞(MSCs)移植治疗脑神经损伤的临床效果和存在的问题。
方法选取自愿并签署知情同意书的2例脑神经损伤患者(脑梗塞患者1例,脑干挫裂伤患者1例),首先抽取自体骨髓细胞悬液,在体外经过分离提取后,制成骨髓间充质干细胞悬液,经L4-5注入蛛网膜下腔,分离后剩余的血液立即经静脉回输给患者,术后常规标准康复治疗。采取手法肌力检查(MMT)进行肌力评定分级,日常生活活动能力(ADL)评定采用Barthel指数评分,偏瘫分级采用Brunnstrom偏瘫运动分级标准。
结果脑梗塞患者(病例1)自体移植MSCs术后1月功能评定无明显变化。脑干挫裂伤患者(病例2)自体移植MSCs术后1月ADL评分提高10分,Brunnstrom偏瘫分级右下肢提升1级;术后3月ADL评分提高15分,右上肢肌力提升1级,Brunnstrom偏瘫分级右侧手指与上肢分别提升了1级。
结论自体MSCs移植治疗脑神经损伤有一定的效果,本报告病例2的肌力评定、ADL评分、Brunnstrom偏瘫分级有所改善,治疗后无副反应发生。但是否真正为MSCs治疗所起的作用,还有待对比研究证实;对MSCs移植的时机、途径、个体差异、效果等还需更深入的研究与探讨。
Objective SCI is not only a threat to human health, but also brings heavy burden for family and society. The main therapies for SCI are surgery, drugs, rehabilitation training and so on, but their effects are limited currently . In recent years, stem cells therapy for SCI brings a light for SCI and it attracts more attention. Some studies have indicated that MSCs have a therapeutic effect on neurological deficit caused by SCI, meanwhile autologous MSCs without immunity rejection and ethic problem are more available therefore, it has become a focused research field. However, adequate clinical data of its effects are still lack.In this study we first report the autologous marrow mesenchymal stem cells transplantation through root artery and subarachnoid spaceto treat patients with SCI, and through observation we investigate the short-term curative effect and the safety of the two therapies.
METHODS 26 SCI patients were enrolled in this study. They were diagnosed by CT or MRI and received surgical or conservative treatment, caused by violence, within 1-month to 2-year of SCI onset, age between 15 years to 60 years, with no coma or other complications, being able to get at least 1-month of standard rehabilitation, and were informed and had signed the informed consent document. Among the 26 enrolled patients, 16 received the stem cells transplantation as well as standard rehabilitation training (8 cases are the transplantation group through abbreviated as subarachnoid space group; another 8 are the transplantation group through root artery abbreviated as root artery group), and 10 patients were control group with standard rehabilitation therapy. The duration of standard rehabilitation treatment for all the enrolled patients was one month. Sensory and motor function assessments adopted the American Spinal Injury Association (ASIA) classification and degree of SCI were evaluated by International Standards for Neurological Classification of Spinal Cord Injury (Sixth Edition, 2006). There were no differences of age, duration of disease, degree of injury between the two groups (p>0.05). Both subarachnoid space group and root artery group were given autologous marrow mesenchymal stem cells transplantation therapy on the basis of comprehensive rehabilitation treatment. The autologous marrow was collected from iliac bone marrow puncture and injected through subarachnoid space and root artery after separation and extraction. The control group was given only conventional rehabilitation treatment. Both groups were received assessment of motor and sensory function and assessment of activities of daily living (ADL) on admission and one
month after transplantation respectively; the control group received those assessments on admission and one month after rehabilitation treatment. The study was evaluated independently by two professional doctors who were not involved in the treatment.
RESULTS 1)Change of neurological function scores: compared with admission,the root artery group had improvement in superficial, deep sensory and motor function scores in one month after transplantation, and there was a significant difference(p<0.01); The subarachnoid space group only had improvement in motor function scores, and there was a significant difference(p<0.01); The control group had improvement in superficial sensory function scores in one month after treatment, and there was a significant difference(p<0.05).
2) Activities of daily living (ADL) score: The ADL scores of stem cells therapy group were all improved between on admission and one month after transplantation , and there was a significant difference (p<0.05); The ADL scores of control group had no significant difference (P>0.05).
3) Comparisons on effect of different therapies: one month after treatment , to compare the different effects of subarachnoid space group, root artery group and control group, scores of superficial and deep sensory as well as motor functions patients in subarachnoid space group and root artery group looked like a better results than that of control group, but no significant difference (P>0.05); on ADL scores, patients in the three groups were nearly the same, and there was no significant difference (P>0.05); Compared between the two transplantation groups, patients had no significant difference on scores of superficial and deep sensory as well as motor functions(P>0.05).
4) The adverse effects of stem cells transplantation: 1 patient got fever after transplantation through subarachnoid space, and the cause was unclear. The symptom relieved after giving intramuscular dexamethasone and there was no recurrence. No adverse effect was found in root artery group.
CONCLUSION Using autologous MSCs transplantation through subarachnoid space and root artery to treat patients with SCI which was first reported, one month after operation the superficial and deep sensory, motor function as well as ADL scores of patients were improved, and there is no serious side effect. Autologous marrow stem cells transplantation has some short-term clinical effects for patients with SCI, and can be easily operated, it is safe and feasible, however, large sample, double-blind, multi-center clinical trials are further needed for evidence based medicine .
Objective To explore the efficacy and clinical problems of autologous transplantation of marrow mesenchymal stem cells (MSCs) for treating patients with cranial nerve damage.
METHODS 2 patients with cranial nerve damage treated by autologous transplantation of marrow mesenchymal stem cells were enrolled, who was volunteered and had signed the informed consent document. One was suffering from cerebral infarction,and the other was brainstem contusion and laceration. At first, extract autologous marrow cells suspension, and after isolation, make it as MSCs suspension; inject it into subarachnoid space through L4-5. The rest isolated blood was transfused back to patients through vein immediately. After operation, patients received conventional rehabilitation treatment. The grade of muscle strength was evaluated by MMT, ADL was assessed by Barthel, and hemiparalysis grade was evaluated by standard Brunnstrom stage.
RESULTS The patient with cerebral infarction (case one) had no apparent change in functional evaluation one month after transplanting autologous MSCs. At the same time, one month after transplanting autologous MSCs the ADL score of the patient with brainstem contusion and laceration (case two) raised 10 points and Brunnstrom stage of right lower extremity raised 1 grade; in 3 month after operation, his ADL score raised 15 points, the muscle strength of right upper extremity increased 1 grade, and Brunnstrom stage of right upper extremity also raised 1 grade.
CONCLUSION Autologous transplantation of marrow mesenchymal stem cells could be an effective method to treat patients with cranial nerve damage. The manual muscle, scores of ADL and Brunnstrom stage of the patient in case two of this report were equally improved, but it still needs to be identified whether the functional improvement was actually gotten from the stem cells therapy. Further studies are needed to explore the timing, paths, individual differences, clinical effects and so on of MSCs transplantation.
引文
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[6] Geffner LF,Santacruz P,Izurieta M,et al.Administration of autologous bone marrow stem cells into spinal cord injury patients via multiple routes is safe and improves their quality of life: comprehensive case studies. Cell Transplant. 2008,17(12):1277-1293.
[7] Inoue M, Honmou O, Oka S, et al. Comparative analysis of remyelinating potential of focal and intravenous administration of autologous bone marrow cells into the rat demyelinated spinal cord[J].Glia.2003,44(2):111-118.
[8]陈东,杨晓华,边立功,等.骨髓间充质干细胞不同移植方法治疗脊髓损伤的实验研究[J].神经解剖学杂志.2007,23(6):635-638.
[9] Vaquero J,Zurita M,Oya S, et al.Cell therapy using bone marrow stromal cells in chronic paraplegic rats:systemic or local administration? [J]Neurosci Lett.2006,398(1-2):129-134.
[10]Fan L,DU F,Cheng BC,et a1.Migration and distribution of bone marrow stromal cells in injured spinal cord with different transplantation techniques[J].Chin J Traumatol.2008,11(2):94-97.
[11]孙其志,任先军.根动脉的解剖特点与脊髓缺血的关系[J].中国脊柱脊髓杂志.2005,15(9):556-559.
[12]Chernykh ER,Stupak W,Muradov GM,et a1.Application of autologous bone marrow stem cells in the therapy of spinal cord injury patients[J].Bull Exp Biol Med.2007,143(4):543-537.
[13]Callera F,do Nascimento RX.Delivery of autologous bone marrow precursor cells into the spinal cord via lumbar puncture technique in patients with spinal cord injury:a preliminary safety study[J].Exp Hemtal.2006,34(2):130-131.
[14]Lee SH, Chung YN, Kim YH, et al. Effects of human neural stem cell transplantation in canine spinal cord hemisection[J].Neurol Res.2009 ,31(9):996-1002.
[15]Satake K,Lou J,Lenke LG.Migration of mesenchymal stem cells through cerebrospinal fluid into injuryed spinal cord tissue[J].Spine.2004,29(18):1971-1979.
[16]Boido M, Rupa R, Garbossa D, et al. Embryonic and adult stem cells promote raphespinal anxon outgrowth and improve functional outcome follwing spinal hemisection in mice[J]. Eur J Neurosci.2008,30(5):833-846.
[17]Isele NB,Lee HS,Landshamer S,et a1.Bone marrow stromal cells mediate protection through stimulation of P13-K/Akt and MAPK signaling in neurons[J].Neurochem Int.2007,50(1):243-250.
[18]Lou S,Gu P,Chen F,et al.The effect of bone marrow stromal cells on neuronal differentiation fo mesencephalic neural stem cells in Sprague-Dawley rates[J].Brain Res.2003,968(1):114-121.
[19]吴碧莲,贾小力,陈少强.静脉注射骨髓间充质干细胞可抑制大鼠损伤脊髓水通道蛋白-4的表达[J].解剖学杂志.2008,31(5):691-693.
[20]翁金森,刘楠,杜厚伟,等.骨髓间充质干细胞移植对脑梗塞大鼠神经功能恢复及突触素表达的影响[J].细胞与分子免疫学杂志.2008,24(1):34-37.
[1]王丁超,刘敬霞等.骨髓干细胞动员治疗脑缺血损伤[J].中国组织工程研究与临床康复.2007,46(11):9365-9366.
[2] Chen J,Li Y,Wang L,et al.Therapeutic benefit of intravenous administration of bone marrow stromal cells after cerebral ischemia in rats[J].Stroke.2001,32:1005-1011.
[3] Hill WD,Hess DC,Martin-StuddardA.SDF-l(CACL12) is upregulated in the ischemic penumbra following stroke:association with bone marrow cell homing to injury[J].NeuroPathol Exp Neurol.2004,63(l):84一96.
[4] Ishibashi S, Sakaguchi M, Kuroiwa T, et al. Human neuralstem/progenitor cells, expanded in long-term neurosphere culture, promote functional recovery after focal ischemia in mongolian gerbils[J]. Neurosci Res. 2004,78:215-223.
[5] Borlongan CV, Hadman M, Sanberg CD,et al.Central nervous system entry of peripherally injected umbilical cord blood cells is not required for neuroprotection in stroke[J]. Stroke.2004,35:2385-2389.
[6] Johnston RE,Dillon-Carter O,Freed WJ,et al.Trophic factor secreting kidney cell lines:in vitro characterization and functional effects following transplantation in ischemic rats[J].Brain Res.2001,900: 268-276.
[7]Kurozumi K, Nakamura K, Tamiya T, et al.Mesenchymal stem cells that produce neurotrophic factors reduce ischemic damage in the rat middle cerebral artery occlusion model[J]. Mol Ther.2005,11:96-104.
[8] Lindholm D.Neurotrophic factors and neuronal plasticity:Is there a link[J].Adv Neurol.1997,73:1-6.
[9] Krupinski J,Stroemer P,Slevin M,et al.Three dimensional structure and survival of newly formed blood vessels after focal cerebral ischemia[J]. Neuroreport. 2003,14:1171-1176.
[10]Asahara T,Takahashi T,Masuda H,et al.VEGF contributes to postnatal neovascularization by mobilizing bone marrow-derived endothelial progenitorcells[J].EMBOJ.1999,18:3964-3972.
[11]Takahashi T,Kalka C,Masuda H,et al.Ischemia and cytokine-induced mobilization of bone marrow-derived endothelial progenitor cells for neovascularization[J].Nat Med.1999,5:434-438.
[12]Shen LH,Li Y,Chen J,et al.Therapeutic benefit of bone marrow stromal cells administered 1 month after stroke[J].J Cereb Blood Flow Metab.2006,27:6-13.
[13]LHShen,YLi,J Chen,et al.Intracarotid transplantation of bone marrow stromal cells increases axonmyelin remodeling after stroke[J].Neuroscience.137:393-399.
[14]Liu Z,Li Y,Zhang X,et al.Contralesional axonal remodeling of the corticospinal system in adult rats after stroke and bone marrow stromal cell treatment[J].Stroke.2008,39:2571-2577.
[15]Chen J,Li Y,Katakowski M,et al.Intravenous bone marrow stromal cell therapy reduces apoptosis and promotes endogenous cell proliferation after stroke in female rat[J].J Neurosci Res.2003,73:778-786.
[16]Parent J M,Vexler ZS,Gong C,et al.Rat forebrain neurogenesis and striatal neuron replacement after focal stroke[J].Ann Neurol.2002, 52:802-813.
[17]Arvidsson A,Collin T,Kirik D,et al.Neuronalreplacement from endogenous precursors in the adult brain after stroke[J].Nat Med.2002, 8:963-970.
[18]Jin K,Minami M,Lan JQ,et al.Neurogenesis in dentate subgranular zone and rostral subventricular zone after focal cerebral ischemia in the rat[J].Proc Natl Acad Sci,2001,98:4710-4715.
[19]李轶,张重功,马杰.骨髓间充质干细胞移植对大鼠脑梗死的治疗作用[J].上海交通大学学报(医学版).2007,27(3):243-245.
[20]Lo EH,Dalkara T,Moskowitz MA,et al.Mechanisms,challenges and opportunities in stroke[J].Nat Rev Neurosei.2003,4(5):399-415.
[21]Li Y,Chen JL,Zhang CL,et al.Gliosis and brain remodeling after treatment of stroke in rats with marow stromal cells[J].Glia.2005,49:407-417.
[22]杨华静,徐光锦等.对比研究经颈动脉和立体定位注射骨髓间充质干细胞治疗缺血性脑卒中[J].卒中与神经疾病.2005,12(2):77-79.
[1] DeVivo MJ, Go BK, Jackson AB. Overview of the national spinal cord injury statistical center database[J]. J Spinal Cord Med.2002,25(4):335-338.
[2] Samadikuchaksaraei A. An overview of tissue engineering approaches for management of spinal cord injuries[J].J Neuroeng Rehabil.2007,4(1):15-31.
[3] Pierdomenico L, Bonsi L, Calvitti M, et al.Multipotent Mesenchymal Stem Cells with Immunosuppressive Activity Can Be Easily Isolated from Dental Pulp[J].Transplantation.2005,80(6):836-842.
[4]陈少强,林建华.不同移植时间窗对静脉移植骨髓间充质干细胞在大鼠损伤脊髓内存活和迁移的影响[J].解剖学杂志.2009,32(2):190-194.
[5] Sykova E, Homola A, Mazanec R, et al. Autologous bone marrow transplantation in patients with subacute and chronic spinal cord injury[J].Cell Transplant.2006,15(8):675-687.
[6] Satake K, Lou J, Lenke LG. Migration of mesenchymal stem cells through cerebrospinal fluid into injured spinal cord tissue[J].Spine. 2004,19(18):1971-1979.
[7] Inoue M, Honmou O, Oka S, et al.Comparative analysis of remyelinating potential of focal and intravenous administration of autologous bone marrow cells into the rat demyelinated spinal cord[J].Glia.2003,44(2):111-118.
[8]陈东,杨晓华,边立功,等.骨髓间充质干细胞不同移植方法治疗脊髓损伤的实验研究[J].神经解剖学杂志.2007,23(6):635-638.
[9] Teng YD, Lavik EB, Qu X, et al. Functional recovery following traumatic spinal cord injury mediated by a unique polymer scaffold seeded with neural stem cells[J].Proc Natl Acad Sci USA.2002,99(5):3024-3029.
[10]Khalatbary AR,Tiraihi T,Boroujeni MB,et al.Effects of epigallocatechin gallate on tissue protection and functional recovery after contusive spinal cord injury in rats[J].Brain Res. 2010,13(6):168-175.
[11]Lee SH, Chung YN, Kim YH, et al.Effects of human neural stem cell transplantation in canine spinal cord hemisection[J].Neurol Res. 2009, 31(9):996-1002.
[12]Satake K,Lou J,Lenke LG.Migration of mesenchymal stem cells through cerebrospinal fluid into injuryed spinal cord tissue[J]. Spine. 2004, 29(18):1971-1979.
[13]Boido M, Rupa R, Garbossa D, et al. Embryonic and adult stem cells promote raphespinal anxon outgrowth and improve functional outcome follwing spinal hemisection in mice[J].Eur J Neurosci.2008,30(5):833-846.
[14]Isele NB,Lee HS,Landshamer S,et a1.Bone marrow stromal cells mediate protection through stimulation of P13-K/Akt and MAPK signaling in neurons[J].Neurochem Int.2007,50(1):243-250.
[15]Lou S,Gu P,Chen F,et al.The effect of bone marrow stromal cells on neuronal differentiation fo mesencephalic neural stem cells in Sprague-Dawley rates[J].Brain Res.2003,968(1):114-121.
[16]吴碧莲,贾小力,陈少强.静脉注射骨髓间充质干细胞可抑制大鼠损伤脊髓水通道蛋白-4的表达[J].解剖学杂志.2008,31(5):691-693.
[17]翁金森,刘楠,杜厚伟,等.骨髓间充质干细胞移植对脑梗塞大鼠神经功能恢复及突触素表达的影响[J].细胞与分子免疫学杂志.2008,24(1):34-37.
[18]张燕青,曾园山,张静,等.体外培养的嗅鞘细胞能够促进骨髓间充质干细胞分化为神经元样细胞[J].中国神经精神疾病杂志.2007,33(10):612-614.
[19]智晓东,吕刚.大鼠骨髓间充质干细胞和雪旺细胞联合移植治疗脊髓损伤[J].中国组织工程研究与临床康复.2008,12(16):3015-3018.
[20]王俊芳,方煌,罗永湘,等.骨髓基质干细胞和神经营养因子悬液移植对脊髓损伤修复的影响[J].中华创伤骨科杂志.2006,8(8):764-768.
[21]康德智,王灯亮,林建华,等.骨髓间充质干细胞和脑源性神经营养因子联合应用促进兔脊髓外伤性截瘫的修复[J].中国临床解剖学杂志.2007,25(1):60-63,67.
[22]杨海平,李和平,王丽荣,等.骨髓间充质干细胞移植联用氨基胍对大鼠脊髓损伤修复的影响[J].中国组织工程研究与临床康复.2009,13(1):141-144.
[23]Li H, Wen Y, Luo Y, et al.Transplantation of bone marrow mesenchymal stem cells into spinal cord injury: a comparison of delivery different times[J]. Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi.2010,24(2):180-184.
[2] Biernaskie J,Sparling JS,Liu J,et al.Skin-derived precursors generate myelinating Schwann cells that promote remyelination and functional recovery after contusion spinal cord injury[J].J Neurosci.2007,27(36):9545-9559.
[3] Chi GF, Kim MR, Kim DW,et al. Schwann cells differentiated from spheroid-forming cells of rat subcutaneous fat tissue myelinate axons in the spinal cord injury[J]. Exp Neurol. 2010,222(2):304-317.
[4] Y Amoh, L Li, K Katsuoka,et al.Multipotent hair follicle stem cells promote repair of spinal cord injury and recovery of walking function[J]. Cell Cycle. 2008,7(12): 1865-1869.
[5] Carvalho KA,Cunha RC,Vialle EN,et al.Functional outcome of bone marrow stem cells after cell therapy in acute spinal cord injury:in exercise training and sedentary rates[J].Transplant Proc.2008,40(3):847-849.
[6] Geffner LF,Santacruz P,Izurieta M,et al.Administration of autologous bone marrow stem cells into spinal cord injury patients via multiple routes is safe and improves their quality of life: comprehensive case studies. Cell Transplant. 2008,17(12):1277-1293.
[7] Inoue M, Honmou O, Oka S, et al. Comparative analysis of remyelinating potential of focal and intravenous administration of autologous bone marrow cells into the rat demyelinated spinal cord[J].Glia.2003,44(2):111-118.
[8]陈东,杨晓华,边立功,等.骨髓间充质干细胞不同移植方法治疗脊髓损伤的实验研究[J].神经解剖学杂志.2007,23(6):635-638.
[9] Vaquero J,Zurita M,Oya S, et al.Cell therapy using bone marrow stromal cells in chronic paraplegic rats:systemic or local administration? [J]Neurosci Lett.2006,398(1-2):129-134.
[10]Fan L,DU F,Cheng BC,et a1.Migration and distribution of bone marrow stromal cells in injured spinal cord with different transplantation techniques[J].Chin J Traumatol.2008,11(2):94-97.
[11]孙其志,任先军.根动脉的解剖特点与脊髓缺血的关系[J].中国脊柱脊髓杂志.2005,15(9):556-559.
[12]Chernykh ER,Stupak W,Muradov GM,et a1.Application of autologous bone marrow stem cells in the therapy of spinal cord injury patients[J].Bull Exp Biol Med.2007,143(4):543-537.
[13]Callera F,do Nascimento RX.Delivery of autologous bone marrow precursor cells into the spinal cord via lumbar puncture technique in patients with spinal cord injury:a preliminary safety study[J].Exp Hemtal.2006,34(2):130-131.
[14]Lee SH, Chung YN, Kim YH, et al. Effects of human neural stem cell transplantation in canine spinal cord hemisection[J].Neurol Res.2009 ,31(9):996-1002.
[15]Satake K,Lou J,Lenke LG.Migration of mesenchymal stem cells through cerebrospinal fluid into injuryed spinal cord tissue[J].Spine.2004,29(18):1971-1979.
[16]Boido M, Rupa R, Garbossa D, et al. Embryonic and adult stem cells promote raphespinal anxon outgrowth and improve functional outcome follwing spinal hemisection in mice[J]. Eur J Neurosci.2008,30(5):833-846.
[17]Isele NB,Lee HS,Landshamer S,et a1.Bone marrow stromal cells mediate protection through stimulation of P13-K/Akt and MAPK signaling in neurons[J].Neurochem Int.2007,50(1):243-250.
[18]Lou S,Gu P,Chen F,et al.The effect of bone marrow stromal cells on neuronal differentiation fo mesencephalic neural stem cells in Sprague-Dawley rates[J].Brain Res.2003,968(1):114-121.
[19]吴碧莲,贾小力,陈少强.静脉注射骨髓间充质干细胞可抑制大鼠损伤脊髓水通道蛋白-4的表达[J].解剖学杂志.2008,31(5):691-693.
[20]翁金森,刘楠,杜厚伟,等.骨髓间充质干细胞移植对脑梗塞大鼠神经功能恢复及突触素表达的影响[J].细胞与分子免疫学杂志.2008,24(1):34-37.
[1]王丁超,刘敬霞等.骨髓干细胞动员治疗脑缺血损伤[J].中国组织工程研究与临床康复.2007,46(11):9365-9366.
[2] Chen J,Li Y,Wang L,et al.Therapeutic benefit of intravenous administration of bone marrow stromal cells after cerebral ischemia in rats[J].Stroke.2001,32:1005-1011.
[3] Hill WD,Hess DC,Martin-StuddardA.SDF-l(CACL12) is upregulated in the ischemic penumbra following stroke:association with bone marrow cell homing to injury[J].NeuroPathol Exp Neurol.2004,63(l):84一96.
[4] Ishibashi S, Sakaguchi M, Kuroiwa T, et al. Human neuralstem/progenitor cells, expanded in long-term neurosphere culture, promote functional recovery after focal ischemia in mongolian gerbils[J]. Neurosci Res. 2004,78:215-223.
[5] Borlongan CV, Hadman M, Sanberg CD,et al.Central nervous system entry of peripherally injected umbilical cord blood cells is not required for neuroprotection in stroke[J]. Stroke.2004,35:2385-2389.
[6] Johnston RE,Dillon-Carter O,Freed WJ,et al.Trophic factor secreting kidney cell lines:in vitro characterization and functional effects following transplantation in ischemic rats[J].Brain Res.2001,900: 268-276.
[7]Kurozumi K, Nakamura K, Tamiya T, et al.Mesenchymal stem cells that produce neurotrophic factors reduce ischemic damage in the rat middle cerebral artery occlusion model[J]. Mol Ther.2005,11:96-104.
[8] Lindholm D.Neurotrophic factors and neuronal plasticity:Is there a link[J].Adv Neurol.1997,73:1-6.
[9] Krupinski J,Stroemer P,Slevin M,et al.Three dimensional structure and survival of newly formed blood vessels after focal cerebral ischemia[J]. Neuroreport. 2003,14:1171-1176.
[10]Asahara T,Takahashi T,Masuda H,et al.VEGF contributes to postnatal neovascularization by mobilizing bone marrow-derived endothelial progenitorcells[J].EMBOJ.1999,18:3964-3972.
[11]Takahashi T,Kalka C,Masuda H,et al.Ischemia and cytokine-induced mobilization of bone marrow-derived endothelial progenitor cells for neovascularization[J].Nat Med.1999,5:434-438.
[12]Shen LH,Li Y,Chen J,et al.Therapeutic benefit of bone marrow stromal cells administered 1 month after stroke[J].J Cereb Blood Flow Metab.2006,27:6-13.
[13]LHShen,YLi,J Chen,et al.Intracarotid transplantation of bone marrow stromal cells increases axonmyelin remodeling after stroke[J].Neuroscience.137:393-399.
[14]Liu Z,Li Y,Zhang X,et al.Contralesional axonal remodeling of the corticospinal system in adult rats after stroke and bone marrow stromal cell treatment[J].Stroke.2008,39:2571-2577.
[15]Chen J,Li Y,Katakowski M,et al.Intravenous bone marrow stromal cell therapy reduces apoptosis and promotes endogenous cell proliferation after stroke in female rat[J].J Neurosci Res.2003,73:778-786.
[16]Parent J M,Vexler ZS,Gong C,et al.Rat forebrain neurogenesis and striatal neuron replacement after focal stroke[J].Ann Neurol.2002, 52:802-813.
[17]Arvidsson A,Collin T,Kirik D,et al.Neuronalreplacement from endogenous precursors in the adult brain after stroke[J].Nat Med.2002, 8:963-970.
[18]Jin K,Minami M,Lan JQ,et al.Neurogenesis in dentate subgranular zone and rostral subventricular zone after focal cerebral ischemia in the rat[J].Proc Natl Acad Sci,2001,98:4710-4715.
[19]李轶,张重功,马杰.骨髓间充质干细胞移植对大鼠脑梗死的治疗作用[J].上海交通大学学报(医学版).2007,27(3):243-245.
[20]Lo EH,Dalkara T,Moskowitz MA,et al.Mechanisms,challenges and opportunities in stroke[J].Nat Rev Neurosei.2003,4(5):399-415.
[21]Li Y,Chen JL,Zhang CL,et al.Gliosis and brain remodeling after treatment of stroke in rats with marow stromal cells[J].Glia.2005,49:407-417.
[22]杨华静,徐光锦等.对比研究经颈动脉和立体定位注射骨髓间充质干细胞治疗缺血性脑卒中[J].卒中与神经疾病.2005,12(2):77-79.
[1] DeVivo MJ, Go BK, Jackson AB. Overview of the national spinal cord injury statistical center database[J]. J Spinal Cord Med.2002,25(4):335-338.
[2] Samadikuchaksaraei A. An overview of tissue engineering approaches for management of spinal cord injuries[J].J Neuroeng Rehabil.2007,4(1):15-31.
[3] Pierdomenico L, Bonsi L, Calvitti M, et al.Multipotent Mesenchymal Stem Cells with Immunosuppressive Activity Can Be Easily Isolated from Dental Pulp[J].Transplantation.2005,80(6):836-842.
[4]陈少强,林建华.不同移植时间窗对静脉移植骨髓间充质干细胞在大鼠损伤脊髓内存活和迁移的影响[J].解剖学杂志.2009,32(2):190-194.
[5] Sykova E, Homola A, Mazanec R, et al. Autologous bone marrow transplantation in patients with subacute and chronic spinal cord injury[J].Cell Transplant.2006,15(8):675-687.
[6] Satake K, Lou J, Lenke LG. Migration of mesenchymal stem cells through cerebrospinal fluid into injured spinal cord tissue[J].Spine. 2004,19(18):1971-1979.
[7] Inoue M, Honmou O, Oka S, et al.Comparative analysis of remyelinating potential of focal and intravenous administration of autologous bone marrow cells into the rat demyelinated spinal cord[J].Glia.2003,44(2):111-118.
[8]陈东,杨晓华,边立功,等.骨髓间充质干细胞不同移植方法治疗脊髓损伤的实验研究[J].神经解剖学杂志.2007,23(6):635-638.
[9] Teng YD, Lavik EB, Qu X, et al. Functional recovery following traumatic spinal cord injury mediated by a unique polymer scaffold seeded with neural stem cells[J].Proc Natl Acad Sci USA.2002,99(5):3024-3029.
[10]Khalatbary AR,Tiraihi T,Boroujeni MB,et al.Effects of epigallocatechin gallate on tissue protection and functional recovery after contusive spinal cord injury in rats[J].Brain Res. 2010,13(6):168-175.
[11]Lee SH, Chung YN, Kim YH, et al.Effects of human neural stem cell transplantation in canine spinal cord hemisection[J].Neurol Res. 2009, 31(9):996-1002.
[12]Satake K,Lou J,Lenke LG.Migration of mesenchymal stem cells through cerebrospinal fluid into injuryed spinal cord tissue[J]. Spine. 2004, 29(18):1971-1979.
[13]Boido M, Rupa R, Garbossa D, et al. Embryonic and adult stem cells promote raphespinal anxon outgrowth and improve functional outcome follwing spinal hemisection in mice[J].Eur J Neurosci.2008,30(5):833-846.
[14]Isele NB,Lee HS,Landshamer S,et a1.Bone marrow stromal cells mediate protection through stimulation of P13-K/Akt and MAPK signaling in neurons[J].Neurochem Int.2007,50(1):243-250.
[15]Lou S,Gu P,Chen F,et al.The effect of bone marrow stromal cells on neuronal differentiation fo mesencephalic neural stem cells in Sprague-Dawley rates[J].Brain Res.2003,968(1):114-121.
[16]吴碧莲,贾小力,陈少强.静脉注射骨髓间充质干细胞可抑制大鼠损伤脊髓水通道蛋白-4的表达[J].解剖学杂志.2008,31(5):691-693.
[17]翁金森,刘楠,杜厚伟,等.骨髓间充质干细胞移植对脑梗塞大鼠神经功能恢复及突触素表达的影响[J].细胞与分子免疫学杂志.2008,24(1):34-37.
[18]张燕青,曾园山,张静,等.体外培养的嗅鞘细胞能够促进骨髓间充质干细胞分化为神经元样细胞[J].中国神经精神疾病杂志.2007,33(10):612-614.
[19]智晓东,吕刚.大鼠骨髓间充质干细胞和雪旺细胞联合移植治疗脊髓损伤[J].中国组织工程研究与临床康复.2008,12(16):3015-3018.
[20]王俊芳,方煌,罗永湘,等.骨髓基质干细胞和神经营养因子悬液移植对脊髓损伤修复的影响[J].中华创伤骨科杂志.2006,8(8):764-768.
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