嗅鞘细胞治疗晚期脊髓损伤短期与长期疗效的Meta分析
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摘要
背景:世界上已开展多项嗅鞘细胞治疗晚期脊髓损伤的临床试验,但其有效性及安全性仍有争议。目的:综合评价嗅鞘细胞移植治疗晚期脊髓损伤安全性及可行性,比较其治疗短期疗效与长期疗效。方法:于2018-07-23检索PubMed、Cochrane图书馆、EMBASE、知网、万方数据库,纳入嗅鞘细胞治疗晚期脊髓损伤的临床研究。安全性研究试验应详细记录不良事件的种类与例数。纳入疗效评价的研究均使用ASIA量表,评估移植前后脊髓损伤患者的运动、轻触觉及针刺觉功能,并记录随访时间。运用Review Manager5.3对疗效数据进行系统评价。结果与结论:无论短期评价还是长期随访,与嗅鞘细胞移植前相比,患者神经功能均有明显提高(P <0.05),且研究结果具有同质性(Ι~2 <50%且P> 0.1)。然而长期疗效不如短期,这可能与慢性排斥反应及嗅鞘细胞存活率相关。嗅鞘细胞治疗晚期脊髓损伤的总不良事件发生率为8.99%,未发现与嗅鞘细胞本身相关的并发症。结果表明,嗅鞘细胞移植治疗晚期脊髓损伤疗效明确,安全可行,但仍需要探索更微创的移植方式,以减少手术并发症。另外,影响嗅鞘细胞长期疗效的因素需要大量高质量的基础及临床试验予以证实。
BACKGROUND: A number of clinical trials addressing olfactory ensheathing cells for the treatment of chronic spinal cord injury have been conducted in the world, but the efficacy and safety are still controversial. OBJECTIVE: To evaluate the safety and efficacy of olfactory ensheathing cell transplantation for chronic spinal cord injury, and to further compare its short-and long-term efficacy. METHODS: PubMed, Cochrane Library, EMBASE, CNKI and WanFang databases were searched at July 23, 2018 for retrieval of clinical trials addressing olfactory ensheathing cells in the treatment of chronic spinal cord injury. Types and cases of adverse events during the safety trial should be recorded in detail. In the enrolled studies, American Spinal Injury Association scale was used to assess the motor, light touch, and pinprick scores of spinal cord injury patients before and after cell transplantation. The follow-up time was recorded. Systematic evaluation of efficacy data was performed using Review Manager 5.3. RESULTS AND CONCLUSION: Both short-and long-term follow-up data showed that the neurological function of patients was significantly improved after olfactory ensheathing cell transplantation(P < 0.05), and the results were homogeneous(I~2 < 50% and P > 0.1). However, the long-term efficacy was not as good as the short-term efficacy, which may be related to chronic rejection and olfactory ensheathing cell survival. The overall adverse event rate was 8.99%, and no complications associated with olfactory ensheathing cells occurred. These findings show that olfactory ensheathing cell transplantation is effective and safe in the treatment of chronic spinal cord injury, but it is still necessary to explore more minimally invasive approaches to reduce surgical complications. In addition, a large number of high-quality experiments and clinical trials are warranted to confirm factors affecting the long-term efficacy of olfactory ensheathing cell transplantation.
BACKGROUND: A number of clinical trials addressing olfactory ensheathing cells for the treatment of chronic spinal cord injury have been conducted in the world, but the efficacy and safety are still controversial. OBJECTIVE: To evaluate the safety and efficacy of olfactory ensheathing cell transplantation for chronic spinal cord injury, and to further compare its short-and long-term efficacy. METHODS: PubMed, Cochrane Library, EMBASE, CNKI and WanFang databases were searched at July 23, 2018 for retrieval of clinical trials addressing olfactory ensheathing cells in the treatment of chronic spinal cord injury. Types and cases of adverse events during the safety trial should be recorded in detail. In the enrolled studies, American Spinal Injury Association scale was used to assess the motor, light touch, and pinprick scores of spinal cord injury patients before and after cell transplantation. The follow-up time was recorded. Systematic evaluation of efficacy data was performed using Review Manager 5.3. RESULTS AND CONCLUSION: Both short-and long-term follow-up data showed that the neurological function of patients was significantly improved after olfactory ensheathing cell transplantation(P < 0.05), and the results were homogeneous(I~2 < 50% and P > 0.1). However, the long-term efficacy was not as good as the short-term efficacy, which may be related to chronic rejection and olfactory ensheathing cell survival. The overall adverse event rate was 8.99%, and no complications associated with olfactory ensheathing cells occurred. These findings show that olfactory ensheathing cell transplantation is effective and safe in the treatment of chronic spinal cord injury, but it is still necessary to explore more minimally invasive approaches to reduce surgical complications. In addition, a large number of high-quality experiments and clinical trials are warranted to confirm factors affecting the long-term efficacy of olfactory ensheathing cell transplantation.
引文
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[11]Lima C,Escada P,Pratas-Vital J,,et al.Olfactory mucosal autografts and rehabilitation for chronic traumatic spinal cord injury.Neurorehabil Neural Repair.2010;24(1):10-22.
[12]Li L,Adnan H,Xu B,et al.Effects of transplantation of olfactory ensheathing cells in chronic spinal cord injury:a systematic review and meta-analysis.Eur Spine J.2015;24(5):919-930.
[13]Huang H,Chen L,Wang H,et al.Influence of patients'age on functional recovery after transplantation of olfactory ensheathing cells into injured spinal cord injury.Chin Med J(Engl).2003;116(10):1488-1491
[14]Zheng Z,Liu C,Zhang L,et al.Olfactory ensheathing cell transplantation in 106 patients with old spinal cord injury Differences in ages,sexes,disease courses,injured types and sites.Neural Regen Res.2007;2(6):380-384.
[15]Wu J,Sun T,Ye C,et al.Clinical observation of fetal olfactory ensheathing glia transplantation(OEGT)in patients with complete chronic spinal cord injury.Cell Transplantation.2012;21 Suppl1(1):S33-7.
[16]张磊,郑遵成,刘超,等.嗅鞘细胞移植部位与剂量的选择对陈旧性脊髓损伤患者60例神经恢复的影响[J].中国民康医学,2008,20(9):870-871.
[17]刘超,郑遵成,高瑞,等.嗅鞘细胞移植术后脊髓损伤患者功能的评价[J].中国组织工程研究与临床康复,2008,12(16):3037-3040.
[18]郑遵成,刘超,高瑞,等.移植时间对嗅鞘细胞移植治疗脊髓损伤效果的影响[J].中国组织工程研究与临床康复,2008,12(3):583-586.
[19]Zheng Z,Liu G,Chen Y,et al.Olfactory ensheathing cell transplantation improves sympathetic skin responses in chronic spinal cord injury.Neural Regen Res.2013;8(30):2849-2855.
[20]黄红云,王洪美,陈琳,等.胚胎嗅鞘细胞移植治疗晚期脊髓损伤影响功能恢复的因素[J].中国修复重建外科杂志,2006,20(4):434-438.
[21]黄红云,陈琳,王洪美,等.嗅鞘细胞移植改善晚期脊髓损伤患者神经功能的近期效应[J].中国临床康复,2006,10(13):190-192.
[22]Chen L,Huang H,Xi H,et al.A prospective randomized double-blind clinical trial using a combination of olfactory ensheathing cells and Schwann cells for the treatment of chronic complete spinal cord injuries.Cell Transplantation.2014;23 Suppl1:S35.
[23]保国锋,崔志明,李卫东,等.嗅鞘细胞移植治疗脊髓损伤5例报告[J].中国组织工程研究与临床康复,2007,11(3):512-514.
[24]Huang H,Chen L,Xi H,et al.[Olfactory ensheathing cells transplantation for central nervous system diseases in 1,255patients.Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi.2009;23(23):14-20.
[25]Wang D,He X,Li H,et al.Five years follow-up observation on patients with spinal cord injury treated with olfactory ensheathing cell transplantation.J Investigative Med.2013:S5-S6.
[26]Huang H,Xi H,Chen L,et al.Long-term outcome of olfactory ensheathing cell therapy for patients with complete chronic spinal cord injury.Cell Transplantation.2012;21 Suppl 1(1):S23.
[27]Rao Y,Zhu W,Guo Y,et al.Long-term outcome of olfactory ensheathing cell transplantation in six patients with chronic complete spinal cord injury.Cell Transplantation.2013;22(1):S21-S25.
[28]Lima C,Pratas-Vital J,Escada P,et al.Olfactory mucosa autografts in human spinal cord injury:a pilot clinical study.JSpinal Cord Med.2006;29(3):191-203.
[29]Mackay-Sim A,Féron F,Cochrane J,et al.Autologous olfactory ensheathing cell transplantation in human paraplegia:a 3-year clinical trial.Brain.2008;131(Pt 9):2376-2386.
[30]Tabakow P,Jarmundowicz W,Czapiga B,et al.Transplantation of autologous olfactory ensheathing cells in complete human spinal cord injury.Cell Transplantation.2013;22(9):1591-1612.
[31]张志成,孙天胜,叶超群,等.胸脊柱脊髓损伤的治疗[J].中国康复理论与实践,2006,12(4):336-338.
[32]Rao Y,Zhu W,Liu H,et al.Clinical application of olfactory ensheathing cells in the treatment of spinal cord injury.J Int Med Res.2013;41(2):473-481.
[33]Rao YJ,Zhu WX,Du ZQ,et al.Effectiveness of olfactory ensheathing cell transplantation for treatment of spinal cord injury.Genet Mol Res.2014;13(2):4124-4129.
[34]Hagell P,Brundin P.Cell survival and clinical outcome following intrastriatal transplantation in Parkinson disease.J Neuropathol Exp Neurol.2001;60(8):741-752.
[35]Kordower JH,Styren S,Clarke M,et al.Fetal grafting for Parkinson's disease:expression of immune markers in two patients with functional fetal nigral implants.Cell Transplantation.1997;6(3):213.
[36]Louveau A,Smirnov I,Keyes TJ,et al.Structural and functional features of central nervous system lymphatic vessels.Nature.2015,523(7560):337-341
[37]陈琳,方明俊,黄红云,等.人胚胎嗅鞘细胞移植供、受者HLA配型方法介绍[J].中国医疗前沿,2009,4(22):20-20.
[38]Xiao J,Chen L,Mao G,et al.Neurorestorative clinical application standards for the culture and quality control of olfactory ensheathing cells.J Neurorestoratol,2017;5:175-179.
[39]Nakhjavan-Shahraki B;Yousefifard M;Rahimi-Movaghar V,et al.Transplantation of olfactory ensheathing cells on functional recovery and neuropathic pain after spinal cord injury;systematic review and meta-analysis.Sci Rep.2018;8(1):325
[40]Jiang Y,Zhu J,Xu G;et al.Intranasal delivery of stem cells to the brain.Expert Opin Drug Deliv.2011;8(5):623-32
[41]Ninomiya K,Iwatsuki K,Ohnishi Y,et al.Intranasal delivery of bone marrow stromal cells to spinal cord lesions.J Neurosurg Spine.2015;23(1):111-119
[42]Nijboer CH;Kooijman E,van Velthoven CT,et al.Intranasal Stem Cell Treatment as a Novel Therapy for Subarachnoid Hemorrhage.Stem Cells Dev.2018;27(5):313-325
[43]Salama M,Sobh M,Emam M,et al.Effect of intranasal stem cell administration on the nigrostriatal system in a mouse model of Parkinson's disease.Exp Ther Med.2017;13(3):976-982
[44]Assinck P,Duncan GJ,Hilton BJ,et al.Cell transplantation therapy for spinal cord injury.Nat Neurosci.2017;20(5):637-647.
[2]Barber PC,Lindsay RM.Schwann cells of the olfactory nerves contain glial fibrillary acidic protein and resemble astrocytes.Neuroscience.1982;7(12):3077-3090.
[3]Ranmón-Cueto A,Valverde F.Olfactory bulb ensheathing glia:a unique cell type with axonal growth-promoting properties.Glia.1995;14(3):163-173.
[4]Doucette R.Glial influences on axonal growth in the primary olfactory system.Glia.2010;3(6):433-449.
[5]朱海涛,朱悦,孙德日.嗅鞘细胞抑制脊髓损伤后硫酸软骨素蛋白聚糖表达的实验研究[J].中国医科大学学报,2007,36(3):244-246.
[6]Doucette R.Glial cells in the nerve fiber layer of the main olfactory bulb of embryonic and adult mammals.Microsc Res Tech.1993;24(2):113-130.
[7]Khankan RR,Griffis KG,Haggerty-Skeans JR,et al.Olfactory Ensheathing Cell Transplantation after a Complete Spinal Cord Transection Mediates Neuroprotective and Immunomodulatory Mechanisms to Facilitate Regeneration.J Neurosci.2016;36(23):6269-6286.
[8]Pérez-Bouza A,Wigley CB,Nacimiento W,et al.Spontaneous orientation of transplanted olfactory glia influences axonal regeneration.Neuroreport.1998;9(13):2971-2975.
[9]Ranmón-Cueto A,Cordero M I,Santosbenito F F,et al.Functional recovery of paraplegic rats and motor axon regeneration in their spinal cords by olfactory ensheathing glia.Neuron.2000;25(2):425-435.
[10]Féron F,Perry C,Cochrane J,et al.Autologous olfactory ensheathing cell transplantation in human spinal cord injury.Brain.2005;128(Pt 12):2951-2960.
[11]Lima C,Escada P,Pratas-Vital J,,et al.Olfactory mucosal autografts and rehabilitation for chronic traumatic spinal cord injury.Neurorehabil Neural Repair.2010;24(1):10-22.
[12]Li L,Adnan H,Xu B,et al.Effects of transplantation of olfactory ensheathing cells in chronic spinal cord injury:a systematic review and meta-analysis.Eur Spine J.2015;24(5):919-930.
[13]Huang H,Chen L,Wang H,et al.Influence of patients'age on functional recovery after transplantation of olfactory ensheathing cells into injured spinal cord injury.Chin Med J(Engl).2003;116(10):1488-1491
[14]Zheng Z,Liu C,Zhang L,et al.Olfactory ensheathing cell transplantation in 106 patients with old spinal cord injury Differences in ages,sexes,disease courses,injured types and sites.Neural Regen Res.2007;2(6):380-384.
[15]Wu J,Sun T,Ye C,et al.Clinical observation of fetal olfactory ensheathing glia transplantation(OEGT)in patients with complete chronic spinal cord injury.Cell Transplantation.2012;21 Suppl1(1):S33-7.
[16]张磊,郑遵成,刘超,等.嗅鞘细胞移植部位与剂量的选择对陈旧性脊髓损伤患者60例神经恢复的影响[J].中国民康医学,2008,20(9):870-871.
[17]刘超,郑遵成,高瑞,等.嗅鞘细胞移植术后脊髓损伤患者功能的评价[J].中国组织工程研究与临床康复,2008,12(16):3037-3040.
[18]郑遵成,刘超,高瑞,等.移植时间对嗅鞘细胞移植治疗脊髓损伤效果的影响[J].中国组织工程研究与临床康复,2008,12(3):583-586.
[19]Zheng Z,Liu G,Chen Y,et al.Olfactory ensheathing cell transplantation improves sympathetic skin responses in chronic spinal cord injury.Neural Regen Res.2013;8(30):2849-2855.
[20]黄红云,王洪美,陈琳,等.胚胎嗅鞘细胞移植治疗晚期脊髓损伤影响功能恢复的因素[J].中国修复重建外科杂志,2006,20(4):434-438.
[21]黄红云,陈琳,王洪美,等.嗅鞘细胞移植改善晚期脊髓损伤患者神经功能的近期效应[J].中国临床康复,2006,10(13):190-192.
[22]Chen L,Huang H,Xi H,et al.A prospective randomized double-blind clinical trial using a combination of olfactory ensheathing cells and Schwann cells for the treatment of chronic complete spinal cord injuries.Cell Transplantation.2014;23 Suppl1:S35.
[23]保国锋,崔志明,李卫东,等.嗅鞘细胞移植治疗脊髓损伤5例报告[J].中国组织工程研究与临床康复,2007,11(3):512-514.
[24]Huang H,Chen L,Xi H,et al.[Olfactory ensheathing cells transplantation for central nervous system diseases in 1,255patients.Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi.2009;23(23):14-20.
[25]Wang D,He X,Li H,et al.Five years follow-up observation on patients with spinal cord injury treated with olfactory ensheathing cell transplantation.J Investigative Med.2013:S5-S6.
[26]Huang H,Xi H,Chen L,et al.Long-term outcome of olfactory ensheathing cell therapy for patients with complete chronic spinal cord injury.Cell Transplantation.2012;21 Suppl 1(1):S23.
[27]Rao Y,Zhu W,Guo Y,et al.Long-term outcome of olfactory ensheathing cell transplantation in six patients with chronic complete spinal cord injury.Cell Transplantation.2013;22(1):S21-S25.
[28]Lima C,Pratas-Vital J,Escada P,et al.Olfactory mucosa autografts in human spinal cord injury:a pilot clinical study.JSpinal Cord Med.2006;29(3):191-203.
[29]Mackay-Sim A,Féron F,Cochrane J,et al.Autologous olfactory ensheathing cell transplantation in human paraplegia:a 3-year clinical trial.Brain.2008;131(Pt 9):2376-2386.
[30]Tabakow P,Jarmundowicz W,Czapiga B,et al.Transplantation of autologous olfactory ensheathing cells in complete human spinal cord injury.Cell Transplantation.2013;22(9):1591-1612.
[31]张志成,孙天胜,叶超群,等.胸脊柱脊髓损伤的治疗[J].中国康复理论与实践,2006,12(4):336-338.
[32]Rao Y,Zhu W,Liu H,et al.Clinical application of olfactory ensheathing cells in the treatment of spinal cord injury.J Int Med Res.2013;41(2):473-481.
[33]Rao YJ,Zhu WX,Du ZQ,et al.Effectiveness of olfactory ensheathing cell transplantation for treatment of spinal cord injury.Genet Mol Res.2014;13(2):4124-4129.
[34]Hagell P,Brundin P.Cell survival and clinical outcome following intrastriatal transplantation in Parkinson disease.J Neuropathol Exp Neurol.2001;60(8):741-752.
[35]Kordower JH,Styren S,Clarke M,et al.Fetal grafting for Parkinson's disease:expression of immune markers in two patients with functional fetal nigral implants.Cell Transplantation.1997;6(3):213.
[36]Louveau A,Smirnov I,Keyes TJ,et al.Structural and functional features of central nervous system lymphatic vessels.Nature.2015,523(7560):337-341
[37]陈琳,方明俊,黄红云,等.人胚胎嗅鞘细胞移植供、受者HLA配型方法介绍[J].中国医疗前沿,2009,4(22):20-20.
[38]Xiao J,Chen L,Mao G,et al.Neurorestorative clinical application standards for the culture and quality control of olfactory ensheathing cells.J Neurorestoratol,2017;5:175-179.
[39]Nakhjavan-Shahraki B;Yousefifard M;Rahimi-Movaghar V,et al.Transplantation of olfactory ensheathing cells on functional recovery and neuropathic pain after spinal cord injury;systematic review and meta-analysis.Sci Rep.2018;8(1):325
[40]Jiang Y,Zhu J,Xu G;et al.Intranasal delivery of stem cells to the brain.Expert Opin Drug Deliv.2011;8(5):623-32
[41]Ninomiya K,Iwatsuki K,Ohnishi Y,et al.Intranasal delivery of bone marrow stromal cells to spinal cord lesions.J Neurosurg Spine.2015;23(1):111-119
[42]Nijboer CH;Kooijman E,van Velthoven CT,et al.Intranasal Stem Cell Treatment as a Novel Therapy for Subarachnoid Hemorrhage.Stem Cells Dev.2018;27(5):313-325
[43]Salama M,Sobh M,Emam M,et al.Effect of intranasal stem cell administration on the nigrostriatal system in a mouse model of Parkinson's disease.Exp Ther Med.2017;13(3):976-982
[44]Assinck P,Duncan GJ,Hilton BJ,et al.Cell transplantation therapy for spinal cord injury.Nat Neurosci.2017;20(5):637-647.
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