人神经前体细胞移植治疗儿童广泛性发育障碍初探

刘卫鹏; 王君; 屈素清; 杜侃; 杨辉; 杨印祥; 汪兆艳; 栾佐

doi:10.7499/j.issn.1008-8830.2013.10.012

PDF(1404 KB)

中国当代儿科杂志 ›› 2013, Vol. 15 ›› Issue (10) : 860-865. DOI: 10.7499/j.issn.1008-8830.2013.10.012

论著·临床研究

人神经前体细胞移植治疗儿童广泛性发育障碍初探

刘卫鹏，王君，屈素清，杜侃，杨辉，杨印祥，汪兆艳，栾佐

作者信息 +

Transplantation of human neural precursor cells in the treatment of children with pervasive developmental disorder

LIU Wei-Peng, WANG Jun, QU Su-Qing, DU Kan, YANG Hui, YANG Yin-Xiang, WANG Zhao-Yan, LUAN Zuo

Author information +

文章历史 +

摘要

目的：观察人神经前体细胞（hNPCs）移植治疗儿童广泛性发育障碍的安全性及疗效。方法：对22例广泛性发育障碍患儿进行研究，其中孤独症9例，Rett综合征13例，经颅骨钻孔侧脑室穿刺注射hNPCs治疗。分别于手术前、术后1个月、术后6个月、术后1年采用孤独症行为评定量表（ABC）对移植患儿进行评估。结果：治疗及随访过程中无严重不良事件发生。移植后22例患儿中，1例失访，17例患儿临床症状出现不同程度的改善，其中孤独症患儿8例，Rett综合征患儿9例。孤独症患儿行ABC量表评估后发现，术后6个月交往因子得分，以及术后1年ABC总分、交往及语言因子得分均低于术前，差异有统计学意义（P<0.05）。结论：临床应用hNPCs移植治疗儿童广泛性发育障碍是安全、可行的，并具有一定疗效，有必要扩大观察病例数进一步研究。

Abstract

OBJECTIVE: To assess the efficiency and safety of human neural progenitor cells (hNPCs) transplantation in the treatment of pervasive developmental disorder (PDD) in children. METHODS: Twenty-two children with PDD were treated, including 13 children with Rett syndrome and 9 children with autism. They accepted hNPCs transplantation voluntarily. hNPCs derived from aborted fetal tissue were injected into the lateral ventricle of the patients under supersonic guidance. All patients were assessed according to the Autism Behavior Checklist before operation, at one and six months post operation, and one year later. RESULTS: No delayed complications resulting from this therapy were observed. The clinical symptoms of 17 patients, including 8 patients with autism and 9 patients with Rett syndrome, improved in varying degrees. The assessment results of the Autism Behavior Checklist for children with autism showed that compared with pre-operative function, social communication scores were significantly reduced at six months after transplantation, and total scores and social communication and language scores were also significantly reduced 1 year after transplantation (P<0.05). CONCLUSIONS: These results suggest that hNPCs transplantation is effective and safe for treatment of PPD in children. It deserves a further study

导出引用

刘卫鹏，王君，屈素清，杜侃，杨辉，杨印祥，汪兆艳，栾佐. 人神经前体细胞移植治疗儿童广泛性发育障碍初探[J]. 中国当代儿科杂志. 2013, 15(10): 860-865 https://doi.org/10.7499/j.issn.1008-8830.2013.10.012

LIU Wei-Peng, WANG Jun, QU Su-Qing, DU Kan, YANG Hui, YANG Yin-Xiang, WANG Zhao-Yan, LUAN Zuo. Transplantation of human neural precursor cells in the treatment of children with pervasive developmental disorder[J]. Chinese Journal of Contemporary Pediatrics. 2013, 15(10): 860-865 https://doi.org/10.7499/j.issn.1008-8830.2013.10.012

参考文献

[1] American psychiatric association. Diagnostic and statistical manual of mental disorders[M]. 4th ed. Washington DC: American Psyserving Chiatric Association, 1994: 65-78.

[2] Garber K. Autism's cause may reside in abnormalities at the synapse[J]. Science, 2007, 317(5835): 190-191.

[3] Blundell J, Blaiss CA, Etherton MR, Esinosa F, Tabuchi K, Walz C, et al. Neuroligin-1 deletion results in impaired spatial memory and increased repetitive behavior[J]. J Neurosci, 2010, 30(6): 2115-2129.

[4] Tabuchi K, Blundell J, Etherton MR, Hammer RE, Liu X, Powell CM, et al. A neuroligin-3 mutation implicated in autism increases inhibitory synaptic transmission in mice[J]. Science, 2007, 318(5847): 71-76.

[5] 栾佐, 尹国才, 胡晓红, 屈素清, 吴南海, 严凤清, 等. 人神经干细胞移植治疗重度新生儿缺氧缺血性脑病一例[J]. 中华儿科杂志, 2005, 49(8): 580-584.

[6] 屈素清, 栾佐, 刘卫鹏, 胡晓红, 尹国才, 金真, 等. 人神经干细胞移植治疗脑瘫并重度视觉障碍患儿的疗效[J]. 实用儿科临床杂志, 2009, 24(10): 771-773.

[7] 刘卫鹏, 屈素清, 栾佐, 龚小军, 汪兆艳. 人神经前体细胞移植治疗重度脑瘫患儿疗效观察[J].中国当代儿科杂志, 2012, 14(10): 759-762.

[8] Bauman ML. Microscopic neuroanatomic abnormalities in autism[J]. Pediatrics, 1991, 87(5): 791-796.

[9] Bauman ML, Kemper TL. Histoanatomoic observations of the brain in early infantile autism[J]. Neurology, 1985, 35(6): 866-874.

[10] Mountz JM, Tolbert LC, Lill DW, Katholi CR, Liu HG. Functional deficits in autistic disorder：characterization by technetium-99m-HMPAO and SPECT[J]. J Nucl Med, 1995, 36(7): 1156-1162.

[11] Cabanlit M, Wills S, Goines P, Ashwood P, Van de water J. Brain-specific autoantibodies in the plasma of subjects with autistic spectrum disorder[J]. Ann NY Acad Sci, 2007, 1107: 92-103.

[12] Tsuchiya KJ, Hashimoto K, Iwata Y, Tsujii M, Sekine Y, Sugihara G, et al. Decreased serum levels of platelet- endothelial adhesion molecule (PECAM-1) in subjects with high-functioning autism：a negative correlation with head circumference at birth[J]. Biol Psychiatry, 2007, 62(9): 1056-1058.

[13] Percy AK, Neul JL, Glaze DG, Motil KJ, Skinner SA, Khwaja O, et al. Rett syndrome diagnostic criteria: lessons from the Natural History Study[J]. Annals of Neurology, 2010, 68(6): 951-955.

[14] Amir RE, Van den Veyver IB, Wan M, Tran CQ, Francke U, Zoghbi HY. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2[J]. Nat Genet, 1999, 23(2): 185-188.

[15] Hauser RA, Freeman TB, Snow BJ, Nauert M, Gauger L, Kordower JH, et al. Long-term evaluation of bilateral fetal nigral transplantation in Parkinson disease[J]. Arch Neurol, 1999, 56(2): 179-187.

[16] Keene CD, Sonnen JA, Swanson PD, Kopyov O, Leverenz JB, Bird TD, et al. Neural transplantation in Huntington disease long-term gragfts in two patients[J]. Neurology, 2007, 68(24): 2093-2098.

[17] Seledtsov VI, Kafanova MY, Rabinovich SS, Poveshchenko OV, Kashchenko EA, Fel'de MA, et al. Cell therapy of cerebral palsy[J]. Bull Exp Biol Med, 2005, 139(4): 499-503.

[18] Ogawa D, Okada Y, Nakamura M, Kanemura Y, Okano HJ, Matsuzaki Y, et al. Evaluation of human fetal neural stem/progenitor cells as a source for cell replacement therapy for neurological disorders: properties and tumorigenicity after long-term in vitro maintenance[J]. J Neurosci Res, 2009, 87(2): 307-317.

[19] Lu S, Lu C, Han Q, Li J, Du Z, Liao L, et al. Adipose-derived mesenchymal stem cells protect PC12 cells from glutamate excitotoxicity-induced apoptosis by upregulation of XIAP through PI3-K/Akt activation[J]. Toxicology, 2011, 279(1-3): 189-195.

[20] Wei X, Zhao L, Zhong J, Gu H, Feng D, Johnstone BH, et al. Adipose stromal cells-secreted neuroprotective media against neuronal apoptosis[J]. Neurosci Lett, 2009, 462(1): 76-79.

[21] Kemp K, Hares K, Mallam E, Heesom KJ, Scolding N, Wilkins A. Mesenchymal stem cell-secreted superoxide dismutase promotes cerebellar neuronal survival[J]. J Neurochem, 2010, 114(6): 1569-1580.

[22] Salgado AJ, Fraga JS, Mesquita AR, Neves NM, Reis RL, Sousa N. Role of human umbilical cord mesenchymal progenitors conditioned media in neuronal/glial cell densities, viability, and proliferation[J]. Stem Cells Dev, 2010, 19(7): 1067-1074.

[23] 郗春艳, 华天懿, 赵云静, 刘晓梅. 孤独症患儿发育倒退特征的研究[J]. 中国当代儿科杂志, 2010, 12(10): 781-783.

[24] 屈素清, 栾佐, 尹国才, 郭万里, 胡晓红, 吴南海, 等. 新生鼠缺氧缺血性脑损伤后经脑室人神经干细胞移植的实验研究[J]. 中华儿科杂志, 2005, 43(8): 576-579.

[25] Einstein O, Karussis D, Grigoriadis N, Mizrachi-Kol R, Reinhartz E, Abramsky O, et al. Intraventricular transplantation of neural precursor cell spheres attenuates acute experimental allergic encephalomyelitis[J]. Mol Cell Neurosci, 2003, 24(4): 1074-1082.

[26] Akesson E, Wolmer-Solberg N, Cederarv M, Falci S, Odeberg J. Human neural stem cells and astrocytes, but not neurons, suppress an allogeneic lymphocyte response[J]. Stem Cell Res, 2009, 2(1): 56-67.

[27] Al Nimer F, Wennersten A, Holmin S, Meijer X, Wahlberg L, Mathiesen T. MHC expression after human neural stem cell transplantation to brain contused rats[J]. Neuroreport, 2004, 15(12): 1871-1875.

[28] Martino G, Pluchino S. The therapeutic potential of neural stem cells[J]. Nat Rev Neurosci, 2006, 7(5): 395-406.

[29] Kelly S, Bliss TM, Shah AK, Sun GH, Ma M, Foo WC, et al. Transplanted human fetal neural stem cells survive, migrate, and differentiate in ischemic rat cerebral cortex[J]. Proc Natl Acad Sci U S A, 2004, 101(32): 11839-11844.

[30] Pluchino S, Quattrini A, Brambilla E, Gritti A, Salani G, Dina G, et al. Injection of adult neurospheres induces recovery in a chronic model of multiple sclerosis[J]. Nature, 2003, 422(6933): 688-694.

[31] Zhu QF, Ma J, Yu LI, Yuan CQ. Grafted neural stem cells migrate to substantia nigra and improve behavior in Parkinsonian rats[J]. Neurosci Lett, 2009, 462(3): 213-218.

[32] Lepore AC, Neuhuber B, Connors TM, Han SS, Liu Y, Daniels MP, et al. Long-term fate of neural precursor cells following transplantation into developing and adult CNS[J]. Neuroscience, 2006, 142(1): 287-304.

[33] Mendez I, Vinuela A, Astradsson A, Mukhida K, Hallett P, Robertson H, et al. Dopamine neurons implanted into people with Parkinson's disease survive without pathology for 14 years[J]. Nat Med, 2008, 14(5): 507-509.