脐带间充质干细胞治疗脑胶质瘤:作用机制、安全性和未来应用前景
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摘要
背景:脐带间充质干细胞是一类具有自我更新能力、高度增殖能力和多向分化潜能的细胞。脐带间充质干细胞的特性尤其是肿瘤嗜性能力使其成为神经胶质瘤细胞治疗的理想工具。这些细胞可以通过旁分泌或者作为基因和药物的递送系统起作用。已经证明脐带间充质干细胞能够抑制脑胶质瘤的生长并改善移植入大脑后的存活。目的:总结脐带间充质干细胞在脑胶质瘤治疗中分子机制和安全性的研究和进展,并为其进一步研究提供有益的参考。方法:应用计算机检索2000至2017年Pub Med和CNKI数据库相关文章,英文检索词为"Glioma;Umbilical cord mesenchymal stem cells",中文检索词为"胶质瘤;脐带间充质干细胞;安全性;分子机制"。根据纳入与排除标准,最终保留55篇文献进行综述。结果与结论:(1)脐带间充质干细胞治疗脑胶质瘤有着明显的作用;(2)脐带间充质干细胞可以通过其归巢特征、旁分泌机制、作为基因载体和共培养对脑胶质瘤进行治疗;(3)脐带间充质干细胞在脑胶质瘤的治疗中具有一定的安全性。
BACKGROUND: Umbilical cord mesenchymal stem cells(UC-MSCs) are a group of cells that have self-renewal, highly proliferative and multidrug differentiation potential. The properties of UC-MSCs and their tumor tropism make them an ideal tool for glioma cell therapy. These cells can act by paracrine or as a delivery system for genes and drugs. It has been demonstrated that UC-MSCs can inhibit the growth of glioma and improve the survival after transplantation into the brain. OBJECTIVE: To summarize the molecular mechanisms and safety of UC-MSCs in the treatment of glioma and to provide a useful reference for further research. METHODS: We searched the Pub Med and CNKI databases from 2000 to 2017 with the English terms of "glioma; umbilical cord mesenchymal stem cells" and the Chinese terms of "glioma; umbilical cord mesenchymal stem cells; safety; molecular mechanism". Based on the inclusion and exclusion criteria, 55 articles were finally reserved for review. RESULTS AND CONCLUSION: UC-MSCs have obvious effect on treating glioma. These cells can treat glioma through homing mechanism and paracrine mechanism as gene carrier and co-culture. Moreover, UC-MSCs have certain safety in the treatment of glioma.
BACKGROUND: Umbilical cord mesenchymal stem cells(UC-MSCs) are a group of cells that have self-renewal, highly proliferative and multidrug differentiation potential. The properties of UC-MSCs and their tumor tropism make them an ideal tool for glioma cell therapy. These cells can act by paracrine or as a delivery system for genes and drugs. It has been demonstrated that UC-MSCs can inhibit the growth of glioma and improve the survival after transplantation into the brain. OBJECTIVE: To summarize the molecular mechanisms and safety of UC-MSCs in the treatment of glioma and to provide a useful reference for further research. METHODS: We searched the Pub Med and CNKI databases from 2000 to 2017 with the English terms of "glioma; umbilical cord mesenchymal stem cells" and the Chinese terms of "glioma; umbilical cord mesenchymal stem cells; safety; molecular mechanism". Based on the inclusion and exclusion criteria, 55 articles were finally reserved for review. RESULTS AND CONCLUSION: UC-MSCs have obvious effect on treating glioma. These cells can treat glioma through homing mechanism and paracrine mechanism as gene carrier and co-culture. Moreover, UC-MSCs have certain safety in the treatment of glioma.
引文
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[2]赖华生,陈志浩,陈祎招.神经胶质瘤与新型抑癌基因的研究进展[J].广东医学,2015,36(7):1122-1124.
[3]谢炯.人脐带间充质干细胞作为细胞载体治疗胶质瘤的研究现状及前景[D].石家庄:河北医科大学,2017.
[4]Wu J,Izpisua Belmonte JC.Stem Cells:A Renaissance in Human Biology Research.Cell.2016;165(7):1572-1585.
[5]Serakinci N,Fahrioglu U,Christensen R.Mesenchymal stem cells,cancer challenges and new directions.Eur J Cancer.2014;50(8):1522-1530.
[6]Baghaban Eslaminejad M,Malakooty Poor E.Mesenchymal stem cells as a potent cell source for articular cartilage regeneration.World J Stem Cells.2014;6(3):344-354.
[7]Fellows CR,Matta C,Zakany R,et al.Adipose,Bone Marrow and Synovial Joint-Derived Mesenchymal Stem Cells for Cartilage Repair.Front Genet.2016;7:213.
[8]n't Anker PS,Scherjon SA,Kleijburg-van der Keur C,et al.Isolation of mesenchymal stem cells of fetal or maternal origin from human placenta.Stem Cells.2004;22(7):1338-1345.
[9]Ding DC,Chang YH,Shyu WC,et al.Human umbilical cord mesenchymal stem cells:a new era for stem cell therapy.Cell Transplant.2015;24(3):339-347.
[10]李慎杰,周杰,张苓,等.间充质干细胞治疗胶质瘤的研究进展[J].广东医学,2016,37(19):2982-2984.
[11]梁硕,焦红亮,迟连凯,等.人脐带间充质干细胞对神经胶质瘤生长的抑制[J].中国组织工程研究,2012,16(49):9179-9185.
[12]Aboody KS,Brown A,Rainov NG,et al.Neural stem cells display extensive tropism for pathology in adult brain:evidence from intracranial gliomas.Proc Natl Acad Sci U S A.2000;97(23):12846-12851.
[13]冉黎婧,史明霞,洪敏.间充质干细胞归巢机制研究进展[J].医学研究生学报,2014,27(4):423-426.
[14]Nakamura K,Ito Y,Kawano Y,et al.Antitumor effect of genetically engineered mesenchymal stem cells in a rat glioma model.Gene Ther.2004;11(14):1155-1164.
[15]Fan C,Wang D,Zhang Q,et al.Migration capacity of human umbilical cord mesenchymal stem cells towards glioma in vivo.Neural Regen Res.2013;8(22):2093-2102.
[16]Li CH,Jiao BH,Kang CS,et al.The Preliminarystudy on the Bone marmw derived mesenehymal stem cells migratingtoward glioma.Chin J Nery Ment Dis.2006;32:289-293.
[17]Ho Wang Yin KY,Loinard C,Bakker W,et al.HIF-prolyl hydroxylase 2 inhibition enhances the efficiency of mesenchymal stem cell-based therapies for the treatment of critical limb ischemia.Stem Cells.2014;32(1):231-243.
[18]范冬梅,张子祥,赵英新,等.人脐带来源间充质干细胞向Hep G2肝癌细胞原位移植瘤的归巢及分化[J].中国肿瘤生物治疗杂志,2017,24(6):595-600.
[19]Bonora M,Wieckowski MR,Chinopoulos C,et al.Molecular mechanisms of cell death:central implication of ATP synthase in mitochondrial permeability transition.Oncogene.2015;34(12):1475-1486.
[20]Rombouts WJ,Ploemacher RE.Primary murine MSC show highly efficient homing to the bone marrow but lose homing ability following culture.Leukemia.2003;17(1):160-170.
[21]张艺凡,胡方方,秦方圆,等.人脐带间充质干细胞与肿瘤治疗研究进展[J].中华实用诊断与治疗杂志,2017,31(4):403-406..
[22]Watson N,Divers R,Kedar R,et al.Discarded Wharton jelly of the human umbilical cord:a viable source for mesenchymal stromal cells.Cytotherapy.2015;17(1):18-24.
[23]Thibeault S,Rautureau Y,Oubaha M,et al.S-nitrosylation of beta-catenin by e NOS-derived NO promotes VEGF-induced endothelial cell permeability.Mol Cell.2010;39(3):468-476.
[24]Chen J,Liu Z,Hong MM,et al.Proangiogenic compositions of microvesicles derived from human umbilical cord mesenchymal stem cells.PLo S One.2014;9(12):e115316.
[25]Kim DS,Kim JH,Lee JK,et al.Overexpression of CXC chemokine receptors is required for the superior glioma-tracking property of umbilical cord blood-derived mesenchymal stem cells.Stem Cells Dev.2009;18(3):511-519.
[26]范存刚,周景儒,张庆俊.人脐带血来源的间充质干细胞在脑胶质瘤治疗中的应用前景[J].国际神经病学神经外科学杂志,2011,38(6):598-602.
[27]Dasari VR,Kaur K,Velpula KK,et al.Upregulation of PTEN in glioma cells by cord blood mesenchymal stem cells inhibits migration via downregulation of the PI3K/Akt pathway.PLo S One.2010;5(4):e10350.
[28]Akimoto K,Kimura K,Nagano M,et al.Umbilical cord blood-derived mesenchymal stem cells inhibit,but adipose tissue-derived mesenchymal stem cells promote,glioblastoma multiforme proliferation.Stem Cells Dev.2013;22(9):1370-1386.
[29]Doucette T,Rao G,Yang Y,et al.Mesenchymal stem cells display tumor-specific tropism in an RCAS/Ntv-a glioma model.Neoplasia.2011;13(8):716-725.
[30]刘晓智,姜忠敏.成体干细胞作为药物载体治疗胶质瘤的作用途径研究进展[J].山东医药,2016,56(43):101-104.
[31]Kim SM,Jeong CH,Woo JS,et al.In vivo near-infrared imaging for the tracking of systemically delivered mesenchymal stem cells:tropism for brain tumors and biodistribution.Int J Nanomedicine.2015;11:13-23.
[32]Wu GS.TRAIL as a target in anti-cancer therapy.Cancer Lett.2009;285(1):1-5.
[33]Yang B,Wu X,Mao Y,et al.Dual-targeted antitumor effects against brainstem glioma by intravenous delivery of tumor necrosis factor-related,apoptosis-inducing,ligand-engineered human mesenchymal stem cells.Neurosurgery.2009;65(3):610-624;discussion 624.
[34]Park JH,Ryu CH,Kim MJ,et al.Combination Therapy for Gliomas Using Temozolomide and Interferon-Beta Secreting Human Bone Marrow Derived Mesenchymal Stem Cells.J Korean Neurosurg Soc.2015;57(5):323-328.
[35]Xu G,Jiang XD,Xu Y,et al.Adenoviral-mediated interleukin-18 expression in mesenchymal stem cells effectively suppresses the growth of glioma in rats.Cell Biol Int.2009;33(4):466-474.
[36]Lozito TP,Tuan RS.Mesenchymal stem cells inhibit both endogenous and exogenous MMPs via secreted TIMPs.J Cell Physiol.2011;226(2):385-396.
[37]郭兴荣,王小莉,袁雅红,等.PTEN m RNA编辑的间充质干细胞对神经胶质瘤U251细胞杀伤作用研究[J].生物技术通报,2016,32(4):234-241.
[38]田毅,关方霞,胡祥,等.人脐带沃顿胶间充质干细胞与脑肿瘤干细胞的共培养[J].中国组织工程研究与临床康复,2010,14(10):1721-1728.
[39]Jiao H,Guan F,Yang B,et al.Human amniotic membrane derived-mesenchymal stem cells induce C6 glioma apoptosis in vivo through the Bcl-2/caspase pathways.Mol Biol Rep.2012;39(1):467-473.
[40]粱阿铭,梁硕,樊锐太,等.直接和间接共培养条件下人脐带间充质干细胞对恶性胶质瘤细胞系SHG44生长的抑制作用[J].中国组织工程研究,2012,16(32):5891-5896.
[41]Fonseka M,Ramasamy R,Tan BC,et al.Human umbilical cord blood-derived mesenchymal stem cells(h UCB-MSC)inhibit the proliferation of K562(human erythromyeloblastoid leukaemic cell line).Cell Biol Int.2012;36(9):793-801.
[42]靳晓亮.人羊膜及脐带间充质干细胞与C6胶质瘤细胞分别共培养的实验研究[D].郑州:郑州大学,2009.
[43]汪玲.肿瘤微环境中h UC-MSCs的生物学特性分析[D].重庆:重庆医科大学,2016.
[44]王娜,陈乃耀.脐带间充质干细胞对小胶质细胞增殖及活化的影响[J].山东大学学报(医学版),2016,54(10):16-20.
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