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摘要：间充质干细胞旁分泌作用的治疗作用逐渐成为研究热点，旁分泌产生的因子参与组织修复、神经血管再生及免疫调节作用。旁分泌产生的因子降低异基因及免疫反应，非常具有治疗前景，值得我们研究。本文以间充质干细胞旁分泌作用机制进行研究，阐述其在神经系统疾病中的作用。
关键词：间充质干细胞；旁分泌作用；脑卒中；神经再生；神经退行性疾病
本文引用格式：赵婧钰,郭荷娜,杨谦.间充质干细胞旁分泌作用在神经系统中作用研究进展[J].世界最新医学信息文摘,2019,19(86):71-73.
Research Progress of Paracrine Effects of Mesenchymal Stem Cells on Neurological Diseases
ZHAO Jing-yu1,GUO He-na2,YANG Qian2*
(1.Xi’an Medical University,Xi’an Shaanxi;2.Department of Neurology,Shaanxi Provincial People’s Hospital,Xi’an Shaanxi)ABSTRACT:Researches of paracrine therapic effects of mesenchymal stem cells MSCs has been a hot topic in recent years,the secreted factors mainly has the effects in tissue repair,nerve and angiogenesis regeneration,immunomodulatory.It also decreased allogene and immune reaction,which made it perspective and a worthy spot.Here,we reviewed the characteristics and effects of cell sources on paracrine,expatiate the role on neurological diseases.
KEY WORDS:Mesenchymal stem cells;Paracrine effect;Stroke;Nerve regeneration;Neurodegenerative diseases
0引言
人体内所有组织都有间充质干细胞(mesenchymal stem cells,MSCs)，有骨髓源性、脂肪源性、牙髓源性、脐带源性和胎盘源性等,不同来源间充质干细胞分泌的物质不同[1]。旁分泌作用时指干细胞自身分泌的各种物质，包括细胞因子、生长因子、microRNAs、蛋白酶和胞外囊泡等。细胞外囊泡（evs）包括外泌体、微泡及凋亡体。目前研究多以外囊泡发挥的作用为主，外泌体与微泡已成为研究热点。外泌体能够通过转移信息至损伤细胞或组织参与组织再生,并且保持与间充质干细胞相同的生物活性[2，3]。MSCs的旁分泌作用可以增加神经及脑血管的保护作用[4]。下文以间充质干细胞旁分泌作用机制进行研究，阐述其在神经系统疾病中的作用。
1间充质干细胞旁分泌作用与脑卒中
缺血性脑卒中在患者死亡及长期致残中占重要原因，溶栓和介入性血管再通是唯一可用的治疗方法。由于副作用和狭窄的治疗时间窗，较少患者受益[5]。间充质干细胞有防卫和警觉作用，被称为人体哨兵[6]，旁分泌产生神经生长因子、脑源性神经营养因子或胶质源性神经营养因子等[7]。而外泌体为30-100nm大小的内质室膜囊泡衍生物，外体可通过受体介导的粘附到细胞质膜上，可通过细胞内吸收和内化或者外体膜与靶细胞膜直接融合，随后外体内容物释放到受体细胞中[8]。间充质干细胞旁分泌作用产生的外泌体与微囊泡，其发挥信息传递作用及功能不通过细胞与细胞跨膜作用，与其他转运体不同的是，他们可以容易的进入血脑屏障，进行信息的双向交流，这是旁分泌作用在中枢神经系统中治疗的一个新的方向[9-11]，研究表明移植干细胞后，其旁分泌作用产生的外泌体可对缺血性卒中恢复有积极作用。外囊泡通过渗漏作用进入血脑屏障（blood brain barrier，BBB），激活星形胶质细胞和小胶质细胞释放促炎细胞因子（TNF，IL1），小胶质转化为促重塑表型，释放生长因子及IL-10，并作用于内皮细胞和血管内皮细胞，调节血管修复和重塑，促进NO诱导的血管扩张[12]。Jeong H[13]的研究表明，目前临床上用于移植来治疗缺血性卒中主要是骨髓或脐带源性MCSc，两者相比，骨髓间充质干细胞治疗效果较好，患者NIHSS评分较前提高。外泌体在缺乏有效治缺血性卒中中，可以作为生物标记物和新型治疗工具，因此具有重要的研究前景[14,15]。
然而有学者担忧旁分泌因子所产生的副作用，因为它可增加体内胆固醇酯（CE）、三酰甘油（TAG）和心磷脂，这些指标都是卒中的风险因素[16，17，18，19]，不仅如此，它还增加了体内可能的肿瘤细胞扩散[20]。
2间充质干细胞旁分泌作用与血管再生
间充质干细胞旁分泌作用对心血管、脑血管、肾脏缺血中治疗作用逐渐引起注意，并显示出了良好前景[21]，旁分泌作用所产生的血管表皮生长因子（VEGF）、基质细胞衍生因子（sdf-1），碱性纤维细胞生长因子、胰岛素样生长因子、促血小板生成素及血小板源性生长因子都与血管生成有关。Lv B[22]的研究证明了，在缺氧诱导下低氧诱导因子-1α(hypoxiainducible factor 1 alpha,HIF-1α)可上调并增加MSC以及其外泌体的血管生成作用。Doan C C和Tancharoen W[23，24]研究表明脐带源及羊水源MSCs不仅仅具有向血管内皮细胞(vascular endothelial cells,VEC)分化的能力，其旁分泌作用可产生血管表皮生VEGF、SDF-1、IL-6，Il-8等，这些因子可增加血管内皮细胞及血管平滑肌增值，使得血管密度增加，促进血管再生。一些学者证明了间充质干细胞及其旁分泌作用促血管生成的可能机制，通过ERK/Akt信号促进VEC迁移和血管形成[25，26，27]。
旁分泌作用产生基质金属蛋白(MMPs)在血管生成中也有重要地位，实验证明MMPs参与了血管内皮损伤后的血管内皮的重塑。体外实验研究发现，加入MMPs抑制剂时，抑制了MCSs对毛细血管内皮结构的形成有促进作用，说明MMPs在促进血管内皮结构生成中起到重要作用[28]。
3间充质干细胞旁分泌作用与中枢神经退行性疾病
阿尔兹海默（Alzheimer’s disease,AD）与帕金森病（Parkinson’s disease，PD）是最常见的两种神经退行性病。Furnoα β D L[29]使用脐带、骨髓及脂肪源MSCs在动物实验中表明，MSCs的旁分泌作用在治疗慢性神经退行性疾病中发挥作用。AD主要病理表现为脑组织β淀粉样蛋白前体蛋白(β-amyloid precursor protein,APP)水解产生的Aβ蛋白异常沉积导致，以及过度磷酸化的tau蛋白形成的双螺旋纤微丝，其他表现还有小胶质细胞介导的脑内炎症反应等，lee[30]利用小鼠脂肪间充质干细胞旁分泌因子，可分化成的成神经干细胞（NSC）并且可减少AD小鼠中枢神经凋亡细胞的数量，并且增加小鼠的认知功能。肾胰岛素残基溶酶(neprilysin,NEP)是一种蛋白酶，体外及细胞实验表明NEP可以降低Aβ的含量，且能改善AD大鼠的行为评分，脂肪间充质干细胞外泌体表达NEP较多，可减少β-淀粉样多肽水平，而β-淀粉样沉积不仅仅是阿尔兹海默症的主要发病机制，同样是路易小体痴呆（DLB）,多系统萎缩(MSA）患者中的病理特征。该研究不仅仅为治疗PD带来前景，也为β-淀粉样变相关疾病提供治疗的新方向[31,32]。Dansokho C[33]最近研究发现细胞的自噬作用与AD的发病有联系，在AD的发病过程中，Aβ周围聚集被激活的神经免疫细胞-小胶质细胞，其产生促炎因子在AD疾病发展过程中加速神经系统的退行性改变[34]，炎性环境可加速神经细胞的自噬作用,而严重的炎症环境使自噬作用减弱，而神经细胞凋亡，进一步加重疾病。同样炎症反应也参与了PD疾病进程，可伴随多巴胺神经元的变性过程。MSCs的旁分泌产生细胞因子，可抑制炎症发生。Li Y[35]从人类牙髓MCSc旁分泌作用产生的外泌体可对啮齿类动物进行免疫抑制，外泌体可促进星形胶质细胞及小胶质细胞激活并释放神经免疫因子，进一步减缓炎症对神经退行性疾病的作用。PD的主要病理特征是中脑多巴胺能神经元减少丢失或者α-突触核蛋白过多异常聚集导致形成的路易小体。牙髓源性间充质干细胞外泌体可抑制多巴胺神经元凋亡并上调多巴胺能神经元数量，目前间充质干细胞旁分泌作用对神经退行性疾作用主要集中在外泌体，利用好外泌体是神经退行性病治疗具有良好发展前景[36-38]。我国已经有临床试验表明，通过颈动脉移植脐带源性间充质干细胞，能够明显改善患者移植后PD患者的UPDRS评分和Webster评分，不仅仅是因为脐带源间充质干细胞分化成为免疫保护作用的胶质细胞，促使神经再生及修复的神经元，旁分泌作用产生的细胞因子同样在减少黑质纹状体的损伤，抑制多巴胺神经元的凋亡起到不可忽视的作用[39]。
4间充质干细胞旁分泌作用与外周神经再生
间充质干细胞被认为是细胞的储存器，具有多功能定向分化作用，骨髓间充质干细胞及脂肪间充质干细胞可以分化成为施万细胞，发挥外周神经修复作用。然而，研究发现他们只是类施万细胞，在体内移植骨髓或骨髓间充质干细胞时，只极小部分分化成施万细胞，而类施万细胞并不能发挥神经修复与轴突再生作用[40,41]。Trohatou和Rani S[42,43]的研究表明了MSCs旁分泌作用产生的某些生物活性物质更为神经再生提供了基础环境，并且促进神经损伤后的再生，脂肪MCSc旁分泌产生一系列的神经营养物质，例如EGF、TGFβ-1、VEGF、BFGF、HGF等因子以及在组织不同阶段分泌的IGF-i和BDNF[44-46]。Ma Y[47]之前的研究也表明了骨髓间充质干细胞旁分泌对神经修复再生促进作用。Doeppner T R[48]将人类骨髓源性间充质干细胞移植到小鼠发现，人骨髓间充质干细胞衍生的外囊泡可改善卒中后神经再生，并可预防小鼠缺血后免疫抑制。人脐带间充质干细胞可以使外周神经损伤后的轴突再生，到达神经修复再生的作用，并且人脐带间充质干细胞的旁分泌作用神经修复再生作用相比脂肪及骨髓源性干细胞的作用更大，同时可以降低异基因及免疫反应[49-54]。
5小结
在我国，脑卒中和神经退行性病变患者病人较多，目前有效的治疗方法效果较少，我们需要仔细研究间充质干细胞旁分泌作用的治疗前景，旁分泌产生的因子参与组织修复、神经血管再生及免疫调节作用，并且降低异基因及免疫反应，应该发挥其在神经系统疾病中的治疗作用。
参考文献
[1]Heo J,Choi Y,Kim H S,et al.Comparison of molecular profiles of human mesenchymal stem cells derived from bone marrow,umbilical???cord blood,placenta and adipose tissue[J].International Journal of Molecular Medicine,2015.
[2]Raghu K.The biology and function of exosomes in cancer[J].Journal of Clinical Investigation,2016,126(4):1208-1215.
[3]Tkach M,Thã©Ry C.Communication by Extracellular Vesicles:Where We Are and Where We Need to Go[J].Cell,2016,164(6):1226-1232.
[4]Ophelders D R M G,Wolfs T G A M,Jellema R K,et al.Mesenchymal Stromal Cell-Derived Extracellular Vesicles Protect the Fet al Brain After Hypoxia-Ischemia[J].Stem Cells Translational Medicine,2016,5(6):754-763.
[5]Doeppner Thorsten R,B?hr Mathias,Giebel Bernd,et al.Immunological and non-immunological effects of stem cell-derived extracellular vesicles on the ischaemic brain[J].Therapeutic Advances in Neurological Disorders,2018,11:175628641878932-.
[6]Caplan,Arnold I.MSCs:The Sentinel and Safe-Guards of Injury[J].Journal of Cellular Physiology,2016,231(7):1413-1416.
[7]Tatiana L,Natalia K,Maxim K,et al.Adipose-Derived Stem Cells Stimulate Regeneration of Peripheral Nerves:BDNF Secreted by These Cells Promotes Nerve Healing and Axon Growth De Novo[J].PLoS ONE,2011,6(3):e17899.
[8]Bang C,Thum T.Exosomes:new players in cell-cell communication[J].Int J Biochem Cell Biol,2012,44(11):2060-2064.
[9]Valadi H,Ekstr?M K,Bossios A,et al.Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells[J].NATURE CELL BIOLOGY,2007,9(6):654-659.
[10]Frühbeis,Carsten,Fr?Hlich D,Kuo W P,et al.Extracellular vesicles as mediators of neuron-glia communication[J].Frontiers in Cellular Neuroscience,2013,7.
[11]Balusu S,Van Wonterghem E,De Rycke R,et al.Identification of a novel mechanism of blood-brain communication during peripheral inflammation via choroid plexus derived extracellular vesicles[J].EMBO Molecular Medicine,2016,8(10):1162-1183.
[12]Norden D M,Fenn A M,Dugan A,et al.TGFβproduced by IL-10 redirected astrocytes attenuates microglial activation[J].Glia,2014,62(6):881-895.
[13]Jeong H,Yim H W,Cho Y S,et al.Efficacy and safety of stem cell therapies for patients with stroke:a systematic review and single arm meta-analysis[J].International Journal of Stem Cells,2014,7(2):63.
[14]Lener T,Gimona M,Aigner L,et al.Applying extracellular vesicles based therapeutics in clinical trials-an ISEV position paper[J].Journal of Extracellular Vesicles,2015,4(4):30087.
[15]Barile L,Vassalli G.Exosomes:Therapy delivery tools and biomarkers of diseases[J].Pharmacology&Therapeutics,2017,174:S0163725817300347.
[16]Llorente,A.,van Deurs,B.,Sandvig,K.Cholesterol regulates prostasome release from secretory lysosomes in PC-3 human prostate cancer cells[J].Eur.J.Cell Biol，2007，86：405-415.
[17]Meer G V,Voelker D R,Feigenson G W.Membrane lipids:where they are and how they behave[J].Nature Reviews Molecular Cell Biology,2008,9(2):112-124.
[18]Strauss K,Goebel C,Runz H,et al.Exosome Secretion Ameliorates Lysosomal Storage of Cholesterol in Niemann-Pick Type C Disease[J].Journal of Biological Chemistry,2010,285(34):26279.
[19]Record M,Poirot M,Silvente-Poirot S.Emerging concepts on the role of exosomes in lipid metabolic diseases[J].Biochimie,2014,96(1):67-74.
[20]Li Y,Cheng Q,Hu G,et al.Extracellular vesicles in mesenchymal stromal cells:A novel therapeutic strategy for stroke[J].Experimental&Therapeutic Medicine,2018,15(5):4067-4079.
[21]Burgos-Silva M,Semedo-Kuriki P,Donizetti-Oliveira C,et al.Adipose Tissue-Derived Stem Cells Reduce Acute and Chronic Kidney Damage in Mice[J].PLOS ONE,2015,10(11):e0142183.
[22]Lv B,Li F,Fang J,et al.Hypoxia inducible factor 1αpromotes survival of mesenchymal stem cells under hypoxia[J].American Journal of Translational Research,2017,9(3):1521.
[23]Doan C C,Le T L,Hoang N S,et al.Differentiation of Umbilical Cord Lining Membrane-Derived Mesenchymal Stem Cells into Endothelial-Like Cells[J].Iranian biomedical journal,2014,18(2):67-75.
[24]Tancharoen W,Aungsuchawan S,Pothacharoen P,et al.Differentiation of mesenchymal stem cells from human amniotic fluid to vascular endothelial cells[J].Acta Histochemica,2017,119(2):113-121.
[25]Luca A D,Gallo M,Aldinucci D,et al.Role of the EGFR ligand/receptor system in the secretion of angiogenic factors in mesenchymal stem cells[J].Journal of Cellular Physiology,2011,226(8):2131-2138.
[26]Liang X,Ding Y,Zhang Y,et al.Paracrine mechanisms of mesenchymal stem cell-based therapy:current status and perspectives.[J].Cell Transplantation,2013,23(9):1045.
[27]Vrijsen K R,Maring J A,Chamuleau S A J,et al.Exosomes from Cardiomyocyte Progenitor Cells and Mesenchymal Stem Cells Stimulate Angiogenesis Via EMMPRIN[J].Advanced Healthcare Materials,2016.
[28]AndréN Tiaden,Bahrenberg G,Mirsaidi A,et al.Novel Function of Serine Protease HTRA1 in Inhibiting Adipogenic Differentiation of Human Mesenchymal Stem Cells via MAP Kinase-Mediated MMP Upregulation[J].Stem Cells,2016,34(6).
[29]Furno D L,Mannino G,Giuffrida R.Functional Role of Mesenchymal Stem Cells in the Treatment of Chronic Neurodegenerative Diseases[J].Journal of Cellular Physiology,2017.
[30]Lee M,Ban J J,Yang S,et al.The exosome of adipose-derived stem cells reducesβ-amyloid pathology and apoptosis of neuronal cells derived from the transgenic mouse model of Alzheimer’s disease[J].Brain Research,2018,1691.
[31]Grimm M O W,Janine M,Stahlmann C P,et al.Neprilysin and AβClearance:Impact of the APP Intracellular Domain in NEP Regulation and Implications in Alzheimer’s Disease[J].Frontiers in Aging Neuroscience,2013,5.
[32]Katsuda T,Tsuchiya R,Kosaka N,et al.Human adipose tissue-derived mesenchymal stem cells secrete functional neprilysin-bound exosomes[J].Scientific Reports,2013,3(1197):1197.
[33]Dansokho C,Heneka M T.Neuroinflammatory responses in Alzheimer’s disease[J].2018.
[34]Trotta T,Porro C,Calvello R,et al.Biological role of Toll-like receptor-4 in the brain[J].Journal of Neuroimmunology,2014,268(1-2):1-12.
[35]Li Y,Yang Y Y,Ren J L,et al.Exosomes secreted by stem cells from human exfoliated deciduous teeth contribute to functional recovery after traumatic brain injury by shifting microglia M1/M2 polarization in rats[J].Stem Cell Research&Therapy,2017,8(1):198.
[36]JarmalavičiūtėA,Tunaitis V,PivoraitėU,et al.Exosomes from dental pulp stem cells rescue human dopaminergic neurons from 6-hydroxy-dopamine-induced apoptosis[J].Cytotherapy,2015,17(7):932-939.
[37]Nakamura Y,Miyaki S,Ishitobi H,et al.Mesenchymal-stem-cell-derived exosomes accelerate skelet al muscle regeneration[J].FEBS Letters,2015,589(11):1257-1265.
[38]Venugopal C,Shamir C,Senthilkumar S,et al.Dosage and Passage Dependent Neuroprotective Effects of Exosomes Derived from Rat Bone Marrow Mesenchymal Stem Cells:An In Vitro Analysis[J].Current Gene Therapy,2018,17(5).
[39]孙丽,贲亮,李巍,等.脐带源间充质干细胞治疗帕金森病的临床研究[J].标记免疫分析与临床,2016,23(10).
[40]Chen J,Wang S Y,Ren Z,et al.Recellularized nerve allografts with differentiated mesenchymal stem cells promote peripheral nerve regeneration.[J].Neuroscience Letters,2012,514(1):96-101.
[41]Sowa Y,Imura T,Numajiri T,et al.Adipose-Derived Stem Cells Produce Factors Enhancing Peripheral Nerve Regeneration:Influence of Age and Anatomic Site of Origin[J].Stem Cells and Developme nt,2012,21(11):1852-1862.
[42]Trohatou O,Roubelakis M G.Mesenchymal Stem/Stromal Cells in Regenerative Medicine:Past,Present,and Future[J].Cellular Reprogramming,2017,19(4):217.
[43]Rani S,Ryan A E,Griffin M D,et al.Mesenchymal Stem Cell-derived Extracellular Vesicles:Toward Cell-free Therapeutic Applications[J].Molecular Therapy the Journal of the American Society of Gene Therapy,2015,23(5):812.
[44]Lopatina T,Kalinina N,Karagyaur M,et al.Adipose-Derived Stem Cells Stimulate Regeneration of Peripheral Nerves:BDNF Secreted by These Cells Promotes Nerve Healing and Axon Growth De Novo[J].Plos One,2011,6(3):e17899.
[45]Mizukami H,Yagihashi S.Exploring a New Therapy for Diabetic Polyneuropathy-The Application of Stem Cell Transplantation[J].Frontiers in Endocrinology,2014,5(5):45.
[46]Widgerow A D,Salibian A A,Lalezari S,et al.Neuromodulatory nerve regeneration:adipose tissue-derived stem cells and neurotrophic mediation in peripheral nerve regeneration[J].Journal of Neuroscience Research,2013,91(12):1517-1524.
[47]Ma Y,Ge S,Zhang J,et al.Mesenchymal stem cell-derived extracellular vesicles promote nerve regeneration after sciatic nerve crush injury in rats[J].Int J Clin Exp Pathol,2017,10:10032-10039.
[48]Doeppner T R,Herz J,Görgens A,et al.Extracellular Vesicles Improve Post-Stroke Neuroregeneration and Prevent Postischemic Immunosuppression[J].Stem Cells Translational Medicine,2015,4(10):1131.
[49]Horwitz E M,Dominici M.How do mesenchymal stromal cells exert their therapeutic benefit?[J].Cytotherapy,2008,10(8):771-774.
[50]Carriel V,Alaminos M,Garzón I,et al.Tissue engineering of the peripheral nervous system[J].Expert Review of Neurotherapeutics,2014,14(3):301.
[51]Wakao S,Matsuse D,Dezawa M.Mesenchymal stem cells as a source of Schwann cells:their anticipated use in peripheral nerve regeneration[J].Cells Tissues Organs,2014,200(1):31.
[52]Guo Z Y,Sun X,Xu X L,et al.Human umbilical cord mesenchymal stem cells promote peripheral nerve repair via paracrine mechanisms[J].Neural Regeneration Research,2015,10(4):651-658.
[53]Lee J C,Kim K C,Yang Y S,et al.Microarray analysis after umbilical cord blood derived mesenchymal stem cells injection in monocrotaline-induced pulmonary artery hypertension rats[J].Anatomy&Cell Biology,2014,47(4):217.
[54]Wang H,Qiu X,Ping N I,et al.Immunological characteristics of human umbilical cord mesenchymal stem cells and the therapeutic effects of their transplantion on hyperglycemia in diabetic rats[J].International Journal of Molecular Medicine,2014,33(2):263-270.
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