Mechanism of umbilical cord mesenchymal stem cell therapy for metabolic syndrome

doi:10.3969/j.issn.2095-4344.2015.01.026

Abstract

Abstract:

BACKGROUND: Studies have shown that stem cells are directly involved in injury repair, secretion of growth factors to promote wound healing, improvement of blood circulation and promotion of angiogenesis, regulation of immune and inflammation, oxidative resistance, which may be used to treat a variety of chronic diseases.
OBJECTIVE: To review the mechanism of umbilical cord mesenchymal stem cell therapy for metabolic syndrome.
METHODS: A computer-based search of VIP, CNKI and PubMed was performed for articles concerning stem cell transplantation therapy for metabolic syndrome published from January 2004 to October 2014. The search terms were “stem cells, umbilical cord-derived mesenchymal stem cells, stem cells transplantation, metabolic syndrome, insulin resistance, diabetes, hyperlipidemia” in Chinese and English, respectively. Finally, 42 articles were included in result analysis.
RESULTS AND CONCLUSION: Umbilical cord mesenchymal stem cells have the ability of self replication and differentiation, which are ideal seed cells for cell replacement therapy. Meanwhile, umbilical cord mesenchymal stem cells also have paracrine and immunomodulatory functions. Currently, technologies for isolation, culture, identification and in vitro amplification of umbilical cord mesenchymal stem cells are quite mature. Moreover, stem cell transplantation as a new method for the treatment of metabolic syndrome can fundamentally make the target organ damage better as well as improve insulin resistance and glucose and lipid metabolism disorder, which have been proved in animal experiments. However, there are still many clinical problems to be solved.

中国组织工程研究杂志出版内容重点：干细胞；骨髓干细胞；造血干细胞；脂肪干细胞；肿瘤干细胞；胚胎干细胞；脐带脐血干细胞；干细胞诱导；干细胞分化；组织工程

全文链接：

Key words: Umbilical Cord, Mesenchymal Stem Cells, Metabolic Syndrome X

CLC Number:

R318

Hu Shuang-shuang, Pan Xing-hua . Mechanism of umbilical cord mesenchymal stem cell therapy for metabolic syndrome[J]. Chinese Journal of Tissue Engineering Research, 2015, 19(1): 146-150.

Figures/Tables 1

2.1 目前应用于治疗代谢综合征的干细胞干细胞是生命的起源细胞，组织器官生长发育的原始细胞，成体组织细胞更新换代、损伤修复的种子细胞，具有自我更新、高度增殖和多向分化潜能。临床前和临床研究的证据表明，在许多情况下用干细胞治疗是安全并且有效的。在临床研究中，干细胞移植可用于治疗多种慢性疾病，如肌肉和骨骼疾病、心血管疾病、肝病、自身免疫性疾病、神经退行性疾病、脑损伤、肾损伤、2型糖尿病及其并发症等[5-9]。目前应用于治疗代谢综合征的干细胞主要有胚胎干细胞、骨髓间充质干细胞和脐带间充质干细胞等。胚胎干细胞(embryo stem cell，ES)是来源于植入前胚泡的内细胞团的细胞和原始生殖细胞，具有体外培养无限增殖、自我更新和多向分化特性的全能干细胞。成体干细胞可来源于骨髓、脐带和脂肪组织等。骨髓间充质干细胞是一群广泛存在于造血系统以及结缔组织中的干细胞，主要存在于骨髓非造血组织，它具有分化成多种细胞类型的潜能[10]。脐带间充质干细胞主要来自中胚层，是从出生后废弃的胚外组织中分离获得的一种具有多向分化潜能的干细胞，可以分化成几种特定类型的细胞如脂肪细胞、成骨细胞、软骨细胞，也反分化为其他细胞系如肌肉细胞和神经元[11]。脂肪干细胞是从脂肪组织中分离得到的一种具有多向分化潜能的干细胞，其单位质量干细胞含量是骨髓的500倍[12]。胚胎干细胞由于道德伦理问题，临床研究和应用很少。骨髓间充质干细胞来源于骨髓，容易取材、免疫原性低，但在骨髓中的含量极低，仅占骨髓有核细胞总数的0.001%，并且随着年龄的增加或体质的衰弱，细胞数目和分化潜能逐渐降低[13]。脐带间充质干细胞主要来自于脐带或胎盘组织，取材更为方便，细胞来源充足，是一种更原始的间充质干细胞群，更适合异基因移植[14]，与胚胎干细胞相比较不受伦理限制以及移植后转化为肿瘤细胞的危险等困扰，比一般的成体干细胞具有更高的分化潜能和增殖能力，故脐带间充质干细胞可以作为治疗代谢综合征的首选种子细胞。 2.2 脐带间充质干细胞治疗代谢综合征可能作用机制代谢综合征的临床症状包括腹部肥胖或超重、脂代谢异常、高血压、糖尿病、胰岛素抵抗和糖耐量异常。目前的调查研究表明，超重/肥胖个体倾向于胰岛素抵抗[15]，胰岛素抵抗是代谢综合征的核心发病机制。代谢综合征主要涉及心血管、代谢、肝脏、胰腺和肾脏的病理改变，容易诱发高血压病、冠心病、2型糖尿病、动脉粥样硬化、肝代谢异常、肾损伤等。现阶段的研究证实，干细胞移植可以降低高血糖、高血脂，改善外周组织对胰岛素介导的葡萄糖的摄取[16]，不仅能改善代谢综合征的临床症状，而且能从根本上对其进行治疗。 2.2.1 脐带间充质干细胞对损伤细胞的修复及再生作用目前应用于代谢综合征治疗的干细胞为全能或多能干细胞，干细胞经静脉进入机体后归巢至损伤部位，通过多种方式直接或通过分泌细胞因子间接参与损伤组织细胞的修复，补充被代谢综合征破坏的细胞库，改善甚至逆转靶器官损害。当机体的组织和细胞受到损伤时，吞噬细胞释放炎症分子如肿瘤坏死因子α、白细胞介素1β、自由基和趋化因子。受损的细胞、血管以及这些炎症分子激活免疫细胞和炎性细胞如巨噬细胞、中性粒细胞、CD4+和CD8+ T细胞和B细胞。这些免疫细胞、炎症分子、成纤维细胞和内皮细胞改变受损组织的微环境，使得干细胞被招募到此并且分化，替换受损组织细胞[17-20]。此外，包括肿瘤坏死因子α、白细胞介素1，γ-干扰素和缺氧等许多因素可以刺激干细胞分泌生长因子，如表皮生长因子(EGF)，成纤维细胞生长因子(FGF)，血小板衍生的生长释放因子(PDGF)，转化生长因子β(TGF-β)，胰岛素样生长因子1(IGF-1)和血管生成素1(Ang-1)等[21-23]。这些生长因子反过来促进成纤维细胞、内皮细胞等进行组织再生和修复的发展。 2.2.2 脐带间充质干细胞促血管再生改善血液循环的作用临床前和临床证据表明，干细胞移植治疗可促进血管再生和更换受损心肌细胞，从而改善血液循环。干细胞可以通过直接分化和旁分泌机制造成血管再生。干细胞可以直接定植于伤口组织并进入脉管系统改善血管生成。干细胞还可以分泌生物活性水平量的促血管生成分子，如血管内皮生长因子、肝细胞生长因子、碱性成纤维细胞生长因子、转化生长因子β和胰岛素样生长因子1，促进血管的自我修复[24]。干细胞不仅能直接修复损伤的心肌细胞，增强心肌细胞的收缩性，还可以促进血管生成因子的表达促进新生血管形成，改善心脏功能的多种参数，包括左室短轴缩短率和室壁运动积分指数等[25]。 2.2.3 脐带间充质干细胞对胰岛素抵抗的作用胰岛素抵抗是指胰岛素作用的靶器官如肝脏、肌肉、脂肪等对胰岛素作用的敏感性下降，即正常剂量的胰岛素产生低于正常生物学效应的一种状态。干细胞来源的β细胞补充破坏的胰岛细胞库β细胞，不仅可以恢复原来的胰岛素分泌模式，也可以阻断自身免疫定向破坏β细胞的免疫调节作用的恶性循环[26]。干细胞移植可以促进β细胞的功能，还可以增加GLUT4的表达和胰岛素受体底物1(IRS-1)和Akt(蛋白激酶B)磷酸化，促进胰岛受体与胰岛素的结合，降低胰岛素的抵抗作用[27]。 2.2.4 脐带间充质干细胞参与免疫调节与抗炎近年来有证据表明，干细胞除了分化能力和参与组织修复，还具有强效的免疫调节功能。脐带间充质干细胞与骨髓间充质干细胞有相似的免疫表型、分化能力和免疫抑制能力，在静息状态和受γ-干扰素刺激后，脐带间充质干细胞表达HLA-Ⅰ的水平显著降低，与骨髓间充质干细胞比较能生产更多的致耐受性的转化生长因子β和白细胞介素10[28-29]。干细胞自身可以作为抗原呈递细胞，具有吞噬功能和诱导T细胞应答能力的功能。干细胞可以通过产生的可溶性因子改变树突状细胞的分泌曲线，使白细胞介素10、抗炎细胞因子的产量增加，γ-干扰素和白细胞介素12的产量减少。干细胞可以通过抑制T细胞的产生，增加CD4+、CD25+、FoxP3+的T调节细胞的数量，从而抑制免疫反应[30-32]。干细胞可促进B细胞的增殖、终末分化为浆细胞和抗体分泌[33]。最近的研究表明，未受刺激的干细胞无法抑制免疫反应，当活化淋巴细胞的上清液，或者用γ-干扰素和肿瘤坏死因子α，白细胞介素1α或白细胞介素1β结合刺激时，它们的免疫抑制效应增强[33]。间充质干细胞免疫原性差，适合自体和异体移植，同样适用于自身免疫性疾病的治疗[34]，并且已被用于治疗类风湿关节炎、系统性红斑狼疮、多发性硬化症、1型糖尿病及其相关并发症[34-40]。最近的研究表明，脐带间充质干细胞移植可以通过增加抗炎因子白细胞介素10的表达和降低促炎因子肿瘤坏死因子α、巨噬细胞炎症蛋白2和γ-干扰素的表达来控制炎症状态[41]。 2.2.5 脐带间充质干细胞与抗氧化应激在应激反应和能量代谢中，活性氧具有调节诱导细胞增殖生长信号的作用。然而，由于不断的氧化应激或不可挽回的DNA损伤，活性氧积累在细胞中，其可通过p53途径导致细胞凋亡或衰老。为了防止活性氧的积聚，细胞有几种抗氧化系统包括酶和氧化还原敏感分子(Trx，APE1/ Ref-1)，它保护细胞免受氧化应激。Bassiouny等[42]的研究证明，脐血单个核干细胞可以维持APE1的高水平，保护细胞免受氧化应激的损害。"

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