The relationship of Slit2 and bone marrow mesenchymal stem cells with the angiogenesis

doi:10.3969/j.issn.2095-4344.2014.37.024

Abstract

Abstract:

BACKGROUND: Bone marrow mesenchyme stem cells are important non-hematopoietic stem cells in the bone marrow, which can stimulate angiogenesis. While, Slit can also stimulate angiogenesis, as many studies have proved.
OBJECTIVE: To review the biological functions, clinical application and effects of bone marrow mesenchymal stem cells and Slit2 on promoting angiogenesis.
METHODS: A computer-based online research of CNKI and PubMed databases was performed to collect articles published between 1980 and 2014 with the keywords “MSCs” and “Slit2” in Chinese and English. There were 436 articles after the initial survey. Finally, 65 articles were included according inclusion and exclusion criteria.
RESULTS AND CONCLUSION: Both bone marrow mesenchymal stem cells and Slit2 play an important role in promoting angiogenesis, but the relevance of bone marrow mesenchymal stem cells and Slit2 is still controversial. If assuming that bone marrow mesenchymal stem cells secrete Slit2, more researches should be done to reveal whether bone marrow mesenchymal stem cells promoting angiogenesis is relevant to Slit2 and through which signaling pathway Slit2/Robo functions to adjust bone marrow mesenchymal stem cells thus to promote angiogenesis. If relevant, the transplantation of the Slit2 and bone marrow mesenchymal stem cells will be a promising treatment of cerebral infarction and other central nervous injuries.

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: bone marrow, mesenchymal stem cells, extracellular matrix proteins, angiogenesis inducing agents

CLC Number:

R318

Jiang Lai, Zhang Jin-ning, Chai Yuan, Li Fu-chun, Qu Yan-ping, Ma Xue-ling . The relationship of Slit2 and bone marrow mesenchymal stem cells with the angiogenesis[J]. Chinese Journal of Tissue Engineering Research, 2014, 18(37): 6034-6039.

Figures/Tables 1

2.1 骨髓间充质干细胞 2.1.1 骨髓间充质干细胞概述间充质干细胞是来自于胚胎时期中胚层的一类具有多项分化潜能和自我更新能力的干细胞。广泛存在于全身结缔组织和器官间质内，如脂肪组织、脐血、肝、羊水和胎盘，以及牙髓及其他来源[6-7]。但骨髓组织中的含量最多，它是骨髓内除了造血干细胞之外的另一种干细胞，在骨髓造血过程中起着不可替代的支持和调控造血的作用。 2.1.2 骨髓间充质干细胞的生物学功能多项分化：骨髓间充质干细胞具有向多种细胞系分化的潜能，在体内外不仅可以分化为中胚层细胞系，还可以分化为内胚层和外胚层细胞系。例如，在一定的条件下可分化为骨、软骨、肌肉[8-9]、脂肪等各种间充质组织的细胞。骨髓间充质干细胞也可分化为非间充质细胞，如肝细胞、神经元、神经胶质细胞等。再加上骨髓间充质干细胞取材广泛，易于分离和体外扩增，也避开了很多伦理道德的问题，这些特性使它成为组织工程和再生医学的理想种子细胞类型[10-11]。促进组织损伤修复：首先骨髓间充质干细胞具有迁移到受损伤组织的能力，其次它可以通过释放细胞因子、炎症递质、细胞外基质成分，以及抗微生物蛋白等来产生相应的组织修复微环境的能力。目前已有报道骨髓间充质干细胞在肺损伤、肾损伤以及软骨和长骨修复中起着重要作用[12]。在角膜和视网膜损伤模型中，骨髓间充质干细胞迁移到受伤组织已经证明可改善伤口愈合[13]。旁分泌作用：骨髓间充质干细胞可分泌多种细胞因子[14-16]，如白细胞介素6、白细胞介素7、白细胞介素8、白细胞介素10、白细胞介素12、γ-干扰素、集落刺激因子等。其中部分因子在神经细胞发育及分化过程中发挥重要作用。例如白细胞介素1等促进损伤区神经干细胞的存活、增殖和分化，减小损失范围；而集落刺激因子则作为一种重要生长因子及保护因子，还可通过与相应的受体结合促进损伤区神经干细胞增殖、分化，以减小损伤区范围。目前还有研究发现白细胞介素10、γ-干扰素等可抑制T细胞增殖，从而起到免疫调节作用。骨髓间充质干细胞也可分泌各种各样的神经营养因子，如脑源性神经营养因子、神经生长因子、血管内皮生长因子及其受体、碱性成纤维生长因子等。这些因子能产生神经保护作用和促进局部血管及神经再生，从而治疗神经损伤。例如血管内皮生长因子是目前所知惟一作用于血管内皮的生长因子，它能够促进内皮细胞增殖、从而加快新生血管形成[17-18]；同时可以通过ERK1/2信号通路抑制脑缺血早期神经细胞的凋亡[19]。神经生长因子能够拮抗兴奋性氨基酸毒性作用，稳定细胞内Ca2+浓度，增强抗氧化性酶活性，减轻自由基损伤，延缓神经元凋亡。 2.1.3 骨髓间充质干细胞与血管生成骨髓间充质干细胞与肿瘤：诸多实验观察到骨髓间充质干细胞可以促进肿瘤的生长发展，骨髓间充质干细胞参与构建肿瘤微环境，促进肿瘤血管发生。一方面骨髓间充质干细胞本身可以分化成为内皮细胞、平滑肌细胞等，直接参与肿瘤新生血管形成。另一方面骨髓间充质干细胞可通过外分泌作用分泌一些血管生成因子，可促进肿瘤微环境中血管发生而促进肿瘤血管生成。Fakler等[20]通过对小鼠黑素瘤的研究发现骨髓来源的间充质干细胞向癌组织趋化后，和肿瘤间质融合成为具有内皮细胞特征的细胞，从而促进肿瘤生长。Keung等[21]研究胰腺癌时将动物体内注射骨髓间充质干细胞，可以促进肿瘤的生长，其机制是促使肿瘤组织出现丰富血管系统。但是也有文章报道骨髓间充质干细胞通过Alk信号传导通路的改变对肿瘤的发展有抑制作用[22]，这可能与其实验的组织对象，注射骨髓间充质干细胞的时间不同有关。骨髓间充质干细胞与心脑血管疾病：目前多项研究证实骨髓间充质干细胞移植可应用于心脑血管疾病。Chen等[23]经尾静脉向大脑中动脉闭塞大鼠模型中注入骨髓间充质干细胞，7 d后的感觉实验和14 d后的运动实验明显改善，坏死细胞减少，而碱性成纤维细胞生长因子表达显著增加。专家发现骨髓间充质干细胞可使受体血管生成增加，而血管生成增加是在血管内皮生长因子及血管内皮生长因子受体2介导下进行的。而近年来Ma等[24]建立了大鼠大脑中动脉闭塞模型，并用免疫荧光评估海马α-微管蛋白的表达。最终发现α-微管蛋白在大鼠脑缺血时表达显著减少，这表明α-微管蛋白在脑缺血时是保护性蛋白，而移植骨髓间充质干细胞后能够使α-微管蛋白表达水平在海马区显著上调。且骨髓间充质干细胞移植也可导致血管生成素1和血管生成素2 mRNA表达显著上调。在心肌梗死模型中，骨髓间充质干细胞移植可减少心肌梗死面积，改善左室射血分数和血管密度及心肌灌注的增加[25]。Kinnaird等[26]实验证实骨髓间充质干细胞可分泌血管内皮生长因子、碱性成纤维细胞因子等，促进血管新生，抑制心肌纤维化，从而改善心功能。Tomita等[27]认为增生的血管并非是由骨髓间充质干细胞分化为内皮细胞所致，可能是宿主心肌中的血管再生造成的。这些研究均提示移植的骨髓间充质干细胞能够在局部微环境的作用下依赖微环境而发生分化或通过旁分泌一些细胞活性因子刺激血管新生或再生。 2.2 神经迁移蛋白Slit2 2.2.1 Slit2概述 Slit是一种由神经胶质细胞分泌的细胞外基质蛋白，在体内对神经元轴突的生长进行导向，在体外与感觉轴突侧支发芽和生长有关。近年来发现其不仅表达在神经系统[28]，还可以表达在许多不同组织，例如肺、肾、胎盘、脾脏、心脏等[29]。Slit是一组相对分子质量为170 000-190 000的细胞外分泌蛋白，其结构域组成包括N端短的信号肽、4个连续的富含亮氨酸的重复序列、9个表皮生长因子样功能区，一个ALPS区域和一个C端富含半胱氨酸的区域[30-31]，在哺乳动物体内发现3种同源的Slit2蛋白，即Slit1-Slit3，而目前研究较多的即是Slit2。Robo1是Slit2的跨膜受体，需要与之结合共同发挥作用。这一传导通路不但能够指引轴突导向[32]，神经细胞迁移[33]，白细胞趋化[34]，而且还在血管生成及肿瘤等方面发挥作用[35]。 2.2.2 Slit2研究现状抗炎作用：一项早期研究表明曾有报道Slit2的抗炎作用。服用外源性Slit2可快速抑制进行性抗肾小球基膜型肾炎中的白细胞渗透、新月体形成和肾功能不全。这个研究中，肾炎患者的内生肾小球性Slit2水平显著降低，Slit2可能起着对抗白细胞的作用[36]。最近，研究发现在缺血再灌注损伤时，肾小管间质中Slit2水平也下降，并且外源性Slit2会阻止中性粒细胞捕获、黏附和穿过缺血再灌注损伤的内皮细胞迁移。这种阻断作用在小鼠急性缺血性肾损伤中，与中性粒细胞低渗透、血管损失和肾功能不全有关[37]。类似地，在气管内给予脂多糖后，服用Slit2可减弱中性粒细胞渗透，肺血管漏和肺损伤[38-39]。这些临床前期的研究综合在一起提示了使用Slit2或其类似物可能会阻止与炎症相关的急性血管损伤。经研究证实Slit2/Robo是白细胞趋化的内源性抑制因子，在炎症反应中能抑制中性粒细胞、淋巴细胞及巨噬细胞的迁移，它主要通过抑制Rho家族GTP酶的极性和活化来发挥作用[40-41]。 Slit2与肿瘤关系：据报道Slit2是不同的肿瘤中一个潜在的肿瘤抑制基因，许多实体瘤如恶性黑色素瘤、乳腺癌、鳞状胃癌和肝癌等存在分泌性Slit2因子[42-45]。牛蕾等[46]采用免疫组化方法检测到Slit2在乳腺癌组织中的表达水平低于正常乳腺组织，提示该蛋白表达缺失可能和乳腺癌的发生有关。且实验还提示Slit2与雌激素受体、孕激素受体表达呈正相关，说明Slit2可能与乳腺癌发展及预后有关。Kim等[47]研究发现，乳腺癌组织中Slit2基因甲基化频率明显高于正常乳腺组织，提示肿瘤组织中Slit2基因发生甲基化从而使其表达降低。而与Slit2相结合的受体不同对肿瘤的发展也不同，例如Robo1可调节血管内皮细胞向肿瘤内迁移，促进肿瘤的新生血管形成从而促进肿瘤快速生长[48]；而敲除斑马鱼体内的Robo4后会导致血管发育延迟[49]。Robo4被认为是肿瘤内皮细胞的标志，说明Slit2/Robo4抑制内皮细胞的迁移[50]，即抑制肿瘤生长。 Slit2/Robo信号传导与血管再生：Slit2/Robo信号传导在调节血管生成过程中很复杂，既有促血管生成作用，又有抗血管生成作用[51]。早期报道显示Slit2对Robo1受体有促血管生成作用，它促进内皮细胞迁移和血管成形[52]。同样地，曾报道Robo1信号对血管内皮生长因子诱导其受体VEGFR2磷酸化的过程中(尤其在有Slit2参与时)起重要作用[48]。而Slit2/Robo4抗血管生成的作用，在Robo4为主的情况下，Slit2抑制血管内皮生长因子诱导的微血管内皮细胞迁移和血管成形[53]。有研究证明Slit2/Robo4活化作用干扰内皮细胞血管内皮生长因子信号，这可能是通过阻止MAP激酶和Arf小GTP酶活化[52,54]。一个最新报道也显示Robo4本身可能作为另一种内皮引导受体(UNC5B)的配体来抑制血管内皮生长因子信号传导[55]。最新研究理论显示Slit2的作用可能取决于细胞类型和/或环境[51]。例如发现促血管生成作用的研究与发现Slit2抗血管生成作用的研究之间的主要区别点是所用的内皮细胞类型不同。Slit2执行促血管生成作用的大多数研究用的是一种大血管内皮细胞(人脐静脉内皮细胞)，而相反，证明Slit2的抗血管生成作用的研究用的则是微血管内皮细胞[53-54]。这种区别的重要性不能低估，因为微血管内皮细胞的Robo4/Robo1值比大血管内皮细胞的值高很多，致使它更倾向于抗血管生成而非促血管生成[56]。 2.3 Slit2与骨髓间充质干细胞经研究发现Slit2可以促进静态造血干细胞进入细胞周期，而Robo4起着造血干细胞的骨髓归巢作用[57]，在紧急造血时，可促进造血干细胞高表达。同时Robo4在骨髓内皮细胞选择性表达，而在骨髓间充质干细胞中可高表达[58]，并在其侧群表型的调控中起关键作用[59]。Robo4对造血干细胞所起的调控作用与骨髓间充质干细胞促进血管再生有无关系目前还研究甚少。"

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