Chinese Journal of Tissue Engineering Research ›› 2013, Vol. 17 ›› Issue (14): 2617-2624.doi: 10.3969/j.issn.2095-4344.2013.14.022
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Lü Wei-liang, Liao Yi, Tong Ting-hui
Received:
2012-07-21
Revised:
2012-09-08
Online:
2013-04-02
Published:
2013-04-02
About author:
Lü Wei-liang★, Studying for Master’s degree, Department of Burn and Plastic Surgery, Luzhou Medical University, Luzhou 646000, Sichuan Province, China
duxiyiren2@163.com
CLC Number:
Lü Wei-liang, Liao Yi, Tong Ting-hui. Research progress in osteogenic differentiation of stem cells induced by estrogen[J]. Chinese Journal of Tissue Engineering Research, 2013, 17(14): 2617-2624.
2.1 雌激素诱导骨髓间充质干细胞成骨的研究成果 骨髓间充质干细胞位于成体骨髓中,是成骨细胞与破骨细胞的祖先。具有强大的增殖能力及多向分化潜能。在不同的诱导条件下, 可使其向成骨细胞、脂肪细胞、软骨细胞、成肌细胞、神经细胞等方向分化[5-7]。作为最主要的骨组织工程种子细胞已经广泛应用。 在对雌激素与骨代谢的研究中发现,骨髓间充质干细胞的终末分化细胞:成骨细胞与破骨细胞均已发现雌激素受体表达。提示在骨髓间充质干细胞上可能存在雌激素受体。张进等[7]证实了在骨髓间充质干细胞上确实存在雌激素的受体,并且雌激素可直接通过其受体作用于骨髓间充质干细胞。体内具体影响过程是雌激素通过血液循环到达骨, 与骨髓间充质干细胞内的雌激素受体作用,促进细胞基因转录合成骨形态发生蛋白2。骨形态发生蛋白2具有高度诱导成骨的活性,通过自分泌或旁分泌的方式促进骨髓间充质干细胞向成骨细胞分化[8]。 间充质干细胞是骨生长和骨修复的细胞来源,成骨细胞由骨髓间充质干细胞在体内的各种调控因素的调节下发展而来,调控因素主要有骨形态发生蛋白,骨形态发生蛋白能促进间充质干细胞向成骨细胞的分化和骨基质的形成,而雌激素对成骨细胞的分化发挥重要的介导作用。 张晓丽[9]总结了雌激素在骨髓间充质干细胞中的表达和作用。在骨重建的过程中,雌激素分泌入血液,通过血液循环到达骨,与间充质干细胞内的雌激素受体作用,促进细胞转录并合成骨形态发生蛋白2,骨形态发生蛋白2在局部以自分泌或旁分泌的方式进而促进间充质干细胞向成骨细胞分化。在促进骨髓间质干细胞成骨细胞的分化同时阻止骨髓脂肪细胞的生成。绝经期妇女,雌激素水平下降,使间充质干细胞向成骨细胞分化的能力降低而向脂肪细胞分化增强,即骨量减少和骨髓中的脂肪组织增多同时发生,从而引起的骨丢失导致骨髓腔增大,骨皮质变薄,小梁骨量减少,最终引发骨质疏松。此外,骨重建的速率由骨吸收和骨形成的循环数决定,骨量则取决于每个循环中骨吸收和骨形成是否平衡。近年的研究表明雌激素缺乏可降低成骨细胞从其前体细胞分化的速率,从而使骨重建循环的次数减少,导致骨量减少。 长期以来骨髓间充质干细胞的体外培养是一个难题。因为其分化后数量及能力的损失,体外有限的扩增数量,以及体内识别的困难,限制了其实际应用。Gopalakrishnan 等[10]通过对糖尿病导致的骨质疏松进行实验研究,证明胰岛素和雌二醇能控制高浓度葡萄糖对骨髓源性基质细胞成骨细胞的增殖和功能的有害影响。DiSilvio等[11]通过实验测试证实了雌激素能刺激人类初级成骨细胞或人骨髓间充质干细胞增殖,但是对于人骨髓间充质干细胞的增殖影响可能存在高剂量依赖性,这需要进一步证明。接着Hong等[12-14]对雌激素诱导骨髓间充质干细胞进行了进一步研究,先是以17β-雌二醇和地塞米松作为培养骨髓间充质干细胞的调节器,并按照浓度不同进行分组。通过MTS法测定细胞增殖数,ELISA及PCR评估成骨标志物和类固醇相关的生长因子转化生长因子β1与骨形态发生蛋白7,检查骨髓间充质干细胞的成骨细胞增殖和分化情况。发现雌激素作用后骨髓间充质干细胞的增殖与分化的情况有所提高。提出类固醇可能作为一有效诱导剂促进干细胞的骨再生能力的结论。为改善和优化骨髓间充质干细胞骨再生并为今后的临床应用提供了重要的信息。 紧接着将雌二醇应用在体外培养人类骨髓间充质干细胞中,并对细胞增殖数、细胞标志物,细胞分化后成骨细胞与脂肪细胞进行检验、实验表明雌二醇的补充能保持干细胞的增殖维持细胞分化特征。证明了在改善人类骨髓间充质干细胞体外扩张中雌激素可以发挥重要作用。提出了在实际组织工程应用中雌激素能有效地促进骨髓间充质干细胞增殖及分化的设想。但是在此实验中雌激素作用的时间短,而且也非持续作用于骨髓间充质干细胞。为了解决这个问题,Hong等制备了具有负载雌二醇的聚乳酸-聚乙醇酸共聚物颗粒。此聚乳酸-聚乙醇酸共聚物颗粒可以保持长达7 d雌二醇释放。将聚乳酸-聚乙醇酸共聚物应用于体外培养人类骨髓间充质干细胞,主要检验了成骨分化标记碱性磷酸酶和骨钙素,发现人骨髓摄取共聚物微粒的雌二醇后碱性磷酸酶及骨钙素显著上调。此实验为骨髓间充质干细胞体外培养建造了一个持续雌激素释放的微环境,一部分模拟了体内干细胞生长环境。比起以往的实验更加有说服能力,而且为干细胞体内移植提供了参考信息。 LIM矿化蛋白是近期发现的诱导成骨细胞分化成熟的细胞内信号因子,促进称骨细胞分化和骨形成,其中LIM矿化蛋白1有诱导成骨能力。杨军等[15]从切除卵巢的小鼠骨髓中提取骨髓间充质干细胞,建立实验进行成骨诱导,对各组LIM矿化蛋白1的mRNA表达进行测定,证实加入雌二醇的实验组中LIM矿化蛋白1的mRNA表达显著高于未处理组。由于长期的体内雌激素不足,骨髓间充质干细胞表现出较低的增殖率与成骨能力[16]。Chen等[17]通过从患有骨质疏松症的绝经后妇女髂骨中提取骨髓间充质干细胞,通过实验检验证实雌二醇通过雌激素受体α增强成骨活性。最新研究表明雌激素不仅能促进骨髓间充质干细胞的增殖还能抑制骨髓间充质干细胞的细胞凋亡,主要机制是通过保护线粒体跨膜电位,减少细胞凋亡抗体caspase-9,c-Jun氨基端激酶(JNK1/2)和原癌基因c-Jun蛋白的表达进而在细胞线粒体死亡途径和JNKs途径发挥抗凋亡的作用同时上调抗凋亡基因Bcl-x(L)和Bcl-2的表达降低骨髓间充质干细胞凋亡率[18-20]。 雌激素通过直接间接作用于骨髓间充质干细胞从而在诱导骨髓间充质干细胞成骨中体现出促进骨髓间充质干细胞增殖,维持骨髓间充质干细胞特性,提高骨髓间充质干细胞成骨能力,并且还有抗细胞凋亡的作用。推论出雌激素能作为一个有效的抗细胞凋亡及诱导剂应用在骨髓间充质干细胞诱导成骨中。 2.2 雌激素诱导脂肪干细胞成骨的研究成果 脂肪干细胞由Zuk等[21]首次报道,是近年来从脂肪组织中分离得到的与成纤维细胞样细胞和骨髓间充质干细胞形态相似的一种具有多向分化潜能的干细胞。脂肪干细胞经过一定的定向培养后,可以分化为成骨细胞、软骨细胞、肌细胞、内皮细胞等成熟组织细胞[22]。聂绪强等[23]就脂肪干细胞的不同培养方法、诱导分化及最新的临床应用进行阐述。由于脂肪干细胞具有储备量大,提取容易, 提取部位广,机体损伤小,增殖速度快等特点,受到越来越多的关注,尤其是在骨与软骨组织工程上[24]。有研究表明雌激素可以调节脂肪干细胞的分化并且可能改善脂肪干细胞为基础的组织工程及再生[25]。 脂肪源间充质干细胞与骨髓间充质干细胞同样来至于中胚层,并且在脂肪干细胞上已发现雌激素受体的表达[26]。提示雌激素能通过受体作用于脂肪干细胞。Dudas等[27]报道了脂肪干细胞在成骨上的潜力,并且提出雌激素信号与其成骨机制有关的结论。陈昕等[28]观察了雌激素对诱导老年大鼠脂肪干细胞体外增殖和成骨分化的影响,通过MTT法测试,骨茜素红染色,RT-PCR检测,证明17-β雌二醇能增强老年大鼠脂肪干细胞体外增殖与诱导成骨分化能力。贾竹亭等[29]开展了雌激素诱导新西兰兔脂肪组织来源的干细胞成骨的实验。首先建立了不同雌激素浓度培养的脂肪干细胞组,在光镜下观察不同组细胞形态、生长特性和碱性磷酸酶染色后反应,证明培养出成骨细胞。然后进一步检验AFP活性,发现虽然0 mol/L雌激素组细胞增殖较快,但是AFP活性明显低与其他雌激素组。通过不同时期光镜下计算钙结节数,在诱导第10天10-8组首次发现钙结节,第20天10-8,10-9,10 -10 mol/L 组均可观察到大量钙结节形成,但是3组无差异性,而0 mol/L组与10-11 mol/L组增长缓慢有差异性。贾竹亭等[29]在得出实验结果后分析了雌激素如何对脂肪干细胞进行作用。第一、雌激素直接作用于脂肪干细胞受体。在低浓度范围内作用,雌激素能有效刺激细胞增殖,并且作用成剂量依赖关系。这与DiSilvio 的报道一致。虽然实验结果中表现出来的碱性磷酸酶差异性不大,但是在钙沉积方面雌激素的作用更加突出。第二、雌激素对脂肪干细胞间接作用效应:雌激素可作用于脂肪干细胞分泌细胞因子,如转化生长因子β,骨形态发生蛋白2等,这些细胞因子发挥诱导或促进脂肪干细胞成骨分化的作用。此间接效应与在骨髓间充质干细胞成骨中的间接效应有很大程度上的相似性。国外Taskiran等[30]分离出大鼠内脏脂肪组织中的脂肪干细胞,同样制备了不同浓度的雌二醇诱导成骨细胞的培养基,并通过von Kossa染色,碱性磷酸酶活性测量和钙离子水平评估,证明了雌二醇有刺激脂肪干细胞体外成骨分化潜能,可以用来作为一种诱导剂以提高效率。但是在研究中发现,脂肪干细胞的细胞增殖是由雌激素外的其他因素负责[31]。 上述雌激素诱导脂肪干细胞成骨实验中表明,雌激素能通过直接作用于脂肪干细胞上的雌激素受体和促进细胞因子的分泌诱导脂肪干细胞成骨,并且在钙沉积上雌激素体现出了突出的作用。 2.3 雌激素诱导胚胎干细胞成骨的研究成果 胚胎干细胞是一种高度未分化细胞。具有能发育为成体动物的所有组织和器官的全能性和无限增殖的能力,即胚胎干细胞经过一定的定向培养后,能被诱导分化为机体几乎所有的细胞类型[32-33]。当Reubinoff等[34]分离出第一个细胞系时,它体现出来的潜力使它成为最有前景的种子细胞之一。目前已有报道研究表明雌激素能增加胚胎干细胞神经定向分化诱导[35-36]。而对诱导胚胎干细胞分化成骨细胞的同时,还发现胚胎干细胞分化出血管内皮细胞,两种分化的细胞按照比例混合后仍然能继续在支架材料上培育和移植,此特点解决了实验后期重新建立血供的难题[37]。 雌激素作用于胚胎干细胞也可以分为直接作用于间接作用。直接作用:胚胎干细胞上也存在相应的雌激素受体及相关表达[38],已有相关报道小鼠胚胎干细胞膜雌激素受体的快速通路[39]。雌二醇刺激胚胎干细胞上相应受体提高蛋白水平,增加原癌基因 (c-fos,c-jun和c-myc)的mRNA表达,提高细胞周期蛋白D1以及细胞周期蛋白依赖性激酶2(CDK2)和CDK4水平,降低CDK抑制物P21(CIP1)和p27(kip1)的水平从而促进胚胎干细胞增殖[40]。在对胚胎干细胞研究中发现Oct4,Sox2和Nanog是胚胎干细胞的自我更新调节转录因子,对胚胎干细胞的特异性表达有重要意义。van den Berg DL等[41]通过研究表明雌激素受体β可以与Oct4相互作用,积极调控Nanog基因的表达。从而影响胚胎干细胞的分化。间接作用:钙是一种普遍的第二信使,使用共聚焦显微镜在胚胎干细胞上发现了钙池操纵的钙入口(SOCE)。在胚胎干细胞的培养中加入SOCE阻滞剂和抑制剂发现,胚胎干细胞的增殖减少并存在浓度依赖性。证明SOEC是胚胎干细胞增殖重要信号通路。实验中还发现转录因子Sox-2,Klf-4,Nanog作用下降,表明SOCE不仅影响着胚胎干细胞增殖,还影响了其自身更新的特性。雌激素介导的刺激对SOCE的主要作用是促进其扩散,进一步有效促进胚胎干细胞的增殖[42]。另外还有报道称雌激素通过PI3K/Akt, ERK1/2等信号通路上调caveolin-1刺激胚胎干细胞增殖[43]。Tielens等[44]研究了抗坏血素,地塞米松,雌二醇对胚胎干细胞成骨分化的影响。实验中通过免疫组织化学法检测了成骨细胞标志物如碱性磷酸酶,转录因子核心结合因子α1和骨钙素,并通过电子显微镜观察了胶原纤维沉积和矿化基质。实验中发现雌二醇培养基碱性磷酸酶的活性逐渐上升,在培养21 d后下降;核心结合因子α1在培养14 d后首次发现,并在后面的培养中继续增加。对比抗坏血素培养基和加入地塞米松的抗坏血素培养基,雌二醇培养基中观察到高数量的成骨样细胞更多,骨样结节更少,并且雌二醇培养基中观察到的胚胎干细胞骨钙素浓度比对照组的多,有差异性。证明雌激素能促进胚胎干细胞诱导成骨。 雌激素可以刺激胚胎干细胞上受体基因介导蛋白激酶,激酶和原癌基因促进胚胎干细胞增殖,保护胚胎干细胞的分化特性的完整性[45],同时也可以直接和间接影响胚胎干细胞重要转录因子,调控胚胎干细胞分化能力。在雌激素诱导胚胎干细胞成骨实验中培育出大量的成骨细胞没有被包裹在骨样结节中,为骨组织工程纯化成骨样细胞创造了可能[44]。"
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