Chinese Journal of Tissue Engineering Research ›› 2017, Vol. 21 ›› Issue (17): 2746-2752.doi: 10.3969/j.issn.2095-4344.2017.17.020
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Chen Yu-hao1, 2, Zhu Xiang-qing1, Pan Xing-hua1
Revised:
2017-01-20
Online:
2017-06-18
Published:
2017-06-29
Contact:
Pan Xing-hua, M.D., Chief physician, Master’s supervisor, Cell Biological Therapy Center of Kunming General Hospital of Chengdu Military Area of Chinese PLA, National and Regional Integrated Engineering Laboratory of Stem Cells and Immunocyte Biological Technology, Stem Cell Engineering Laboratory of Yunnan Province, Key Laboratory of Stem Cells and Regenerative Medicine of Kunming City, Kunming 650032, Yunnan Province, China
About author:
Chen Yu-hao, Studying for master’s degree, Cell Biological Therapy Center of Kunming General Hospital of Chengdu Military Area of Chinese PLA, National and Regional Integrated Engineering Laboratory of Stem Cells and Immunocyte Biological Technology, Stem Cell Engineering Laboratory of Yunnan Province, Key Laboratory of Stem Cells and Regenerative Medicine of Kunming City, Kunming 650032, Yunnan Province, China
Supported by:
the National Support Project of China, No. 2014BIO1B01; the Major Project of Kunming City, No. 2015-1-S-00973
CLC Number:
Chen Yu-hao, Zhu Xiang-qing, Pan Xing-hua. Bone marrow mesenchymal stem cells: aging features and relevant treatments[J]. Chinese Journal of Tissue Engineering Research, 2017, 21(17): 2746-2752.
2.1 骨髓间充质干细胞的生物学特征 国际细胞治疗学会(International Society For Cellular Therapy,ISCT)用以下标准来定义间充质干细胞:在单层细胞培养时贴壁生长;在标准的体外分化条件下有分化成软骨细胞、成骨细胞和脂肪细胞的潜能;表达CD105、CD73、CD90,而缺乏CD45、CD34、CD14、CD11b、CD79α、CD19和HLA-DR等表面标志[3]。这些标准尽管方便实用,但对群体研究的帮助非常有限,因为他们是基于人为的体外观察,而骨髓间充质干细胞的免疫表型可由体外培养人为改变,体内的情况更为复杂,通过免疫标记进行研究会使得结果不那么可靠[4]。与此同时,其他可能的阳性和阴性抗原标记也被其他研究者提出,甚至是有着显著差异的骨髓间充质干细胞抗原标记组合,因此,关于骨髓间充质干细胞特征的标准还有待商榷[5]。 现在普遍认为CD271是间充质干细胞最一致的标记之一,而且CD271+间充质干细胞是决定细胞增殖和分化能力的重要因素[5]。也有研究者发现,CD146+间充质干细胞经过12周的体外扩增培养,不仅能向成骨、成软骨、成脂和造血基质细胞分化,还能够分泌生长因子复合物,调节造血干细胞的分泌[6],虽然CD146的表达在人群中是不一致的,但Sacchetti等[7]发现CD146+CD45-细胞亚群在人的骨髓间充质干细胞中数量丰富,CD146的表达可作为骨髓间充质干细胞区别于其他成骨细胞系的标志之一。体内细胞活性分析所得出的结论最为可靠。因此,CD146可能是骨髓间充质干细胞或早期骨髓间充质干细胞祖细胞亚群特征性的标记。Delorme等[8]也认为,CD146是骨髓间充质干细胞相较于造血干细胞特有的标记,能在体外分化出软骨、骨和脂肪细胞。此外,随着年龄增加,骨髓间充质干细胞表达CD146将会减少[9]。 总之,在骨髓间充质干细胞系的特征性标志上还没有一致的观点。人体的免疫功能随着一些不同的细胞衰老而降低,而更多的炎性细胞因子存在于高龄患者体内,这也许意味着老年人骨髓间充质干细胞存在一个生物学上更具挑战的环境,他们也是最需要细胞治疗的人群。 2.2 骨髓间充质干细胞的衰老特征 骨髓间充质干细胞的衰老是一种极其复杂的生理过程,易受微环境的影响。有实验表明,老年小鼠的内环境能够抑制成体干细胞的功能[10]。衰老多源于骨髓间充质干细胞的不断增殖,在细胞增殖的过程中易出现DNA损伤,当DNA损伤积累到一定程度时,即可能导致细胞周期调控发生异常,甚至出现恶变。长期体外培养的细胞会发生自发转化,转化的骨髓间充质干细胞表现出衰老的特点,出现端粒逐渐缩短,细胞再生能力减弱[11]。另外,骨髓间充质干细胞作为脂肪细胞和骨细胞的共同祖细胞,随着细胞老化,成骨-成脂分化的平衡被打破,骨髓间充质干细胞更倾向于分化为脂肪细胞[12]。 衰老的骨髓间充质干细胞对活性氧的敏感性增加,对心肌梗死的治疗效果减弱。Li等[13]将衰老的骨髓间充质干细胞移植到急性心肌梗死模型大鼠上,梗死区域衰老骨髓间充质干细胞的存活率迅速降低。也有其他研究者发现,快速老化小鼠的骨髓间充质干细胞周期停滞在G0/G1期,细胞内活性氧增加,可能是由于衰老导致免疫系统紊乱[14]。由此可见,活性氧水平是观察骨髓间充质干细胞衰老的重要指标。与此同时,衰老骨髓间充质干细胞的细胞因子和趋化因子受体减少,受损部位骨髓间充质干细胞的活化和动员能力降低[15],因而组织修复能力明显减弱。骨髓间充质干细胞的抗氧化能力和迁移能力都会因细胞衰老而减弱。Choudhery等[16]发现衰老小鼠的口愈合、血管生成、增殖和抗凋亡能力下降,伴随着依赖于烟酰胺腺嘌呤二核苷酸的组蛋白脱乙酰酶(SIRT1)表达降低,也一定程度上抑制了骨髓间充质干细胞功能。 衰老的骨髓间充质干细胞也能改变组织微环境,通过分泌细胞因子和生长因子影响肿瘤的生长、转移和血管生成[17]。 2.2.1 骨髓间充质干细胞衰老的诱发因素 衰老作为一种复杂的生命过程,有多种因素参与并发挥重要作用,主要包括体内信号通路中某个因子的基因突变、转录调节因子的异常调节作用、染色体状态异常及外界环境的改变等。 随着年龄增加,成体干细胞的功能性储备会逐渐减少,组织器官的再生潜能在很大程度上减弱了。将骨髓间充质干细胞进行长期体外培养,细胞会逐渐衰老,多能性、增殖能力和分化潜能降低。骨髓间充质干细胞的寿命与功能受到氧化应激的影响,通常,增加活性氧会抑制间充质干细胞的增殖,提早出现衰老,成脂分化增多,而成骨分化减少,抑制间充质干细胞的免疫调节功能[18]。过量的自由基会造成不利的分子改变,通过脂肪、蛋白质、RNA和DNA氧化,导致衰老、突变和癌变。细胞内活性氧的水平与细胞衰老存在显著联系[19]。而Yang等[20]认为活性氧是双刃剑,其好坏取决于在间充质干细胞的浓度,如果各种环境压力使氧自由基过量堆积在细胞内,将会导致骨髓间充质干细胞衰老,出现异常分化。还有研究者认为,氧化应激并不能完全解释细胞衰老的现象[21]。 表观遗传因子的活化,包括组蛋白乙酰基转移酶和DNA甲基转移酶,在DNA衰老进程中调节基因表达。P16(INK4A)和高迁移率族蛋白A2抗原(HMGA2)在调控间充质干细胞多能性方面发挥着重要作用,核纤层蛋白A的缺陷也会导致间充质干细胞衰老[22]。Mateos等[23]用核纤层蛋白A或其突变体早老蛋白通过慢病毒转染间充质干细胞,导致其成软骨分化能力缺陷,其原因是由于氧化应激失衡。 Lee等[24]发现氨酰tRNA合成酶复合多功能相互作用蛋白3(AIMP3)是复杂的大分子DNA合成酶,发挥着抑制肿瘤的作用。AIMP3/p18在衰老的人和鼠骨髓间充质干细胞中显著增加,AIMP3/p18的过表达会诱导细胞出现衰老表型,影响集落生成和出现成脂分化倾向。AIMP3通过miRNA(miR-543和miR-590-3p)影响骨髓间充质干细胞的老化。 在骨髓间充质干细胞衰老过程中,溶血磷脂酸是膜磷脂合成普遍存在的代谢物。与细胞衰老相关的p16(Ink4a)、Rb、p53、p21(Cip1)会因溶血磷脂酸信号通路受到抑制而减少,阻断信号通路也伴随着细胞形态的改变,防止溶血磷脂酸受体的参与,还有利于泛素化介导的原癌基因c-Myc进入静止状态,使原癌基因不在间充质干细胞中表达[25]。在衰老过程中,原癌基因被激活,肿瘤抑制因子如p16(Ink4a)、Rb、p53等表达受到抑制,很可能包含着衰老异常变化的分子机制。在一定程度上也解释了肿瘤好发个体多存在于衰老群体中。 Wnt/β-catenin 信号通路是一条高度保守的信号通路,在动物的生长发育中起着关键作用,参与细胞的增殖、分化、凋亡。Zhang等[26]利用Wnt/β-catenin信号通路通过增加活性氧,诱导骨髓间充质干细胞衰老。在加入活性氧清除剂N-乙酰半胱氨酸后,Wnt/β-catenin信号诱导的衰老骨髓间充质干细胞显著减少,DNA损伤减轻,p16(INK4A)、p53和p21的表达也减少了。 2.2.2 骨髓间充质干细胞衰老的相关疾病 骨髓间充质干细胞易受衰老的内环境影响,相反地,骨髓间充质干细胞的衰老也可能促进衰老相关疾病的发生。衰老导致机体的生理功能和修复能力降低,其中一部分原因是由于干细胞的再生能力受损,尤其是骨髓间充质干细胞的成骨分化能力下降,因而骨生成减少,骨质流失增多,老年人的骨折风险增加,骨折愈合困难[27],易患骨关节病、骨质疏松症等疾病。骨质疏松症是年龄相关的进行性骨病,Liu等[28]发现Trp53(p53)不仅是衰老标记,也是骨质疏松中重要的转录调节因子,p53通过miRNA信号通路抑制骨髓间充质干细胞的成骨分化能力,因而老年人的骨质量和骨髓间充质干细胞的成骨分化能力显著降低。 心肌梗死与衰老之间存在着很大关系。心肌干细胞的衰老在心肌梗死中起着重要作用,由于衰老的心肌干细胞向心肌细胞分化的能力降低,使损伤的心肌细胞不能得到有效恢复,导致心肌功能下降并诱发心肌梗死。骨髓间充质干细胞是理想细胞治疗心肌梗死的自体干细胞。肌醇焦磷酸通过Akt信号调节骨髓间充质干细胞的衰老。肌醇焦磷酸6激酶(IP6Ks)和肌醇焦磷酸7(IP7)在衰老引起骨髓间充质干细胞的缺氧损伤和旁分泌功能受损中起着重要作用,这与Akt信号通路的活性降低有关[29]。 机体老化最突出的风险之一是导致神经退行性疾病的发展,老化会损害神经细胞的自我修复能力且会逐步恶化,其结果就会导致神经系统的功能发生异常改变,而且一旦这种异常的变化出现就很难逆转,如阿尔茨海默病、帕金森病等[30]。Babaei等[31]发现,移植骨髓间充质干细胞能够改善阿尔茨海默症小鼠的记忆力。骨髓间充质干细胞能够显著改善衰老和鹅膏蕈氨酸诱导的记忆功能障碍,骨髓间充质干细胞有望治疗衰老和大脑基底核损害引起的认知功能减退。 先天性角化不良是由于端粒基因种系突变导致端粒缩短和造血干细胞增殖潜能受限,骨骼中的骨髓间充质干细胞有助于血液表型。先天性角化不良患病来源的骨髓间充质干细胞表现出集落生成减少,自发地分化为脂肪细胞和纤维细胞,体外也表现出衰老的体征,将之移植到小鼠体内,角化病和端粒生物学障碍患病来源的骨髓间充质干细胞不能够发挥正常的骨形成和造血支持作用,这些发现与骨骼干细胞和骨髓间充质干细胞缺陷造成角化病和端粒生物学障碍的骨髓衰竭表现一致[32]。 有研究表明,阻断骨髓间充质干细胞的功能可能导致年龄相关的代谢综合征,致使能量利用障碍的病情进展加速[33]。由此可以推测,干细胞可能被代谢综合征的成脂需要而耗尽,正如代谢综合征所观察到的那样,脂肪组织退化[34]。与此同时,2型糖尿病和前驱糖尿病中也观察到代谢综合征通过晚期糖基化终产物的产生导致骨髓间充质干细胞的功能异常。这些产物可能聚集在骨基质,抑制扩增,引起细胞凋亡,增加细胞内活性氧的产生,类似的代谢变化也在早年衰老综合征中观察到,这是一种加速老化的遗传学疾病,在婴儿时期就出现进行性老年性退行性改变。早年衰老综合征由LMNA(一种核支架蛋白质)突变引起,编码Lamin-A,也影响着骨髓间充质干细胞的分化 [35]。Lamin A基因所负责编码的蛋白质是细胞结构的支架,也参与基因表现和DNA复制。Lamin A基因突变与早年衰老综合征的细胞老化有关,是由于Lamin A通过尚未明确的机制导致细胞形态、表观遗传和基因损害以及间充质干细胞的体内损耗[36]。总之,骨髓间充质干细胞的调节异常与衰老的细胞外基质相互作用,参与代谢综合征相关的衰老进程,还需要进一步的研究确定这些通路中与人体内衰老进程的关系。 2.3 延缓骨髓间充质干细胞衰老的途径 ISCT推荐将骨髓间充质干细胞的免疫学特性更广泛地应用于临床,特别是利用骨髓间充质干细胞的固有免疫调节功能[37]。所以掌握更多确切的特性,包括免疫表型、功能分析和基因表达研究,在骨髓间充质干细胞老化背景下显得尤为重要。考虑到表观基因研究是2份DNA,基因表达研究是多份mRNA,正确地翻译将更为困难,相比基因表达分析用于检测年龄相关的改变,甲基化分析可能是更为敏感的方法[38]。 细胞遗传工程是防止骨髓间充质干细胞体外老化的方法之一。DNA复制离不开每个DNA分子末端的复制,该过程在端粒酶的催化下进行,端粒会在每次细胞分裂后缩短一些,除了一些表达端粒酶的细胞,比如大多数肿瘤细胞,最终形成的非常短的端粒,随后通过一些尚未明确的步骤来激发新基因的表达,这些新基因能进一步阻断有丝分裂的周期,但不会导致细胞凋亡[39]。因而端粒酶可作为很好的衰老指征,在人类细胞中由于端粒酶过短导致的细胞变化,可能是细胞对DNA损伤的反应,随着年龄增加,衰老细胞在长寿和非长寿的物种中通过不同的机制累积。一些研究者尝试通过诱导端粒酶的异位表达对抗复制性衰老,或提高骨髓间充质干细胞的效能[40]。然而,这并不能理想地用于临床治疗当中,因为这存在恶变的风险和成骨诱导的倾向[41]。系统性红斑狼疮患者存在衰老相关的p16过表达,敲除患者的p16,可改变衰老表型的过早出现[42]。有研究显示,衰老基因p16(Ink4a)作为抗癌和抗衰老机制间的平衡调节者,在衰老过程中扮演着重要角色,Ink4a作为细胞衰老时细胞增殖停顿的因素之一,在细胞衰老的过程中细胞被诱导Ink4a表达水平升高,说明衰老的干细胞确实像普通细胞衰老一样,可能是生命早期防止肿瘤的一种演化机制。并且,Ink4a可致使在衰老的骨髓、大脑和胰腺中干细胞功能的减弱[39]。同样的,激活p53/p21通路会抑制骨髓间充质干细胞的增殖,敲除p21基因能够逆转系统性红斑狼疮患者骨髓间充质干细胞的衰老[43]。p53是调节细胞衰老的重要成员,它通过调节其下游基因发挥作用。研究发现,随着p53上调、雷帕霉素靶蛋白(mTOR)下调和Rb磷酸化,衰老骨髓间充质干细胞的单丹磺酰尸胺染色和自噬相关基因(LC3和atg12)增加,超过85%骨髓间充质干细胞的β-半乳糖苷酶(SA-β-gal)染色阳性,增加了衰老相关基因的表达(p16ink4a和p21waf1)。敲除p53能够延缓衰老,降低骨髓间充质干细胞衰老进程中的自噬活性,并伴随着mTOR表达水平上调和Rb磷酸化。这些结果说明,骨髓间充质干细胞进入复制性衰老状态时自噬作用增强,而p53在上调自噬作用中起着关键作用[44]。 抗氧化剂能够改善骨髓间充质干细胞的存活和功能。在大鼠模型中,将骨髓间充质干细胞培养在老年动物血清中,发现细胞的存活和分化能力均有下降[45]。出现这种结果是由于细胞内活性氧产生增加,损伤了细胞蛋白质。这种效应能够通过降低体外的氧化应激或在体内应用抗氧化剂改变[46]。低剂量的异硫氰酸酯能够延缓骨髓间充质干细胞的体外衰老,其主要作用也是减少氧化应激和保护骨髓间充质干细胞免遭化学诱导的氧化损伤[47]。 药物方法和特定的代谢物可用来防止骨髓间充质干细胞衰老。组蛋白乙酰转移酶抑制剂通过抑制组蛋白去乙酰化酶活性,能够阻止骨髓间充质干细胞衰老[18]。Liu等[48]通过移植SIRT1介导的衰老间充质干细胞提高心肌梗死大鼠的心功能。类似的,Chen等[49]通过SIRT1提高三肽氨基肽酶表达,增加端粒酶活性和减少DNA损伤,改善了年龄引起的骨髓间充质干细胞衰老。SIRT1在骨髓间充质干细胞中表达,能够增加细胞培养的代数,选择性敲除SIRT1会出现细胞生长减慢,细胞加速衰老,而SIRT1的过表达会延缓骨髓间充质干细胞的衰老,保持成骨和成脂分化潜能。溶血磷脂酸是磷脂膜合成的关键,也在骨髓间充质干细胞衰老中发挥着作用,通过拮抗溶血磷脂酸受体通路达到抗衰老的目的[25]。Shuai等[50]将骨髓间充质干细胞进行长期的体外培养,发现褪黑素对其自我更新和分化能力有很好的保护作用,褪黑素能够激活抗氧化防御系统,抑制细胞衰老通路,保护基因多能性的表达。有研究通过低剂量的脂多糖激活转录因子NF-κB,使衰老骨髓间充质干细胞在基础水平上有所提高,能够改善衰老引起的骨质丢失,提高老年患者骨愈合效率[51]。重组HSP70和温和的热休克也能够使衰老的骨髓间充质干细胞年轻化[52]。 生长因子也被用来维持骨髓间充质干细胞的自我更新和分化能力,特别是成纤维细胞生长因子2、血小板源生长因子、抗坏血酸盐和表皮生长因子,能够提高骨髓间充质干细胞的体外增殖,延缓衰老,但治疗后不能维持成骨、成软骨和成脂分化能力[53]。Yasuhiro等[54]发现外源性的粒细胞集落刺激因子治疗能够提高来自老年供者骨髓间充质干细胞的增殖活性和生长因子数量,提高其对外伤性脑损伤的治疗效果。同样的,因为骨髓间充质干细胞具有的亲神经特性,在用于治疗脑卒中和其他神经系统治疗也是不错的选择,虽然体外扩增会出现钝化现象[55],不过能够用多种生长因子恢复其活性[56]。与此同时,外源基因的表达,像血管内皮生长因子等生长因子也被用来体外延长骨髓间充质干细胞的寿命。研究发现,通过特定的细胞因子(如碱性成纤维细胞生长因子和血管内皮生长因子)预处理老年人骨髓间充质干细胞,能够恢复其功效,达到年轻人的骨髓间充质干细胞在治疗心肌梗死模型中的作用[57]。骨髓间充质干细胞移植能够减缓心脏的自然衰老,对受损心脏发挥保护作用[58]。 机械刺激可能是另一种调节分化能力的手段。有研究指出机械力会抑制骨髓间充质干细胞体外的成脂分化,即使存在过量的脂肪形成补充剂依然有效[59]。Styner等[60]也得到了类似的结果,通过机械力控制骨髓间充质干细胞体外成脂分化的信号,发现机械力能够抑制正CCAAT/增强子结合蛋白β(C/EBPβ)的表达,有助于减少脂肪形成和增加内质网抗压能力,改善细胞整体的健康水平。通过机械力能够抑制骨髓间充质干细胞的成脂分化,那么是否通过机械刺激能够在骨骼促进骨生成方面发挥作用,还有待研究。还有研究者提出运动增加骨髓间充质干细胞的数量,提高成骨分化和降低成脂分化。运动可延缓衰老引起的肌肉骨骼功能退化[61]。 先前有研究报道,能量限制能够提高间充质干细胞的增殖能力,减少细胞凋亡。研究者用低糖培养基(1.4 mmol/L)和普通培养基(5.5 mmol/L)比较倍增时间、SA-β-gal活性、活性氧和成骨及成脂分化的能力,发现低糖培养基组的成骨分化能力更高、SA-β-gal阳性率更低[62]。"
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