Sirtuins in stem cell regulation: roles and prospects

doi:10.3969/j.issn.2095-4344.2016.36.019

Abstract

Abstract:

BACKGROUND: Efficacy of stem cell therapy is considerably influenced by oxidative stress. Sirtuin (SIRT) family of mammals is an important deacetylation and antioxidant enzyme that can regulate endogenous antioxidant activities in stem cells and cell cycle related signaling pathways to reduce the damage and enhance the viability of stem cells.
OBJECTIVE: To review the regulating function and mechanism of SIRT family.
METHODS: A computer-based search of Web of Science, PubMed and CNKI from 1990 to 2015 was performed for relevant articles about SIRT and stem cell oxidative stress, using the key words of “SIRT, stem cell, oxidative stress, molecular mechanisms” in English and Chinese, respectively. After eliminating literatures which have poor authority or have similar contents, 55 articles were involved.
RESULTS AND CONCLUSION: NAD⁺-dependent SIRT family is the key enzyme for deacetylation of histones and other proteins. It plays vital regulation roles in metabolism, genomic stability, DNA damage/repair, and chromatin remodeling/stress reaction. Progress in the SIRT-targeted stem cell research will definitely provide more clues for clinical stem cell transplantation therapy.

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

Key words: Stem Cells, Sirtuins, Antioxidants, Tissue Engineering

CLC Number:

R318

Mao Zhong-fu, Li Yi-fang, Hiroshi Kurihara, He Rong-rong. Sirtuins in stem cell regulation: roles and prospects[J]. Chinese Journal of Tissue Engineering Research, 2016, 20(36): 5450-5457.

Figures/Tables 1

2.1 SIRT1-干细胞寿命或多能性的调节因子 SIRT1蛋白主要定位于细胞核中，并能够在细胞核与细胞质中穿梭，是哺乳动物细胞中发现的与酵母沉默信息调节因子SIRT2同源性最高的同系物，在生物发育的各个阶段表达丰富且与众多基因的转录调控、能量代谢和衰老过程的调节有关，SIRT1除了可以去乙酰化组蛋白，还可以去乙酰化很多重要的转录因子和调节蛋白，从而调控多种生物学过程[13-14]。SIRT1基因的缺失会导致新生动物的过早死亡，骨骼、心脏和造血系统发育迟缓[11]。最近的研究表明，在氧化应激条件下，SIRT1蛋白主要是通过以下3个途径影响干细胞寿命：一是SIRT1蛋白调控PPAR-γ减少细胞的脂质过氧化损伤。如Schilling等[15]研究发现，SIRT1能够通过去乙酰化PPAR-γ与Runx2来降低氧化应激反应和增加间充质干细胞向成骨细胞分化；二是SIRT1蛋白通过调控P53的活性影响细胞寿命。如SIRT1可以调控P53的去乙酰化，继而调控SDF-1，促进心脏干细胞的增殖和存活，而SIRT1的小分子激活剂白藜芦醇能够通过激活SIRT1对突发性心肌梗死模型小鼠起到保护作用[16]。三是SIRT1蛋白通过调控FOXO的信号通路，启动细胞的抗氧化途径，延缓细胞衰老。在三苯氧胺诱导SIRT1基因缺失的小鼠模型中，SIRT1通过调控长寿转录因子FOXO3对造血干细胞的自我更新和稳态起到关键作用[17]。同时，在SIRT1基因敲除的造血干细胞体外模型实验中发现，SIRT1缺失会导致损伤DNA的累积和衰老相关分子的表达增加[18]。除了以上3种主要因素之外，研究人员还发现在CCl4肝损伤小鼠中移植人羊膜间质干细胞，其HGF、SIRT1、α-SMA和P-27kip1等基因都会表达上调，表明SIRT1是肝脏干细胞移植治疗中再生的关键因素[19]。同时SIRT1在抗干细胞老化的研究中也发现，SIRT1被小分子激活剂白藜芦醇激活后，能够降低端粒的缩短或减少，保证干细胞存活，同时促进干细胞增殖形成具有长端粒的新生细胞[20-21]。由于SIRT1能够协调干细胞的多能性，因此其在干细胞的分化进程中也发挥着重要的作用。已有研究指出SIRT1是间充质干细胞分化为成骨细胞所必需的，SIRT1能够辅助调控间充质干细胞分化为成骨细胞的标志性因子Runx2的表达，并且调控SIRT1和IL-1β信号通路能够保证软骨发育中软骨特异性蛋白和软骨特异性转录因子SOX9的表达以及去乙酰化NF-κB来减少肥大细胞和炎性细胞的产生，进而对间充质干细胞分化的整体进程起到调控作用[22-23]。综上所述，SIRT1在调节干细胞寿命以及干细胞功能中起到关键的作用。 2.2 SIRT2-干细胞增殖的调节因子 SIRT2作为发现最早的SIRT家族成员，其在细胞周期和增殖中的作用已经得到了深入的研究。在细胞增殖方面，有丝分裂过程中的磷酸化可稳定SIRT2并促进SIRT2移入核内与染色质共定位。共定位研究表明SIRT2能够通过去乙酰化H4-K16来实现在氧化应激时阻止染色质凝聚延缓有丝分裂进程，这提示它可能作为一种分裂期检查点蛋白在DNA损伤时调控细胞分裂[24]。在有关癌症干细胞的研究中发现，SIRT2能够激活ALDH1，降低ALDH1A1的乙酰化水平，进而激活NOTCH信号通路来保证癌症干细胞的自我更新和复制[25]。在氧化应激发生时，SIRT2 可反应性地去乙酰化FOXO来保护机体免受活性氧的损伤[26]。也有文献证明SIRT2是细胞死亡的一个调控因子，能够通过去乙酰化调控RIP1-RIP3复合物的形成和肿瘤坏死因子α刺激的坏死，进而促进肿瘤干细胞的凋亡[27]。以上表明，SIRT2是程序化坏死的一个重要调控因子，是防止坏死性损伤中一个有希望的药物作用靶标，能够用于肿瘤干细胞的研究并为临床上治疗肿瘤提供可靠的依据。在相关神经疾病的研究中，Sayd等[28]发现，SIRT2可被小分子白藜芦醇激活，从而有效调控胶质瘤干细胞的增殖。SIRT2除了能够调节氧化应激条件下干细胞的增殖，其对神经再生及神经干细胞的分化也具有一定的调节作用。有研究表明，在缺血再灌注氧化损伤的大鼠模型中，NAD+依赖性的SIRT2能够保护神经再生从而对该模型造成的脑血管病起到恢复作用[29]。同时，在神经干细胞分化为功能神经元的过程中SIRT2也扮演着极其重要的角色，它能够调节Ngn2和β-Ⅲ的基因表达使神经干细胞分化成为少突胶质细胞[30]。以上表明SIRT2在调控干细胞的结构和功能调控中具有十分复杂的作用，能够缓解氧化应激造成的干细胞损伤，并有效调节肿瘤干细胞的凋亡和神经干细胞的增殖与分化，但是其作用机制与信号调节仍要进行深入的研究。 2.3 SIRT3-干细胞线粒体内的抗氧化调节因子 SIRT3是第1个被定位于哺乳动物细胞线粒体的SIRT家族成员，同时也被发现少量存在于细胞核，因此其对线粒体相关的生物学进程起到关键的调节作用，如Duan等[31]研究表明，SIRT3可以通过介导线粒体自噬来缓解由氧化应激诱导的小鼠脾细胞凋亡。在能量代谢中，王国恩等[32-33]的研究发现SIRT3能够调节线粒体氧化应激并在生物碱1，3，7，9-四甲基尿酸减少高脂饮食小鼠肝脏脂肪化进程中发挥重要作用。暗示着其在脂肪酸的代谢和酶促反应中发挥重要的生物学作用。随着科研人员对干细胞结构和功能研究的深入，SIRT3在干细胞中的作用及其机制也逐渐被阐明。Wang等[34]已经证明了干细胞在缺失SIRT3的情况下更容易受到氧化应激损伤。有研究表明，氧化应激负荷时，干细胞SIRT3表达量增加，此时SIRT3不仅通过去乙酰化作用使SOD2活化，还可调节异柠檬酸脱氢酶2(IDH2)的活化，进而减少氧化应激所致的DNA损伤[35]。另外，SIRT3还可在体内和体外将基质酶谷氨酸盐脱氢酶(GDH)去乙酰化。这些酶的活化可提供更多的呼吸链、三羧酸循环及糖原合成的中间产物，可能也是SIRT3保护干细胞氧化损伤的重要机制之一。此外，已有研究发现，SIRT3可与线粒体渗透转运孔(mPTP)中的亲环蛋白相互作用，直接调节亲环蛋白并阻止mPTP开放[36]，这也说明SIRT3的基本功能是抑制mPTP开放和随后发生的线粒体功能失调，从而能够为SIRT3调控干细胞的结构和功能提供参考。在SIRT3调控干细胞的凋亡实验中，Calenic等[37]指出SIRT3能够保护P53信号通路诱导的口角质干细胞凋亡，但其下游调控机制有待进一步研究。总之，SIRT3的缺失会导致线粒体结构和功能完整性破坏，线粒体膜电位紊乱，活性氧大量产生，并使干细胞内Mn-SOD，GPX等抗氧化酶体功能下调，进而导致线粒体细胞色素C的大量释放并促进干细胞内促凋亡蛋白表达上调，从而导致干细胞的凋亡。 2.4 SIRT4-干细胞能量代谢和衰老的调节因子 SIRT4 是另一个调节细胞能量代谢的线粒体蛋白。但是SIRT4只有ADP-核糖基转移酶活性却没有去乙酰化酶活性[38]。与SIRT3依赖的GDH去乙酰化激活相比，SIRT4可使线粒体基质中的GDH失活[39]，预示着其在线粒体代谢中具有与SIRT3不同的调控作用。Kofman等[40]的研究表明，在进行分化和趋向衰老的精原干细胞中，SIRT4的基因水平会持续增加，暗示着SIRT4基因水平的增加可能与精原干细胞的衰老和分化相关。这也进一步证明了其可能与SIRT3缓解干细胞衰老，促进干细胞增殖的作用相反，但是其在干细胞中具体的生物调控功能和作用机制仍有待于研究。 2.5 SIRT5-干细胞线粒体凋亡途径的调节因子 SIRT5同样定位于线粒体基质，在机体的心脏和胸腺以及淋巴细胞中大量表达，预示着其在免疫与血液系统的疾病中有着重要的作用[41]。细胞水平的相关研究表明，SIRT5可将细胞色素C去乙酰化[42]，进而影响细胞色素C在细胞呼吸及细胞线粒体途径凋亡中的功能，并减少细胞色素C的释放，这可能是SIRT5调控干细胞存活的重要机制，但是其对于干细胞增殖和分化的生物学作用有待深入研究。 2.6 SIRT6-干细胞DNA复制重组的调节因子 SIRT6是异常染色质相关核蛋白，参与碱基切除修复(BER)[43]。SIRT6高表达于大脑和骨骼肌，在体外它不但具有去乙酰化酶活性，还有强大的ADP-核糖基转移酶活性[44]。研究表明，在SIRT6敲除的小鼠胚胎干细胞中，细胞自我复制增殖的能力降低，进一步研究发现SIRT6敲除的小鼠胚胎干细胞表现出BER缺陷引起的多种染色体缺陷，如片段化、不完整中心粒、缺口及移位[45]。Kaidi等[46]发现，SIRT6 可促进DNA同源重组过程DNA双链缺口(DSB)修复中关键环节：再交叉终止。再交叉蛋白CtIP是SIRT6 的相互作用蛋白，SIRT6依赖的CtIP的去乙酰化可激活再交叉。当SIRT6缺失后将损坏重组蛋白A与DSB处的单链DNA结合，这将降低DNA的同源重组率，进一步损伤干细胞的自我复制。研究表明，人参皂苷可以通过调节SIRT6/NF-κB信号通路来缓解造血干细胞的衰老[47]。另外，SIRT6与多功能诱导干细胞的衰老也有一定的联系，SIRT6可以反馈性调节人多功能诱导干细胞中的mir-766转录，阻碍已衰老人多功能诱导干细胞的基因重组[48]。同时，SIRT6在调节干细胞分化的过程中也扮演着重要的作用，如SIRT6可以通过调控NF-κB信号通路来调节间充质干细胞往成骨细胞方向的分化[49]。此外，SIRT6还会受到SIRT1的调控，共同协调干细胞内环境的稳态。Zhao等[25]的研究表明，SIRT1和SIRT6缺失的神经干细胞不具有增殖的能力，但分化成为功能性神经元的能力增强。综上表明，SIRT6除了能够与SIRT1等蛋白协同调节干细胞的分化功能外，主要通过调节DNA的复制与重组来调控干细胞的增殖与衰老。 2.7 SIRT7-干细胞rRNA转录的调节因子 SIRT7是定位于核仁的一种调节因子，不仅广泛表达于小鼠增殖活跃的组织如肝、睾丸和脾，也在非增生组织如心、脑和骨骼肌中低水平表达[50]，这可能暗示着SIRT7在调控机体生物功能中发挥重要的作用。SIRT7无去乙酰化酶活性及ADP-核糖基转移酶活性，但是可以通过与RNA聚合酶1(Pol 1)相互作用参与激活rRNA基因转录。过表达SIRT7基因可增加Pol 1介导的转录，保证干细胞存活，而敲除SIRT7基因可阻滞细胞增殖并启动凋亡[51]。SIRT7除了在调控干细胞增殖中发挥重要作用外，其在干细胞的活力和功能调节中也起到关键的作用，如Zhou等[52]发现，SIRT7可以通过调控其结合蛋白NRF-1和GABP1来缓解造血干细胞的衰老，并促进造血干细胞的代谢和增殖。总之，SIRT7可以通过与其他生物活性成分的结合来调控干细胞的结构与功能，在干细胞增殖与代谢中发挥关键作用。"

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