氧化压力与干细胞移植

doi:10.3969/j.issn.2095-4344.2015.36.028

中国组织工程研究 ›› 2015, Vol. 19 ›› Issue (36): 5898-5904.doi: 10.3969/j.issn.2095-4344.2015.36.028

• 干细胞综述 stem cell review • 上一篇

氧化压力与干细胞移植

杨敏¹，王新发¹，刘映霞²，肖佳^2，3，4

1南华大学深圳市第三人民医院，广东省深圳市 518112； 2传染病学国家重点学科，深圳市第三人民医院，广东省深圳市 518112； 3暨南大学免疫生物学、组织移植和免疫学研究所, 广东省广州市 510632； 4香港大学解剖学系，香港

出版日期:2015-09-03 发布日期:2015-09-03
通讯作者: 刘映霞，博士，主任医师，传染病学国家重点学科，深圳市第三人民医院，广东省深圳市 518112
作者简介:杨敏，女，1991年生，湖南省益阳市人，汉族，在读硕士，主要从事干细胞研究。
基金资助:
the National Natural Science Foundation of China, No. 31300813

Oxidative stress and stem cell transplantation

Yang Min¹, Wang Xin-fa¹, Liu Ying-xia², Xiao Jia^{2, 3, 4}

1Shenzhen Third People’s Hospital of University of South China, Shenzhen 518000, Guangdong Province, China; 2State Key Discipline of Infectious Diseases, Department of Infectious Diseases, Shenzhen Third People’s Hospital, Shenzhen 518112, Guangdong Province, China; 3Department of Immunobiology, Institute of Tissue Transplantation and Immunology, Jinan University, Guangzhou 510632, Guangdong Province, China; 4Department of Anatomy, the University of Hong Kong, Pokfulam, Hong Kong

Online:2015-09-03 Published:2015-09-03
Contact: Liu Ying-xia, M.D., Chief physician, State Key Discipline of Infectious Diseases, Department of Infectious Diseases, Shenzhen Third People’s Hospital, Shenzhen 518112, Guangdong Province, China
About author:Yang Min, Studying for master’s degree, Shenzhen Third People's Hospital of University of South China, Shenzhen 518000, Guangdong Province, China
Supported by:
the National Natural Science Foundation of China, No. 31300813

摘要/Abstract

摘要：

背景：干细胞来源广泛，具有自我分化和更新的潜能，且自体干细胞更能最大程度避免移植后的免疫排斥反应，已成为组织器官移植最有前途的替代方法之一，但是受移植部位氧化压力等恶劣环境影响，现今干细胞的移植效率还较为低下。
目的：综述氧化压力对干细胞本身及移植效率的影响和机制。
方法：由第一作者检索1990至2015年PubMed数据库收录的与干细胞移植有关的文献。英文检索词为“stem cell transplantation，stem cell，oxidative stress，molecular mechanisms”。共纳入97篇文章进行综述。
结果与结论：内源氧化压力对干细胞移植有直接且重要的影响，各类型干细胞抗氧化压力水平有差异，但高氧化水平能引起干细胞增殖停止、过早衰老、凋亡、癌变，也能引起肿瘤细胞的凋亡。干细胞可通过多条通路调节其内源性抗氧化水平，应用各种方法提高内源抗氧化压力水平可以提高干细胞的移植效率及预防氧化压力导致的干细胞癌变发生，使干细胞移植治疗能更广泛更安全的应用于临床。

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

关键词: 干细胞, 移植, 干细胞移植, 氧化压力, 抗氧化水平, 分子机制, 细胞衰老, 细胞凋亡, 国家自然科学基金

Abstract:

BACKGROUND: Stem cells with wide variety of sources have the potential of differentiation and self-renewal. In additional, autologous stem cells can avoid immune rejection after transplantation, and thus it has become one of the most promising alternative strategies for tissue/organ transplantation. However, due to the adverse environments at injured sites, such as oxidative stress and inflammation, current stem cell transplantation efficacy is relatively low.

OBJECTIVE: To review the effects of oxidative stress on stem cells and on their transplantation efficiency as well as relevant mechanisms.

METHODS: PubMed database was searched by the first author for relevant articles about stem cells published from 1990 to 2015. The keywords were “stem cell transplantation, stem cell, oxidative stress, molecular mechanism”. After eliminating literatures which had poor authority or similar content, 97 articles were involved in result analysis.

RESULTS AND CONCLUSION: Different types of stem cells have different basal endogenous antioxidant stress levels. Oxidative stress through multiple molecular pathways causes cell aging, apoptosis and cancer, which also can result in apoptosis of cancer cells. Stem cells can adjust endogenous antioxidant levels through multiple paths. To improve the endogenous antioxidant stress level using a variety of methods can increase stem cell transplantation efficiency and prevent stem cell cancerization due to oxidative stress, which makes the clinical application of stem cell transplantation therapy safer and more popular.

Key words: Stem Cell Transplantation, Apoptosis, Antioxidants

中图分类号:

R318

杨敏，王新发，刘映霞，肖佳. 氧化压力与干细胞移植[J]. 中国组织工程研究, 2015, 19(36): 5898-5904.

Yang Min, Wang Xin-fa, Liu Ying-xia, Xiao Jia. Oxidative stress and stem cell transplantation[J]. Chinese Journal of Tissue Engineering Research, 2015, 19(36): 5898-5904.

图/表（结果） 1

2.1 干细胞移植效率低下的原因目前，多种干细胞已经进入临床试验阶段^[9]，如胚胎干细胞、间充质干细胞、神经干细胞、诱导多能干细胞、造血干细胞等，并取得了一定疗效，但总体来说干细胞临床治疗还处于非常早期阶段，干细胞移植效率仍然低下^[10-11]。一项同种异基因干细胞移植治疗T细胞淋巴瘤的疗效结果显示，其3年总生存率为49.6%，与自体干细胞移植总生存率差异无显著性意义^[13]。一项自体骨髓干细胞移植治疗525例冠心病患者的随机荟萃分析结果显示干细胞治疗不能促进左室重建，而对左室射血分数平均改善幅度也仅为5%-10%^[14]。动物实验也显示了相似的结果，如脐带间充质干细胞治疗药物所致的急性肝衰竭小鼠模型时，移植的干细胞只占据不到10%的小鼠肝脏面积^[15]。干细胞移植效率低下主要归因于受损部位的强氧化压力、低氧和炎症环境^[16-17]。有报道认为，干细胞的内源性抗氧化水平影响其在受损部位的存活时间和治疗效率。如经过抗氧化剂N-乙酰半胱氨酸处理后的肌源干细胞在小鼠心肌缺血模型中展现了更高的治疗效果，更好地改善了小鼠的心功能^[18]。在LY83583诱导的氧化应激环境中，人内皮祖细胞与人脐静脉内皮细胞和人冠状动脉内皮细胞相比，有更强的抗氧化水平，从而增加了其DNA修复能力，导致其对氧化压力造成的细胞凋亡不敏感^[19]。最近一项研究也发现，经过N-乙酰-5-甲氧基色胺(一种常见的抗氧化剂)处理后的脂肪干细胞治疗小鼠急性间质性膀胱炎时有更好的疗效^[20]。因此，移植前提高干细胞的内源性抗氧化水平很可能是提高干细胞移植疗效的一个策略。 2.2 氧化压力对干细胞的影响 2.2.1 不同类型干细胞内源抗氧化水平的差异众所周知，不同程度的氧化水平对细胞有不同的影响^[21]，如在人成纤维细胞模型中，不同体积分数H₂O₂引起的氧化压力对细胞的影响差异明显，表现为低体积分数的H₂O₂刺激细胞增殖，中等体积分数的H₂O₂使细胞生长停滞及衰老，而高体积分数的H₂O₂使细胞迅速凋亡^[22]。不同类型的干细胞有不同的抗氧化压力水平，但高氧化水平一般引起细胞凋亡^[23-26]，包括肿瘤细胞的凋亡^[27-28]。Chen等^[29]研究结果显示，H₂O₂对人类胚胎肺成纤维细胞株IMR-90的影响随着体积分数发生变化：在亚致死H₂O₂条件下，细胞增殖停止并开始衰老，但在其致死体积分数下才出现细胞凋亡。胚胎干细胞是一种全能干细胞，来源于胚胎早期胚囊细胞团，能自我更新、增殖及分化成3个胚层的各个细胞类型^[30]。胚胎干细胞对氧化压力敏感，内源抗氧化水平低，但其有独特的低抗氧化能力能够维持细胞自我更新和抗衰老反应^[31-32]。在甲基-硝基-亚硝基胍诱导细胞凋亡模型中，与分化的小鼠胚胎干细胞后代细胞相比，未分化的小鼠胚胎干细胞对活性氧和DNA损伤物质更加敏感，导致它们更容易受其影响而引起细胞凋亡^[33-34]。另一个在以亚甲蓝为光敏剂或H₂O₂诱导氧化压力环境对胚胎干细胞影响的研究则显示，未分化的人胚胎干细胞抗氧化压力水平高于人胚胎干细胞分化的后代，这主要归因前者于压力诱导的负转录调控抗氧化基因水平高，从而展示出比已分化胚胎干细胞更高的抗氧化水平^[35-38]。对于间充质干细胞，研究显示未分化间充质干细胞内氧化压力的低活性反应组分、处理氧化水平的基本酶系及谷胱甘肽水平比由间充质干细胞分化而来的类肝细胞要高，使其有更高的内源抗氧化压力水平^[39]。但也有相反的报道指出，与角质细胞相比，来源于人皮肤的间充质干细胞抗氧化压力水平较低，暴露在H₂O₂环境下造成相对更多的细胞凋亡^[40]。来源于脐血的间充质干细胞由于其本底基因表达水平较低导致其抗氧化酶活性也比人成纤维细胞及癌细胞低，因此，与后两者相比较，间充质干细胞在活性氧及电离辐射诱导的氧化压力环境中更易受氧化压力影响而导致细胞凋亡^[41-42]。神经干细胞存在于中枢神经系统，能够维持神经细胞和神经胶质细胞的再生^[43-44]。它们有很强的自我更新和自发分化成神经细胞、星型胶质细胞和少突胶质细胞的能力^[45]，使其成为治疗神经系统疾病的重要种子细胞之一^[46]。研究显示，与造血干细胞和胚胎干细胞类似，神经干细胞的转录组包含一系列“干性”基因(如Hox和Id等)，这些基因产物不仅使干细胞具备多能性，还使这些细胞具有更高的抗氧化压力水平^[47-48]。而且，神经干细胞自身的氧化还原状态能调控细胞本身的自我更新、增殖和细胞凋亡^[49]。Madhavan等^[50]研究显示与有丝分裂后的神经细胞相比，暴露在线粒体毒素3-硝基丙酸环境下，神经干细胞能抵抗更强的抗氧化压力水平并且受损的细胞有更强的恢复能力，提示神经干细胞自身保持了较高水平抗氧化压力的“警戒”状态。骨髓通常被认为是一种低氧供组织，造血干细胞生态的一个显著特点就是低氧含量^[51]，其细胞内源性活性氧水平和活性调节信号调控是维持造血干细胞自我更新、增殖和分化的中心信号。当活性高于正常水平时会导致细胞氧化压力和DNA损伤^[52]，故造血干细胞易受氧化压力影响，内源抗氧化压力水平低于许多类型的干细胞，细胞增殖引起氧化压力的积累会导致干细胞功能衰竭，如在Atm^-^/^-小鼠模型中，细胞内活性氧水平升高，导致造血干细胞处于静止状态，自我更新能力丧失，一连串的造血干细胞移植重建造血功能失败^[53]。以上研究显示，各干细胞抗氧化压力水平不尽相同，但对引起该差异的分子机制和信号调控网络有待进一步研究，这将为在临床干细胞移植中选择理想的细胞来源提供坚实的依据。 2.2.2 氧化压力影响干细胞移植效率的分子机制氧化压力对干细胞影响的分子机制尚不明确，现阶段研究显示干细胞有多种通路调节其内源性抗氧化水平。Nrf2是一种可以调控基础和诱导的细胞保护基因的转录因子^[54]。Nrf2的激活能减轻氧化压力和减少SOD产物的产生^[55-56]。大量研究显示，MAPK和PKC途径能直接调控Nrf2的转录活性，令Nrf2通过调控下游基因的转录活性来发挥抗氧化压力的作用^[57-58]。近期研究亦发现用依达拉奉或马来酸二乙酯预处理的人脐血间充质干细胞在LPS/H₂O₂诱导的氧化压力环境中能够通过MAPK-PKC-Nrf2通路调节其内源抗氧化水平^[59-60](图1)。 Sirt3是一种重要的抗氧化压力因子，其在细胞生理功能和病理特征下的作用已被广泛研究^[61-64]。它其中一个主要功能是令Foxo3a转录因子脱去乙酰基，然后进入细胞核使基因表达抗氧化酶MnSOD和CAT，触发活性氧的去除作用，从而降低氧化压力所导致的细胞死亡^[65-67]。Sirt3在氧化压力作用下还能直接激活MnSOD蛋白^[68-69]。人造血干细胞暴露在H₂O₂诱导的氧化压力环境中，严重的氧化应激使Sirt3的表达下调，进而导致两个抗氧化酶MnSOD和CAT下调，人造血干细胞的抗氧化能力下降^[70]。在氧化应激环境下，Akt的激活也能导致细胞过早衰老。Akt引起细胞衰老是通过调节细胞内的活性氧起作用的。在野生型或Akt1和Akt2都敲除的鼠胚成纤维干细胞模型中，氧化应激能导致Akt缺陷细胞活性氧升高，其途径有两条：第一，通过增加耗氧量增加活性氧的产生；第二，通过抑制FoxO转录因子(FoxO转录因子能降低细胞内活性氧水平和阻止细胞凋亡)阻止活性氧的清除，进而导致细胞增殖停止及引起细胞凋亡^[71-73]。总而言之，虽然氧化压力影响干细胞移植效率的分子机制研究取得了一定成果，但氧化压力对干细胞移植效率的具体影响机制尚需更深入研究。 2.2.3 氧化压力对干细胞移植安全性的影响一些动物实验和临床研究提供了确切的证据，证明氧化应激能导致干细胞癌变^[74]。持续暴露在由正常细胞新陈代谢和生理活动产生的内源或外源性氧化压力下，细胞内部DNA将不可避免地遭受损伤。在人造血干细胞移植治疗免疫缺陷小鼠模型中，细胞内活性氧水平持续增加，每个细胞周期将可能会导致细胞DNA损伤，导致人造血干细胞功能障碍，最终导致功能丧失^[75]。DNA损伤已被广泛接受为导致细胞功能障碍和致癌作用的一个重要诱因^[76-79]。近些年来，许多研究试图解释与年龄相关的细胞或组织功能衰竭，其中包括自由基理论，即过多的活性氧(如H₂O₂、超氧化物、羟自由基等)能引起细胞损伤，导致细胞过早老化^[77，80]。例如在Fancc^-/-小鼠模型中，过多的活性氧产物能引起小鼠造血干细胞DNA链断裂及细胞衰老^[81]。有研究已经发现，在人造血干细胞移植治疗免疫缺陷小鼠模型中，活性氧的持续积累可导致造血干细胞自我更新能力严重受损，导致细胞丧失干性和过早老化，可能导致癌变^[75]。在成年的TXNIP⁽^-/-) 大鼠模型中，造血细胞的抗氧化通路缺陷，细胞内活性氧不断积累，导致大鼠贫血及造血组织的恶性肿瘤，因此，高水平的氧化压力导致造血细胞功能障碍，亦可导致造血干细胞产生变异的造血细胞^[82]。肿瘤干细胞被认为是化疗或放疗后剩余的有高度耐药性导致癌症复发的恶性肿瘤细胞群^[83-84]。与普通细胞相比，肿瘤细胞有更高的抗氧化压力水平^[85-87]。但也有研究显示人和小鼠乳腺癌干细胞与没有发生癌变的细胞相比，抗氧化水平更低^[87]。与正常细胞相比，原发癌组织和肿瘤细胞内活性氧清除酶(包括SOD、谷胱甘肽过氧化物酶、过氧化物还原酶)活性发生了显著的变化^[88-90]。更为重要的是，肿瘤细胞内活性氧清除酶水平的改变会显著影响抗肿瘤药物在细胞内的代谢，从而引起细胞耐药性的产生，影响肿瘤的治疗效果^[91-92]。一些研究表明间充质干细胞能直接抑制肿瘤细胞的生长和增殖^[93-95]，如在免疫缺陷小鼠模型中，注入相同数量人间充质干细胞和人肝癌细胞的实验组与未注入人间充质干细胞的对照组相比较，前者肿瘤形成的潜伏期延长，形成的肿瘤较小^[92]。而另一些研究则发现其有促进肿瘤生长的作用^[96-97]。暴露在MDAMB231人乳腺癌培养基中，人间充质干细胞激活并分化成肿瘤相关的成纤维细胞，因此干细胞治疗肿瘤仍然是未来再生医学领域最具挑战的课题之一。此外，在干细胞移植过程中，如何避免干细胞的成瘤性已成为亟待解决的任务之一，更进一步的研究干细胞成瘤性及影响其成瘤性的分子机制是提高干细胞移植安全性的重要前提和指导。

参考文献

[1] Keeffe EB. Liver transplantation: current status and novel approaches to liver replacement. Gastroenterology. 2001; 120(3):749-762.

[2] Lerou PH, Daley GQ. Therapeutic potential of embryonic stem cells. Blood Rev. 2005;19(6):321-331.

[3] Watt FM, Driskell RR. The therapeutic potential of stem cells. Philos Trans R Soc Lond B Biol Sci. 2010;365(1537): 155-163.

[4] Wetzler M, Watson D, Stock W, et al. Autologous transplantation for Philadelphia chromosome-positive acute lymphoblastic leukemia achieves outcomes similar to allogeneic transplantation: results of CALGB Study 10001 (Alliance).Haematologica. 2014;99(1):111-115.

[5] Wesson RN, Cameron AM. Stem cells in acute liver failure. Adv Surg. 2011;45:117-130.

[6] Ham O, Lee CY, Kim R, et al. Therapeutic Potential of Differentiated Mesenchymal Stem Cells for Treatment of Osteoarthritis. Int J Mol Sci. 2015;16(7):14961-14978.

[7] van Poll D, Parekkadan B, Cho CH, et al. Mesenchymal stem cell-derived molecules directly modulate hepatocellular death and regeneration in vitro and in vivo. Hepatology. 2008; 47(5):1634-1643.

[8] Rountree CB, Mishra L, Willenbring H. Stem cells in liver diseases and cancer: recent advances on the path to new therapies. Hepatology. 2012;55(1):298-306.

[9] Fox IJ, Daley GQ, Goldman SA, et al. Stem cell therapy. Use of differentiated pluripotent stem cells as replacement therapy for treating disease. Science. 2014;345(6199): 1247391.

[10] Ryu KH, Kim SY, Kim YR, et al. Tonsil-derived mesenchymal stem cells alleviate concanavalin A-induced acute liver injury. Exp Cell Res. 2014;326(1):143-154.

[11] Yuasa M, Ishiwata K, Sugio T, et al. Herpes simplex virus type 2 fulminant hepatitis after umbilical cord blood transplantation for acute myeloid leukemia. Rinsho Ketsueki. 2014;55(6): 682-686.

[12] Lunde K, Solheim S, Aakhus S, et al. Intracoronary injection of mononuclear bone marrow cells in acute myocardial infarction.N Engl J Med. 2006;355(12):1199-1209.

[13] Wei J, Xu J, Cao Y, et al. Allogeneic stem-cell transplantation for peripheral T-cell lymphoma: a systemic review and meta-analysis. Acta Haematol. 2015;133(2): 136-144.

[14] Zhang SN, Sun AJ, Ge JB, et al. Intracoronary autologous bone marrow stem cells transfer for patients with acute myocardial infarction: a meta-analysis of randomised controlled trials. Int J Cardiol. 2009;136(2):178-185.

[15] Zhou R, Li Z, He C, et al. Human umbilical cord mesenchymal stem cells and derived hepatocyte-like cells exhibit similar therapeutic effects on an acute liver failure mouse model. PLoS One. 2014;9(8):e104392.

[16] Dernbach E, Urbich C, Brandes RP, et al. Antioxidative stress-associated genes in circulating progenitor cells: evidence for enhanced resistance against oxidative stress. Blood. 2004;104(12):3591-3597.

[17] Chang W, Song BW, Moon JY, et al. Anti-death strategies against oxidative stress in grafted mesenchymal stem cells Histol Histopathol. 2013;28(12):1529-1536.

[18] Drowley L, Okada M, Beckman S, et al. Cellular antioxidant levels influence muscle stem cell therapy. Mol Ther. 2010; 18(10):1865-1873.

[19] He T, Peterson TE, Holmuhamedov EL, et al. Human endothelial progenitor cells tolerate oxidative stress due to intrinsically high expression of manganese superoxide dismutase Arterioscler Thromb Vasc Biol. 2004;24(11): 2021-2027.

[20] Chen YT, Chiang HJ, Chen CH, et al. Melatonin treatment further improves adipose-derived mesenchymal stem cell therapy for acute interstitial cystitis in rat. J Pineal Res. 2014; 57(3):248-261.

[21] Yoon SO, Yun CH, Chung AS. Dose effect of oxidative stress on signal transduction in aging. Mech Ageing Dev. 2002; 123(12):1597-1604.

[22] Taniyama Y, Griendling KK. Reactive oxygen species in the vasculature: molecular and cellular mechanisms. Hypertension. 2003;42(6):1075-1081.

[23] Cao C, Lu S, Kivlin R, et al. AMP-activated protein kinase contributes to UV- and H2O2-induced apoptosis in human skin keratinocytes. J Biol Chem. 2008;283(43):28897-28908.

[24] Ou X, Lee MR, Huang X, et al. SIRT1 positively regulates autophagy and mitochondria function in embryonic stem cells under oxidative stress. Stem Cells. 2014;32(5):1183-1194.

[25] Kujoth GC, Hiona A, Pugh TD, et al. Mitochondrial DNA mutations, oxidative stress, and apoptosis in mammalian aging. Science. 2005;309(5733):481-484.

[26] Giorgio M, Trinei M, Migliaccio E, et al. Hydrogen peroxide: a metabolic by-product or a common mediator of ageing signals. Nat Rev Mol Cell Biol. 2007;8(9):722-728.

[27] Sonoda Y, Watanabe S, Matsumoto Y, et al. FAK is the upstream signal protein of the phosphatidylinositol 3-kinase-Akt survival pathway in hydrogen peroxide-induced apoptosis of a human glioblastoma cell line. J Biol Chem. 1999;274(15):10566-10570.

[28] Ding B, Chi SG, Kim SH, et al. Role of p53 in antioxidant defense of HPV-positive cervical carcinoma cells following H2O2 exposure. J Cell Sci. 2007;120(Pt 13):2284-2294.

[29] Chen QM, Bartholomew JC, Campisi J, et al. Molecular analysis of H2O2-induced senescent-like growth arrest in normal human fibroblasts: p53 and Rb control G1 arrest but not cell replication. Biochem J. 1998;332 ( Pt 1):43-50.

[30] Wagers AJ, Weissman IL. Plasticity of adult stem cells. Cell. 2004;116(5):639-648.

[31] Saretzki G, Armstrong L, Leake A, et al. Stress defense in murine embryonic stem cells is superior to that of various differentiated murine cells. Stem Cells. 2004;22(6):962-971.

[32] Guo YL, Chakraborty S, Rajan SS, et al. Effects of oxidative stress on mouse embryonic stem cell proliferation, apoptosis, senescence, and self-renewal. Stem Cells Dev. 2010;19(9): 1321-1331.

[33] Roos WP, Christmann M, Fraser ST, et al. Mouse embryonic stem cells are hypersensitive to apoptosis triggered by the DNA damage O(6)-methylguanine due to high E2F1 regulated mismatch repair. Cell Death Differ. 2007;14(8):1422-1432.

[34] Tichy ED, Stambrook PJ. DNA repair in murine embryonic stem cells and differentiated cells. Exp Cell Res. 2008;314(9): 1929-1936.

[35] Saretzki G, Armstrong L, Leake A, et al. Stress defense in murine embryonic stem cells is superior to that of various differentiated murine cells. Stem Cells. 2004;22(6):962-971.

[36] Saretzki G, Walter T, Atkinson S, et al. Downregulation of multiple stress defense mechanisms during differentiation of human embryonic stem cells. Stem Cells. 2008;26(2):455-464.

[37] Saretzki G, Walter T, Atkinson S, et al. Downregulation of multiple stress defense mechanisms during differentiation of human embryonic stem cells. Stem Cells. 2008;26(2):455-464.

[38] George S, Heng BC, Vinoth KJ, et al. Comparison of the response of human embryonic stem cells and their differentiated progenies to oxidative stress. Photomed Laser Surg. 2009;27(4):669-674.

[39] Allameh A, Esmaeli S, Kazemnejad S, et al. Differential expression of glutathione S-transferases P1-1 and A1-1 at protein and mRNA levels in hepatocytes derived from human bone marrow mesenchymal stem cells. Toxicol In Vitro. 2009; 23(4):674-679.

[40] Orciani M, Gorbi S, Benedetti M, et al. Oxidative stress defense in human-skin-derived mesenchymal stem cells versus human keratinocytes: Different mechanisms of protection and cell selection. Free Radic Biol Med. 2010;49(5):830-838.

[41] Valle-Prieto A, Conget PA. Human mesenchymal stem cells efficiently manage oxidative stress. Stem Cells Dev. 2010; 19(12):1885-1893.

[42] Ko E, Lee KY, Hwang DS. Human umbilical cord blood-derived mesenchymal stem cells undergo cellular senescence in response to oxidative stress. Stem Cells Dev. 2012;21(11):1877-1886.

[43] Pluchino S, Martino G. The therapeutic plasticity of neural stem/precursor cells in multiple sclerosis. J Neurol Sci. 2008; 265(1-2):105-110.

[44] Reynolds BA, Tetzlaff W, Weiss S. A multipotent EGF-responsive striatal embryonic progenitor cell produces neurons and astrocytes. J Neurosci. 1992;12(11):4565- 4574.

[45] Martino G, Pluchino S. The therapeutic potential of neural stem cells Nat Rev Neurosci. 2006;7(5):395-406.

[46] Wang Q, Chuikov S, Taitano S, et al. Dimethyl Fumarate Protects Neural Stem/Progenitor Cells and Neurons from Oxidative Damage through Nrf2-ERK1/2 MAPK Pathway. Int J Mol Sci. 2015;16(6):13885-13907.

[47] Ivanova NB, Dimos JT, Schaniel C, et al. A stem cell molecular signature. Science. 2002;298(5593):601-604.

[48] Ramalho-Santos M, Yoon S, Matsuzaki Y, et al. "Stemness": transcriptional profiling of embryonic and adult stem cells. Science. 2002;298(5593):597-600.

[49] Noble M, Smith J, Power J, et al. Redox state as a central modulator of precursor cell function. Ann N Y Acad Sci. 2003; 991:251-271.

[50] Madhavan L, Ourednik V, Ourednik J. Increased "vigilance" of antioxidant mechanisms in neural stem cells potentiates their capability to resist oxidative stress. Stem Cells. 2006;24(9): 2110-2119.

[51] Eliasson P, Jönsson JI. The hematopoietic stem cell niche: low in oxygen but a nice place to be. J Cell Physiol. 2010; 222(1):17-22.

[52] Davies KJ. Oxidative stress: the paradox of aerobic life. Biochem Soc Symp. 1995;61:1-31.

[53] Ito K, Hirao A, Arai F, et al. Reactive oxygen species act through p38 MAPK to limit the lifespan of hematopoietic stem cells. Nat Med. 2006;12(4):446-451.

[54] Francois S, Mouiseddine M, Allenet-Lepage B, et al. Human mesenchymal stem cells provide protection against radiation-induced liver injury by antioxidative process, vasculature protection, hepatocyte differentiation, and trophic effects. Biomed Res Int. 2013;2013:151679.

[55] Shi M, Zhang Z, Xu R, et al. Human mesenchymal stem cell transfusion is safe and improves liver function in acute-on-chronic liver failure patients. Stem Cells Transl Med. 2012;1(10):725-731.

[56] Paul MK, Bisht B, Darmawan DO, et al. Dynamic changes in intracellular ROS levels regulate airway basal stem cell homeostasis through Nrf2-dependent Notch signaling. Cell Stem Cell. 2014;15(2):199-214.

[57] Kim YS, Pi SH, Lee YM, et al. The anti-inflammatory role of heme oxygenase-1 in lipopolysaccharide and cytokine-stimulated inducible nitric oxide synthase and nitric oxide production in human periodontal ligament cells. J Periodontol. 2009;80(12):2045-2055.

[58] Zipper LM, Mulcahy RT. Erk activation is required for Nrf2 nuclear localization during pyrrolidine dithiocarbamate induction of glutamate cysteine ligase modulatory gene expression in HepG2 cells. Toxicol Sci. 2003;73(1): 124-134.

[59] Zeng W, Xiao J, Zheng G, et al. Antioxidant treatment enhances human mesenchymal stem cell anti-stress ability and therapeutic efficacy in an acute liver failure model. Sci Rep. 2015;5:11100.

[60] Yang M, Xiao J, Liu YX. Endogenous antioxidant level of stem cell is important for the transplantation efficacy. Inflammation & Cell Signaling. 2015; 2: e946.

[61] Kim HS, Patel K, Muldoon-Jacobs K, et al. SIRT3 is a mitochondria-localized tumor suppressor required for maintenance of mitochondrial integrity and metabolism during stress. Cancer Cell. 2010;17(1):41-52.

[62] Bao J, Lu Z, Joseph JJ, et al. Characterization of the murine SIRT3 mitochondrial localization sequence and comparison of mitochondrial enrichment and deacetylase activity of long and short SIRT3 isoforms. J Cell Biochem. 2010;110(1):238- 247.

[63] Iwahara T, Bonasio R, Narendra V, et al. SIRT3 functions in the nucleus in the control of stress-related gene expression Mol Cell Biol. 2012;32(24):5022-5034.

[64] Chen CJ, Fu YC, Yu W, et al. SIRT3 protects cardiomyocytes from oxidative stress-mediated cell death by activating NF-κB. Biochem Biophys Res Commun. 2013;430(2):798-803.

[65] Jacobs KM, Pennington JD, Bisht KS, et al. SIRT3 interacts with the daf-16 homolog FOXO3a in the mitochondria, as well as increases FOXO3a dependent gene expression. Int J Biol Sci. 2008;4(5):291-299.

[66] Tan WQ, Wang K, Lv DY, et al. Foxo3a inhibits cardiomyocyte hypertrophy through transactivating catalase. J Biol Chem. 2008;283(44):29730-29739.

[67] Tseng AH, Shieh SS, Wang DL. SIRT3 deacetylates FOXO3 to protect mitochondria against oxidative damage. Free Radic Biol Med. 2013;63:222-234.

[68] Tao R, Coleman MC, Pennington JD, et al. Sirt3-mediated deacetylation of evolutionarily conserved lysine 122 regulates MnSOD activity in response to stress. Mol Cell. 2010;40(6): 893-904.

[69] Qiu X, Brown K, Hirschey MD, et al. Calorie restriction reduces oxidative stress by SIRT3-mediated SOD2 activation. Cell Metab. 2010;12(6):662-667.

[70] Wang XQ, Shao Y, Ma CY, et al. Decreased SIRT3 in aged human mesenchymal stromal/stem cells increases cellular susceptibility to oxidative stress. J Cell Mol Med. 2014;18(11): 2298-2310.

[71] Budanov AV, Sablina AA, Feinstein E, et al. Regeneration of peroxiredoxins by p53-regulated sestrins, homologs of bacterial AhpD. Science. 2004;304(5670):596-600.

[72] Tothova Z, Kollipara R, Huntly BJ, et al. FoxOs are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress. Cell. 2007;128(2):325-339.

[73] Nogueira V, Park Y, Chen CC, et al. Akt determines replicative senescence and oxidative or oncogenic premature senescence and sensitizes cells to oxidative apoptosis. Cancer Cell. 2008;14(6):458-470.

[74] Pillai CK, Pillai KS. Antioxidants in health. Indian J Physiol Pharmacol. 2002;46(1):1-5.

[75] Yahata T, Takanashi T, Muguruma Y, et al. Accumulation of oxidative DNA damage restricts the self-renewal capacity of human hematopoietic stem cells. Blood. 2011;118(11): 2941-2450.

[76] Garinis GA, van der Horst GT, Vijg J, et al. DNA damage and ageing: new-age ideas for an age-old problem. Nat Cell Biol. 2008;10(11):1241-1247.

[77] Lombard DB, Chua KF, Mostoslavsky R, et al. DNA repair, genome stability, and aging. Cell. 2005;120(4):497-512.

[78] Sharpless NE, DePinho RA. How stem cells age and why this makes us grow old. Nat Rev Mol Cell Biol. 2007;8(9):703-713.

[79] Schumacher B, Garinis GA, Hoeijmakers JH. Age to survive: DNA damage and aging. Trends Genet. 2008;24(2):77-85.

[80] Beckman KB, Ames BN. The free radical theory of aging matures. Physiol Rev. 1998;78(2):547-581.

[81] Zhang X, Sejas DP, Qiu Y, et al. Inflammatory ROS promote and cooperate with the Fanconi anemia mutation for hematopoietic senescence. J Cell Sci. 2007;120(Pt 9): 1572-1583.

[82] Jung H, Kim MJ, Kim DO, et al. TXNIP maintains the hematopoietic cell pool by switching the function of p53 under oxidative stress. Cell Metab. 2013;18(1):75-85.

[83] Visvader JE, Lindeman GJ. Cancer stem cells in solid tumours: accumulating evidence and unresolved questions. Nat Rev Cancer. 2008;8(10):755-768.

[84] Eyler CE, Rich JN. Survival of the fittest: cancer stem cells in therapeutic resistance and angiogenesis. J Clin Oncol. 2008;26(17):2839-2845.

[85] Szatrowski TP, Nathan CF. Production of large amounts of hydrogen peroxide by human tumor cells. Cancer Res. 1991; 51(3):794-798.

[86] Kawanishi S, Hiraku Y, Pinlaor S, et al. Oxidative and nitrative DNA damage in animals and patients with inflammatory diseases in relation to inflammation-related carcinogenesis. Biol Chem. 2006;387(4):365-372.

[87] Toyokuni S. Novel aspects of oxidative stress-associated carcinogenesis. Antioxid Redox Signal. 2006;8(7-8): 1373-1377.

[88] Hu Y, Rosen DG, Zhou Y, et al. Mitochondrial manganese-superoxide dismutase expression in ovarian cancer: role in cell proliferation and response to oxidative stress. J Biol Chem. 2005;280(47):39485-39492.

[89] Saydam N, Kirb A, Demir O, et al. Determination of glutathione, glutathione reductase, glutathione peroxidase and glutathione S-transferase levels in human lung cancer tissues. Cancer Lett. 1997;119(1):13-19.

[90] Oberley TD, Oberley LW. Antioxidant enzyme levels in cancer. Histol Histopathol. 1997;12(2):525-535.

[91] Townsend DM, Tew KD. The role of glutathione-S-transferase in anti-cancer drug resistance. Oncogene. 2003;22(47): 7369-7375.

[92] Yadav S, Zajac E, Singhal SS, et al. Linking stress-signaling, glutathione metabolism, signaling pathways and xenobiotic transporters. Cancer Metastasis Rev. 2007;26(1):59-69.

[93] Qiao L, Xu Z, Zhao T, et al. Suppression of tumorigenesis by human mesenchymal stem cells in a hepatoma model. Cell Res. 2008;18(4):500-507.

[94] Lu YR, Yuan Y, Wang XJ, et al. The growth inhibitory effect of mesenchymal stem cells on tumor cells in vitro and in vivo. Cancer Biol Ther. 2008;7(2):245-251.

[95] Abdel aziz MT, El Asmar MF, Atta HM, et al. Efficacy of mesenchymal stem cells in suppression of hepatocarcinorigenesis in rats: possible role of Wnt signaling. J Exp Clin Cancer Res. 2011;30:49.

[96] Bagley RG, Weber W, Rouleau C, et al. Human mesenchymal stem cells from bone marrow express tumor endothelial and stromal markers. Int J Oncol. 2009;34(3):619-627.

[97] Mishra PJ, Mishra PJ, Humeniuk R, et al. Carcinoma-associated fibroblast-like differentiation of human mesenchymal stem cells. Cancer Res. 2008 ;68(11): 4331-4339.

引言

器官移植已成为治疗一些器官终末期病变的惟一有效治疗方法。然而，全球普遍存在的器官短缺问题及移植后的免疫排斥反应显著限制了其在临床上的应用^[1]。干细胞有自我更新并能分化成多种细胞谱系的能力，而且来源广泛，能从多种器官、组织中得到，如骨髓、脂肪组织、脾、滑液、肺、肝、牙齿，更为重要的是自体干细胞能够最大程度避免移植后的免疫排斥反应，目前已经成为临床治疗多种疾病的有力手段^[2-3]。有明确报道的临床进展包括急性淋巴细胞白血病^[4]、急性肝衰竭^[5]、骨关节炎等^[6]，给传统医学治疗带来了巨大影响。在各种替代治疗策略中，利用干细胞替代受损宿主细胞及促进宿主内源性细胞再生的再生医学疗法将是最有前景的方法之一^[7-8]。然而，干细胞移植仍属于非常早期阶段，干细胞移植效率仍然低下^[10-11]。有报道显示骨髓单核细胞移植治疗ST段抬高的前壁心肌梗死患者，在冠状动脉介入治疗后经冠状动脉注入骨髓单核细胞的49例患者与对照组(未注入骨髓单核细胞的患者)相比，左心室功能改善及左心室梗死面积无差异^[12]。还有报道认为，干细胞的内源性抗氧化水平影响其在受损部位的存活时间和治疗效率。如经过抗氧化剂N-乙酰半胱氨酸(NAC)处理后的肌源干细胞在小鼠心肌缺血模型中展现了更高的治疗效果，更好地改善了小鼠的心功能。氧化压力对干细胞本身及移植效率的影响和机制及氧化压力是否会造成干细胞癌变尚不明确。本研究通过检索与干细胞移植及抗氧化压力密切相关的可靠性高的文献，比较了不同类型干细胞的内源抗氧化压力水平、氧化压力对干细胞移植效率影响的分子机制及氧化压力对干细胞移植安全性的影响。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

氧化压力与干细胞移植

Oxidative stress and stem cell transplantation

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