修回日期: 2014-11-27
接受日期: 2014-12-05
在线出版日期: 2015-01-08
肝脏疾病相关的死亡率及发病率仍在逐渐上升, 目前, 肝移植仍是终末期肝病的唯一有效的治疗方法, 但供肝短缺、手术风险、长期并发症等问题严重限制其临床发展. 目前迫切需要新的治疗方法, 而肝干细胞(hepatic stem cell, HSC)是一种具有自我更新能力及分化为肝细胞潜能的细胞, 因此成为细胞治疗的新选择. 虽然HSC临床前研究获得较好的结果, 但用于人类的证据仍然缺乏, 目前需要更多关于HSC的研究为人类带来福音.
核心提示: 肝干细胞(hepatic stem cell, HSC)是一种多源性兼性细胞, 具有分化成肝细胞、胆管上皮细胞及其他类型细胞的潜力. HSC的研究在肝病的基础与临床研究中有着极为重要的意义. 利用HSC可改进目前生物人工肝支持系统, 通过肝细胞移植和基因治疗, 使之在肝病相关的疾病治疗中发挥重要的作用.
引文著录: 周阳, 陈嘉勇. 肝干细胞的研究进展. 世界华人消化杂志 2015; 23(1): 64-70
Revised: November 27, 2014
Accepted: December 5, 2014
Published online: January 8, 2015
Liver disease is a rising cause of mortality and morbidity, and treatment options remain limited. Liver transplantation is curative but limited by donor organ availability, operative risk and long-term complications. There is currently a clear need for new therapies for liver disease, and it is possible that hepatic stem cell (HSC) therapy represents an exciting new therapeutic option. HSCs are undifferentiated cells with the unique ability to self-renew and potentially provide a source of human hepatocytes for regeneration of the injured liver. Evidence from pre-clinical studies is encouraging, but conclusive evidence that this translates into humans remains lacking. Further studies of the mechanisms responsible for the beneficial effects of HSC therapy are needed.
- Citation: Zhou Y, Chen JY. Progress in research of hepatic stem cells. Shijie Huaren Xiaohua Zazhi 2015; 23(1): 64-70
- URL: https://www.wjgnet.com/1009-3079/full/v23/i1/64.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v23.i1.64
终末期肝病是人类健康的杀手, 发病率正在全世界逐渐增加. 目前, 肝移植仍是终末期肝病的唯一有效的治疗方法[1], 但供肝短缺、手术损伤、免疫排斥反应、手术难度高以及费用高昂等问题严重阻碍了肝移植技术的发展[2,3]. 与之相比, 干细胞移植具有供体细胞来源丰富、手术损伤小、免疫排斥少、费用低等优点, 为终末期肝病的治疗开辟新的道路, 也可作为肝移植前后肝功能支持的有效手段之一[4,5].
干细胞是一种能自我更新并具有多项分化潜能的细胞. 根据其原始程度又可分为全能干细胞、多能干细胞和专能干细胞. 肝干细胞(hepatic stem cell, HSC)并非特指某一种类的细胞, 而是与肝脏发育及再生有关的各类具有干细胞特性细胞类型的总称. HSC是一类具有双向分化(可同时向肝细胞和胆管细胞分化)、自我更新的原始细胞, 参与肝脏损伤后的结构重建与功能修复, 与肝脏的发育、再生、纤维化及癌变等生理、病理过程密切相关. HSC是多源的, 据其起源不同, 可分为肝源性HSC和非肝源性HSC, 肝源性HSC包括成熟肝细胞、肝卵圆细胞、小肝细胞、胎HSC等. 非肝源性HSC主要包括胚胎干细胞(embryonic stem cell, ESC)、骨髓干细胞等.
人肝源性干细胞在正常肝脏中处于静止状态, 当肝脏受到严重损伤, 且肝细胞的增殖受到抑制时才会被活化, 分裂增殖[6], 分化为肝实质细胞和胆管上皮细胞, 使得肝功能得以重建[7]. 非肝源性HSC主要来源于ESC、骨髓干细胞等.
1956年Farber揭开了HSC研究的新篇章, 他首次提出在肝内存在小上皮细胞, 在由化学因素诱导的肝细胞癌早期, 这种细胞大量增殖, 修复受损肝脏. 因其形态学特征为细胞体积小、胞质少、核大呈卵圆形故命名为卵圆细胞. 随后人们在龋齿类动物的肝组织中发现了具有双向分化潜能的卵圆细胞[8], HOC高度表达白蛋白(albumin, ALB)、甲胎蛋白(alpha fetoprotein, AFP)等肝细胞表面标志物, 也表达细胞角蛋白(cytokeratin, CK)7、19胆管上皮细胞的表面标志物及骨髓干细胞CD34等表面标志物, 但目前无特定的细胞表面标志物[9]. HOC具有自我复制及双向分化能力, 许多体内研究表明卵原细胞能分化为肝细胞和胆管上皮细胞[10,11]. Li等[12]采用2-乙酰氨基芴/四氯化碳方法建立HOC增殖模型, 证明了大鼠HOC体外可大量增殖并且保留其干细胞的双向分化潜能HOC主要位于哺乳动物肝脏胆管末端的Hering管. 细胞周围微环境在肝再生中发挥重要作用[9], 细胞外基质重构促进卵原细胞的激活、增殖及修复过程[13].
Chen等[14]在肝细胞原代培养的培养基中加入尼克酰胺和表皮生长因子时, 出现单个核小细胞增生, 并形成克隆, 被称为小肝细胞. 小肝细胞具有增殖潜能, 能双向分化为肝细胞和胆管上皮细胞. 有观点认为小肝细胞是肝祖细胞分化成熟为肝细胞过程中的一种中间细胞, 有研究认为他可能是肝细胞的专能祖细胞[15], 小肝细胞在肝内无确切定位, 目前对其来源及定位有待进一步研究.
以往认为成熟肝细胞为终末细胞, 但近年认为他具有高度增殖和分化能力. 成熟肝细胞来源于肝母细胞, 肝母细胞可分化为肝细胞和胆管上皮细胞[1], 成熟的肝细胞高度表达细胞色素P450、ALB, 并能储存糖原, 合成尿素及结合游离胆红素, 但表达AFP的能力降低[16,17]. 分化成熟的肝细胞属于稳定细胞, 在生理情况下增殖现象不明显, 只有极少数量的成熟肝细胞分裂, 参与正常肝组织的更新, 当肝脏受损时或给予恰当刺激, 肝细胞被激活, 通过增殖、分化、再生, 以完成肝脏结构重建和功能修复. 但此类细胞分裂增殖能力有限, 在许多疾病或肝脏严重受损情况下增殖能力不能满足机体需要, 此外, 某些疾病如脂肪肝时的高氧化应激反应也可以抑制肝细胞的增殖.
胎HSC在早期胚胎肝脏出现, 是一类来源于腹侧前肠内胚层、具有自我更新和双向分化潜能的原始细胞, 可分化为肝细胞和胆管上皮细胞. 胎HSC除表达ALB和CK19外, 还多表达造血干细胞相关分子标志物如CD133、CD34等, 及间充质干细胞(mesenchymal stem cells, MSC)相关标志物如CD90、CD29等, 三者之间的谱系关系目前尚无定论[18,19].
ESC是从早期囊胚的内胚层中分离出来的一类多潜能干细胞, 具有强大的自我增殖及分化潜能[1]. Touboul等[20]应用激活素、成纤维细胞生长因子等诱导ESC分化, 并成功获得了成熟肝细胞. 目前可以通过简化的3个步骤将ESC直接分化为肝细胞样细胞, 且有效性达到90%[20,21]. 国际上虽对胚胎HSC的研究取得巨大进步, 但对其生物学特性、体外诱导分化及其应用于肝硬化治疗等方面的研究仍不充分[22]. 且其主要来源于体外受精的胚胎和流产的胎儿, 临床应用面临伦理学挑战, 而ESC无限增殖可能致畸胎瘤等问题也有待解决.
脐血中含有无限制成体干细胞、造血干细胞等多种干细胞成分. 脐血中干细胞比例明显高于成人骨髓及外周血[23], 且来源为产后丢弃的脐带, 采取脐带血对母体及婴幼儿无任何损伤. 目前, UCBSC分化为成熟肝细胞的可行性及其移植的疗效也已经得以证实[24].
骨髓干细胞主要包括骨髓造血干细胞和骨髓MSC, 具有多向分化潜能, 可以分化为多种组织细胞, 包括肝细胞、神经细胞、心肌细胞和骨骼肌细胞等[25]. 最早Petersen等[26]报道了关于骨髓来源干细胞可促进肝再生, 逐渐有较多的研究表明骨髓干细胞分化为肝细胞用于肝再生[27-29]. 关于粒细胞集落刺激因子动员自体骨髓和造血干细胞移植用于治疗人类终末期肝硬化也出现了明显的效益[30], 白介素-8、基质金属蛋白酶等已被证明是促进对肝造血干细胞的归巢和植入[31]. 最新的研究还发现骨髓MSC具有免疫调节功能, 通过免疫调节可抑制肿瘤的发生及生长[25,32]. 目前, 骨髓MSC用于治疗终末期肝病的一期和二期临床实验均获得较好的结果[33].
IPSC是一项通过基因转染技术把一些特定的转录因子导入体细胞而获得干细胞样特性的体细胞[1]. Takahashi等[34]首次报道IPSC, 目前已证明IPSC可分化为多种细胞类型[9,35], 包括肝细胞. Sullivan等[36]证实IPSC可分化为肝脏内胚层细胞, 且有效分化率为70%-90%, IPSC源性肝细胞可合成ALB、AFP等肝脏功能性蛋白. IPSC衍生的肝细胞携带原代细胞的所有异常或疾病的表型, 可用于探讨疾病发病机制及药物个体化使用[37,38]. 我国Yu等[39]实现了小鼠成纤维细胞向HSC分化的重编程, 并证明了获得的IPSC具有与活体内自然存在的HSC相似的生物学特性. 因其体外获得而被广泛接受, 但其具体分化目的不确定性及潜在的致癌性需进一步研究.
尽管目前临床诊治技术及肝移植有所发展, 但急性肝功能衰竭死亡率仍高. 有数据表明, 暴发性肝衰竭可能从人HSC移植治疗中获益[40]. 在急性肝损伤大鼠模型, 人类MSC培养液治疗可导致肝细胞凋亡减少90%, 显著降低大鼠死亡率[41,42]. 此外, 干细胞也可分泌一些如肝细胞生长因子、表皮生长因子和神经生长因子等刺激肝细胞增殖并维持肝细胞功能, 在暴发性肝衰竭和肝损伤模型中这些分泌可促进肝脏再生[43]. 而在慢性肝损伤方面, 较多的研究表明HSC治疗能降低肝脏炎症程度[44], 促进肝细胞再生, 降低肝纤维化及死亡率[44-48]. Li等[43]研究发现, 移植骨髓MSC及造血干细胞均能增高存活率及降低肝纤维化, 但MSC治疗效果较HSC好, 并提出MSC与HSC有协同增强效应.
目前细胞治疗可作为肝移植的替代疗法, 大量的实验室及临床研究鼓励细胞移植用于临床治疗各种肝病[27]. Kim等[49]一项关于10例乙型肝炎相关肝硬化研究表明, 自体骨髓干细胞移植能改善肝硬化患者ALB水平, Child-Pugh评分及磁共振测量下肝容积, 并能改善生活质量, 且无严重并发症发生. Peng等[50]对527例乙型肝炎相关肝硬化患者进行研究, 53例治疗组(经肝动脉自体骨髓干细胞移植)与105例空白对照组比较, 短期内(1-48 wk)治疗组肝功能得到改善, 且长期观察治疗组未发现肿瘤发生率增高. 一项关于熊去氧胆酸不完全应答原发性胆汁性肝硬化患者的研究显示, 接受脐血MSC移植后部分患者瘙痒、乏力症状明显改善[51]. Ivantes等[52]报道259例丙型肝炎患者在进行骨髓干细胞移植后, 10年随访91例存活, 术后存活率明显提高.
尽管干细胞的使用受益颇多, 但其使用长期安全性仍需进一步研究, 特别是肿瘤发生的可能性. 肝癌发病率在全球十大恶性肿瘤中位居第5位, 而死亡率仅次于肺癌和结肠癌位居第3位[53]. 目前公认的肝癌发生机制有两种: (1)由肝脏干细胞的异常分化引起; (2)由成熟肝细胞去分化导致. 肝癌细胞表达与HSC相关的蛋白, 其增殖的调节有某些相同的信号通路, 如Wnt、Shh、Notch等信号通路. 目前, 经典Wnt信号通路与肝癌干细胞的增殖、凋亡研究较多[54], 经典Wnt信号途径的异常激活可能导致肝癌的发生[55,56]. 肿瘤发生也可能源于肿瘤干细胞, 而肿瘤干细胞的来源可能是正常干细胞的凋亡失调, 使得干细胞突变积累等原因所致[57]. 干细胞也可能通过抑制免疫反应及直接供给肿瘤细胞营养而促进肿瘤的发生[58]. Shinagawa等[59]研究表明对健康裸鼠移植结肠肿瘤细胞及干细胞肿瘤明显较对照组(单独移植肿瘤细胞)大, 可能与干细胞促进血管生成及阻碍肿瘤细胞凋亡导致. 而Jensen等[60]研究发现增加移植干细胞数量并未促进肿瘤的发生.
过去几年关于干细胞生物型人工肝研究较多, 但其应用于临床仍存在许多问题, 包括干细胞的获得及保持体外存活及分化能力[1]. 生物人工肝可过滤和转化体内有毒物质, 从而为等待肝移植患者争取时间, 也可用于辅助治疗急慢性肝功能衰竭[9]. Stutchfield等[61]研究表明, 生物人工肝支持治疗较传统的治疗方法能降低急性肝功能衰竭的死亡率, 但因其应用于人工肝肝细胞体外功能障碍而限制其临床应用. 体外培养HSC其强大的增殖能力及多生物学特点为生物人工肝提供了一种新的细胞来源, ES和iPS细胞可作为一种混合型人工肝细胞来源.
HSC用于治疗先天性代谢性肝病治疗的基础为具有高度增殖能力及双向分化潜能, 通过将缺陷基因导入HSC, 筛选出阳性细胞移植人肝脏可纠正肝脏代谢紊乱, 用于治疗代谢性肝病[1,62]. 大量干细胞移植实验获得成功, 促进临床应用干细胞治疗急慢性肝衰竭、肝硬化及成人和儿童代谢性肝病治疗的发展[63], Muraca等[64]报道干细胞成功治疗糖原累积综合症一例. Song等[65]也报告利用腺相关病毒技术对鼠源性肝前体细胞进行基因修饰, 认为利用基因修饰的HSC可作为治疗α1抗胰蛋白酶缺乏等肝病的独特途径.
HSC可以为肝衰竭患者度过危险期、等待肝源进行肝移植的一个过渡方法, 又能直接修复损伤肝脏, 作为细胞疗法应用于临床治疗肝衰竭及各种终末期肝病. HSC是目前肝病基础研究的重点之一, 但其应用于临床仍有许多问题, 如人HSC建系困难, 不易分离、纯化, 人HSC生长缓慢, 体外培养易分化, 失去分裂增殖能力, 且干细胞治疗的长期有效及安全性缺乏相关资料. 在克服了一系列困难之后, HSC移植将为生物人工肝、终末期肝病治疗、药物研究以及肝脏肿瘤预防等领域的研究带来新的曙光和希望.
终末期肝病是人类健康的杀手, 发病率正在全世界逐渐增加. 肝移植因供肝短缺、手术损伤、免疫排斥反应、手术难度高以及费用高昂等问题临床应用受限. 干细胞移植具有供体细胞来源丰富、手术损伤小、免疫排斥少等优点, 为终末期肝病的治疗开辟了新的道路.
许戈良, 教授, 安徽省立医院
生物人工肝可过滤和转化体内有毒物质, 从而为等待肝移植患者争取时间, 也可用于辅助治疗急慢性肝功能衰竭, 生物人工肝支持治疗较传统的治疗方法能降低急性肝功能衰竭的死亡率. 体外培养肝干细胞(hepatic stem cell, HSC)其强大的增殖能力及多生物学特点, 为生物人工肝提供了一种新的细胞来源.
诱导型多能干细胞(induced pluripotent stem cell, IPSC)是一项通过基因转染技术把一些特定的转录因子导入体细胞而获得干细胞样特性的体细胞. 我国胡以平等实现了小鼠成纤维细胞向HSC分化的重编程, 并证明了获得的IPSC具有与活体内自然存在的HSC相似的生物学特性.
HSC用于治疗先天性代谢性肝病, 通过将缺陷基因导入HSC, 筛选出阳性细胞移植人肝脏可纠正肝脏代谢紊乱. 目前已有关于治疗糖原累积综合症、α1抗胰蛋白酶缺乏等肝病的报道.
HSC可以为肝衰竭患者度过危险期、等待肝源进行肝移植的一个过渡方法, 又能直接修复损伤肝脏, 促进生物人工肝、终末期肝病治疗、药物研究以及肝脏肿瘤预防等领域的发展.
本文参考文献较新, 能够很好地反映当前关于HSC的研究进展和方向, 详细阐述了HSC研究与生物人工肝、终末期肝病治疗、药物研究以及肝脏肿瘤预防等领域的相关问题.
编辑:韦元涛 电编:都珍珍
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