修回日期: 2008-03-22
接受日期: 2008-05-20
在线出版日期: 2008-05-28
肝脏疾病是影响人类健康的严重疾病, 目前尚没有令人满意的治疗措施, 肝移植技术由于供体的数量、昂贵的价格等因素使其应用受到限制. 近年来, 越来越多的研究对干细胞进行了探索, 研究表明, 肝干细胞在一定条件下可以分化为肝实质细胞, 并在肝损伤修复中起重要作用, 本文就干细胞在肝脏疾病中的应用研究作一综述.
引文著录: 姚鹏, 李绍祥. 肝干细胞与肝损伤的研究进展. 世界华人消化杂志 2008; 16(15): 1655-1660
Revised: March 22, 2008
Accepted: May 20, 2008
Published online: May 28, 2008
The liver diseases remain major causes of death all over the world. Although orthotopic liver transplantation is an effective treatment for end-stage liver diseases. However, shortage of healthy livers for transplantation worldwide have urgently limited the use of liver transplantation for acute and chronic liver diseases. Stem cells play an important role in the concert of liver regeneration. Hepatic stem cells have been shown experimentally to participate in liver proliferation. Furthermore, it has been postulated that hepatic stem cells are able to transdifferentiate into both hepatocytes and bole duct cells. These data indicate a possible role and therapeutic potential of hepatic stem cells in liver diseases. In this paper, we reviewed the application of stem cells in liver diseases.
- Citation: Yao P, Li SX. Advance in hepatic stem cells and liver injury. Shijie Huaren Xiaohua Zazhi 2008; 16(15): 1655-1660
- URL: https://www.wjgnet.com/1009-3079/full/v16/i15/1655.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v16.i15.1655
肝功能严重衰竭, 目前还没有特效的治疗措施, 尽管肝移植为肝衰竭患者提供了有效的治疗方法, 但是由于其费用高昂, 供体肝源有限, 从而使肝移植的广泛应用受到了限制. 最近几年关于肝再生机制和干细胞的可塑性研究发现, 在严重肝损伤的动物模型实验、供受者性别不同的人类肝移植、骨髓移植等研究中证实, 干细胞向肝细胞转化和参与了肝脏功能重建, 体外诱导分化研究也证实, 干细胞具有向肝细胞转化的潜能[1], 最近也有人在人体治疗实验中发现骨髓干细胞参与肝脏再生[2], 这些结果均提示干细胞可能在肝脏结构与功能重建中发挥治疗作用.
干细胞是指具有无限或可被延长自我修复能力的细胞, 按分化能力而言分为: 原始干细胞, 具有多种分化能力[3], 可以自我更新, 并参与有机体的一生组织修复; 前体细胞, 存在于有机体某一组织器官内, 仅向有限的几种组织细胞分化; 成熟组织中的分化细胞, 不能自我修复, 不具有分化能力. 肝干细胞属于前体细胞, 来源于肝脏Herring(汇管区和终末小胆管的连接部分)狭隙和肝内胆管[4-5], 具有双向分化潜能, 能够分化为肝实质细胞和胆管上皮细胞[6-8]. 这种细胞具有特殊的形态特征: 形态较小、核质比率高, 具有卵圆形细胞核, 故又称卵圆细胞[9].
早在1958年Wilsion et al就提出假说: 在肝组织中可能存在干细胞[10]. 之后人们在龌齿类动物的肝组织中发现了双向分化潜能的卵圆细胞[11-12], Haruna et al[13]证实在人的肝组织中也存在这种双潜能的肝祖细胞. 科学家进一步对卵圆细胞进行了克隆和鉴定, 发现其在体外培养能够大量增殖, 细胞移植后在形态和功能上可分化为肝细胞和胆管上皮细胞, 这种具有强大增殖能力和分化潜能的细胞即为肝干细胞. 肝干细胞及其生物功能的确认, 使肝干细胞的研究进入了一个新的时代. 以后大量的实验证实了肝干细胞的分化潜能. 体外实验培养的肝干细胞经诱导可分化为肝实质细胞[13-14], 植入动物体内肝干细胞也可分化为肝实质细胞及胆管上皮细胞, 含肝干细胞的肝细胞悬液移植动物脾内可获得大量的由干细胞分化而来的肝实质细胞[14-15], 并能够提高实验性肝衰竭动物的存活率; 肝干细胞在正常情况下处于静止状态, 但在肝再生能力受到毁灭性打击时, 可以观察到肝干细胞的激活、增殖并向肝细胞等分化[15]. 此时肝干细胞的增殖与分化可能对肝损伤修复具有极为重要的意义.
肝干细胞是一族异源细胞群, 表达肝细胞系及胆系不同的细胞形态标志. 根据其形态特征及定位将其分为3个细胞型. Ⅰ型细胞, 具有原始的形态, 定位于增生的胆管附近并且围绕肝细胞呈腺状排列; Ⅱ型细胞, 与Ⅰ型细胞具有相似的共同形态特征, 但只定位于胆管增生区, 与胆小管细胞毗邻; Ⅲ型细胞, 具有Ⅰ型细胞的共同特征, 并具有成熟肝细胞的形态, 即突出的细胞核和丰富的细胞质[16]. 在大鼠也发现了类似的3种具有不同免疫学特性的细胞群: 原始的卵圆细胞, 不表达甲胎蛋白(AFP), 角蛋白19(CK19), OV-6或谷胱甘肽S-转移酶(p-GST); 肝细胞样卵圆细胞, 表达AFP, 但不表达OV-6或p-GST; 胆管样卵圆细胞, 不表达 AFP但表达CK19, OV-6和p-GST. 大多数卵圆细胞表达胚胎和胆管特异的细胞标志, 只有少数细胞共同表达胚胎和成熟肝细胞标志[17-20].
肝干细胞的存在, 最初是在2-乙酰氨基芴(2-AAF)处理的小鼠肝内[20], 发现有卵圆细胞的诱导增殖, 表达AFP, 推测卵圆细胞可能来自肝内定位的前体细胞. 进一步研究显示, 增殖及分化为肝细胞的前体细胞首先发现在Hering管, 因此认为, Hering管是肝祖细胞及其子代卵圆细胞的来源.
Suzuki et al[21]在发育的小鼠肝脏分离出一种肝干细胞群, 具有多向分化潜能及自我更新能力. 然而, 不像卵圆细胞, 他们不表达肝细胞及胆管细胞特有的细胞标志. 他们能够在体外扩增并且在体内重构肝细胞、胆管细胞、胰岛及肠上皮结构, 这种细胞可能代表定居肝内的肝祖细胞.
另外, 从胰腺分离的胰岛前体细胞体外培养也可分化为肝样细胞[22-23], 这是否提示在胚胎发育过程中, 一些原始的多能干细胞一直保持着未分化状态, 滞留在机体组织内. 无论怎样, 研究肝干细胞的起源是一个十分重要的课题, 对于肝干细胞的进一步基础及临床应用研究具有重要意义.
骨髓内存在大量的成体干细胞, 被称为自体损伤细胞修复库. 研究表明骨髓干细胞具有向一些成体细胞分化的潜能, 可以分化为包括神经细胞[24]、心肌细胞[25]、血管内皮细胞[26-27]、软骨细胞[28]以及肝实质细胞[29]. 在体外诱导剂的作用下, 骨髓干细胞可以向肝实质细胞转化. 在体内, 肝脏微环境诱导骨髓干细胞向肝实质细胞转化也得到研究的证实.
1999年Petersen et al[30]发现肝干细胞和一些肝细胞可能部分来源于骨髓或与骨髓相关. 他们进行了以下研究: (1)将♂大鼠的骨髓移植到致死量照射的同源♀大鼠, 用DNA探针检测受鼠肝内有无雄性来源的Y染色体; (2)用表达MHCⅡ类抗原L21-6的Lewis大鼠作为受体, 不表达L21-6的Brown-Norway大鼠作为供体进行全肝移植, 以确定肝外来源的L21-6阳性细胞是否能够定位于移植的肝脏; 他们发现, 在骨髓移植后13 d, 在肝内检测到了Y染色体信号, 在这一时间卵圆细胞开始分化为肝细胞. 如果分化为肝细胞的卵圆细胞来自肝脏, 将不会有肝细胞表达Y染色体信号, 但结果显示, 一些肝细胞表达明显的Y染色体信号, 表明他们来源于骨髓供体细胞. 同样, 他们在全肝移植后发现, 在移植的肝脏内发现有明显的L21-6阳性细胞, 这表明一些卵圆细胞来源于肝外. 实验表明, 骨髓中含有能够分化为肝细胞潜能的干细胞, 一些卵圆细胞可能来源于骨髓.
骨髓干细胞可以分化为肝细胞, 这种现象是也可发生在人类. 2000年英国科学家Theise et al[31]报道, 在接受男性骨髓移植的女性患者肝脏标本中检测到了Y染色体阳性信号, 接受来自女性肝脏的男性肝移植患者也发现了Y染色体阳性的骨髓来源细胞, 来自骨髓的细胞分化成了肝细胞并表达肝细胞的表面标志. 实验表明, 人类骨髓干细胞确实可以转移定位于肝脏并分化为成熟的肝实质细胞, 而部分肝干细胞也来源于骨髓细胞. 这种现象被称为"转移分化"现象, 多在肝损伤时发生, 分化发生的刺激可能是多方面的, 包括细胞因子、内环境的改变、肝损伤等.
科学家还发现在新鲜的骨髓细胞中检测到表达AFP的肝前细胞, 表达AFP的肝前细胞能够被旁分泌的HGF诱导分化. 骨髓干细胞能够分化为多种细胞, 包括骨[32-33]、肌肉、脂肪、心肌细胞等. 上述研究表明骨髓干细胞同样可能分化成为肝实质细胞. 骨髓中的肝前细胞可以用于肝衰竭的移植治疗而不必考虑组织相容性抗原(major histocompatibility, MHC)的配型问题[34], 因为患者自身的骨髓细胞就可以用于移植. 此外HGF[35-36]也可以通过促进包括骨髓干细胞的肝前细胞分化用于肝硬化治疗, 血液病[37-39]治疗, 肌肉损伤修复[40], 神经系统疾病[41]及心血管疾病[42-43]已应用于临床, 并取得了良好效果. 自体骨髓干细胞移植治疗肝损伤将为肝脏疾病的治疗提供新的途径.
在对肝细胞损害的反应中, 肝脏启动一种免疫应答机制[44-46], 分泌一系列复杂的细胞因子和化学增活素, 这些信号将促进Kupffer细胞和星状细胞浸润到损害区. 肝干细胞可能通过诱导趋化因子如干细胞因子(stem cell factor, SCF)[47-48], 从骨髓中募集而来. 肝干细胞迁移到肝脏并且通过Hering管浸润到肝小叶. 此外, 肝内定居的原始细胞可能是肝干细胞的另一来源. Kupffer细胞和星状细胞释放一系列细胞因子, 包括EGF[49], aFGF, TGF-a、HGF和TNF, 刺激卵圆细胞的增殖、分化[50], 参与肝损伤的修复及肝细胞再生. 最后, Kupffer细胞和星状细胞释放的TGF-a触发卵圆细胞的凋亡机制[51-53], 并且最终导致卵圆细胞介导的肝再生停止. 这样, Kupffer细胞、星状细胞和卵圆细胞释放的细胞因子协同作用, 调控卵圆细胞的增殖和肝实质的重构.
肝脏疾病是影响人类健康的严重疾病, 目前尚没有理想的治疗方法. 干细胞研究具有广泛前景, 在发育生物学、基因功能、细胞治疗和组织细胞替代治疗等领域发挥重要作用, 干细胞本身及诱导分化产生的肝实质细胞可以广泛应用于基因治疗、细胞移植及生物人工肝等方面.
干细胞移植是将干细胞植入体内, 分化为有功能的实质细胞, 以替代因退变、损伤、基因缺陷或自身免疫而受损的细胞, 重构组织器官的结构和功能. 细胞移植已具有较为完备的实验及理论基础, 在理论与技术方面均为干细胞在肝脏疾病中的应用提供了保障, 蕴涵着巨大的潜能. 骨髓干细胞可直接来源于成人的骨髓或外周血, 采集方便, 不存在伦理上的争议, 使其有成为干细胞移植的理想选择[62].
Shi et al[63]将胚胎干细胞经脾脏进行移植, 治疗Wilson's病模型鼠, 移植后在肝内可见胚胎干细胞来源的肝细胞增殖, 说明脾脏内移植的胚胎干细胞有分化为成熟肝细胞的能力. 苏娟 et al[64]用人胎肝干细胞在小鼠脾内移植, 移植后发现胎肝干细胞能在损伤肝脏中增殖并分化为肝细胞. Kushida et al[65]也通过门静脉进行干细胞移植治疗Wilson's病小鼠.
我们成功地采用患者自体骨髓分离纯化骨髓干细胞, 经肝动脉方式移植入肝脏治疗慢性肝功能衰竭[66]. 初步临床应用结果显示, 患者接受自体骨髓干细胞移植治疗后肝功能改善且临床症状有所改善. 然而, 由于该项目开展的时间较短, 病例数有限, 对于其疗效和副作用的准确评估还需要进一步观察.
人工肝支持系统是终末期肝病患者度过危险期或肝移植等待治疗的手段之一[67-69], 然而, 获取足够数量的肝细胞供临床应用十分困难, 猪肝细胞作为肝细胞源已广泛应用[70-73], 但尚存争议. 干细胞具有很强的的再生能力及定向分化潜能, 将干细胞在一定条件下培养扩增, 诱导分化成为成熟肝细胞, 作为肝细胞源, 将具有很好的应用前景.
对于遗传性代谢障碍方面的肝脏疾病, 可以利用转基因技术将缺陷基因转入干细胞, 筛选出阳性细胞移植入患病肝脏, 纠正代谢机能障碍.
总之, 干细胞的研究已挑战了传统的细胞生物学理论, 为疾病的治疗开辟了新的领域. 相信在不久的将来, 干细胞会在肝病的细胞治疗、组织工程和基因治疗方面发挥越来越重要的作用, 为肝病的治疗开辟崭新的途径[74].
肝功能严重衰竭, 目前还没有特效的治疗措施, 肝移植技术由于供体的数量、昂贵的价格等因素使其应用受到限制, 最近的研究发现干细胞可能在肝脏结构与功能重建中发挥治疗作用.
许戈良, 教授, 安徽省立医院肝胆外科; 陈光, 教授, 吉林大学第一医院消化器官外科.
肝干细胞的起源, 骨髓干细胞向肝实质细胞的转化, 干细胞移植治疗肝脏疾病是该研究领域的热点.
2000年英国科学家Theise et al报道, 在接受男性骨髓移植的女性患者肝脏标本中检测到了Y染色体阳性信号, 接受来自女性肝脏的男性肝移植患者也发现了Y染色体阳性的骨髓来源细胞, 来自骨髓的细胞分化成了肝细胞并表达肝细胞的表面标志. 实验表明, 人类骨髓干细胞确实可以转移定位于肝脏并分化为成熟的肝实质细胞, 而部分肝干细胞也来源于骨髓细胞.
本文论述了肝干细胞的存在和在肝损伤时发挥作用, 肝干细胞和骨髓干细胞之间的联系, 并重点论述骨髓干细胞是肝细胞的重要来源并在肝损伤的修复中起着重要的作用.
骨髓干细胞直接来源于成人的骨髓或外周血, 采集方便, 不存在伦理上的争议, 使其有成为干细胞移植的理想选择.
干细胞的研究是组织工程中的重要课题, 为疾病治疗开辟了新领域, 本文为肝脏干细胞研究的综述性文章, 具有较好的学术价值, 但论述缺乏新意.
编辑:李军亮 电编:何基才
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