肝卵圆细胞与肝脏疾病

肝卵圆细胞(Ｈｅｐａｔｉｃｏｖａｌｃｅｌｌ,ＨＯＣ)是在慢性肝病患者的肝脏中出现的一种具有多分化潜能的原始细胞,可分化为过渡细胞小肝细胞和成熟肝细胞,也可向胆管细胞分化[１,２]。ＨＯＣ参与了肝组织的再生,与肝肿瘤的发生有密切的关系。下面就ＨＯＣ与慢性肝病和肝肿瘤的关系作一综述。     

卵圆细胞介导肝脏再生信号通路的研究进展

肝细胞凋亡、坏死、衰老与卵圆细胞的激活和扩增密切相关,此外,卵圆细胞介导肝脏再生是肝损伤后再生的重要组成部分。目前已有多个实验证实了多种细胞因子、激素及神经递质参与此过程。回顾了近年研究结果,简要介绍TWEAK/Fn14、Hedgehog及甲状腺激素等多个信号通路与卵圆细胞介导肝脏再生的关系及研究进展,阐明各个信号通路在卵圆细胞介导肝脏再生中起的作用,了解其调节肝脏再生的机制,或许能对未来临床用药指明靶点。     

肝卵圆细胞在肝脏疾病中的研究现状

近年来,肝卵圆细胞(hepatic oval cells,HOC)逐渐成为研究热点,其参与肝脏结构与功能重建已得到初步证实,这为探讨肝损伤、肝炎、肝纤维化、肝硬化、肝癌等肝脏疾病的发生、发展机制及防治方法提供了新方向和突破点,但其分子机制仍有待深入研究.     

ABC转运蛋白在大鼠肝脏卵圆细胞中的表达

目的研究ABC转运蛋白基因家族的三个主要成员MDR1、MRP1和Bcrp1基因在大鼠肝脏卵圆细胞中的表达及意义。方法建立大鼠2-乙酰氨基芴／三分之二肝切除模型，两步胶原酶灌注结合Percoll密度梯度离心分离大鼠肝脏卯圆细胞和肝细胞，采用免疫组织化学染色检测大鼠肝脏组织中MDR1、MRP1、Bcrp1转运蛋白的表达；采用荧光定量PCR方法检测MDR1、MRP1和Bcrp1基因mRNA在卵圆细胞和肝细胞中的表达水平。结果免疫组织化学染色显示大鼠肝脏组织中MDR1表达位于门静脉区附近，呈放射状分布，Bcrp1表达定位在细胞膜上。大鼠肝脏卵圆细胞MDR1、MRP1和Bcrp1基因mRNA的表达水平分别是肝细胞的9倍、1．5倍和13．8倍。结论卵圆细胞表达高水平的ABC转运蛋白，后者参与卵圆细胞免受外源性化学物质损伤的自我保护机制。     

肝脏卵圆细胞分选与向胰岛β细胞分化研究现状

肝脏卵圆细胞是具有多向分化潜能的干细胞,可转化为胰岛β细胞,为糖尿病的治疗带来了新的希望.目前对于肝脏卵圆细胞的分选主要有Percoll密度梯度离心法、流式细胞技术结合免疫荧光标记单克隆技术(FACS)、免疫磁珠分选技术(MACS)等.分选得到的肝脏卵圆细胞通过一系列转录因子的介导作用可转化为胰岛β细胞,主要的转录因子包括胰腺十二指肠同源盒基因-1(Pdx1)、神经元素3(Ngn3)、神经元分化因子(NeuroD)等,本文从肝脏卵圆细胞的分选和分化等方面对肝脏卵圆细胞向胰岛β细胞分化的研究现状作一综述.     

黄芪汤对肝硬化大鼠肝脏卵圆细胞肝向分化的作用

目的:研究黄芪汤对肝硬化大鼠肝脏卵圆细胞肝向分化的作用机制。方法:应用二甲基亚硝胺制备大鼠肝硬化模型,用黄芪汤治疗,进行肝功能、肝脏病理学检测;应用共聚焦免疫荧光技术检测肝脏卵圆细胞与肝细胞及胆管细胞共定位染色。结果:黄芪汤能显著降低模型大鼠血清AST、TBil水平和肝组织Hyp含量,减少肝组织α-SMA的表达,在模型大鼠肝纤维化逆转过程中,黄芪汤可使Thy1.1与CK19共定位细胞数量显著增加,使肝脏卵圆细胞(HOC)表型和功能发生改变。结论:黄芪汤通过诱导肝脏卵圆细胞肝向分化作用来促进肝硬化逆转。     

二甲基亚硝胺致大鼠肝损害对肝脏卵圆细胞的诱导变化

目的观察肝脏卵圆细胞(Hepatic oval cells，HOC)在二甲基亚硝胺(Dimethylnitrosamine，DMN)致大鼠肝硬化过程中表达的动态变化，探讨其病理生理意义。方法应用DMN造成大鼠肝硬化动物模型，进行常规组织学观察，透射电镜观察HOC超微结构，免疫组化方法检测Thy1．1在模型不同时间点的表达变化。结果于造模4周肝纤维化最重，形成假小叶，伴大面积出血坏死，6周开始缓解，8周炎症明显减轻并以不完全纤维间隔为主。Thy1．1阳性染色细胞2周开始散在分布，4周增多于纤维间隔周围，6周大量出现于汇管区，8周开始减少。超微电镜曼示HOC具有形态小，核以卵圆型为主，高的核／浆比例等特点。结论在DMN大鼠肝硬化形成与消减过程中，Thy1．1染色的肝脏卵圆细胞呈现曼著的阳性表达并有一定的动态变化特征，在肝硬化消减过程中可能具有重要的作用。     

肝卵圆细胞调控机制研究进展

肝卵圆细胞是一类存在于成年肝脏、具有自我更新和多向分化潜能的肝干细胞。当肝脏发生严重损伤且肝细胞再生障碍时,卵圆细胞被激活并大量增殖,参与肝脏损伤的修复与重建。肝卵圆细胞增殖分化是多因素作用的结果。现就肝卵圆细胞的定位、来源及调控机制的研究进展作一概述。     

肝卵圆细胞——肝干细胞研究进展

<正>近年来对干细胞的研究不断深入,人们发现成年肝组织内存在具有干细胞特性的细胞,在特定环境因素作用下可向肝细胞和胆管细胞分化,甚至可向肝癌细胞方向分化,该细胞被称为肝卵圆细胞或肝前体细胞,是具有一定共性的干细胞群体,与其分化的上下游细胞难以区分,本文就     

Hepatic non-parenchymal cells and extracellular matrix participate in oval cell-mediated liver regeneration

AIM： To elucidate the interaction between non- parenchymal cells, extracellular matrix and oval cells during the restituting process of liver injury induced by partial hepatectomy （PH）. METHODS： We examined the localization of oval cells, non-parenchymal cells, and the extracellular matrix components using immunohistochemical and double immunofluorescent analysis during the proliferation and differentiation of oval cells in N-2- acetylaminofluorene （2-AAF）/PH rat model. RESULTS： By day 2 after PH, small oval cells began to proliferate around the portal area. Most of stellate cells and laminin were present along the hepatic sinusoids in the periportal area. Kupffer cells and fibronectin markedly increased in the whole hepatic Iobule. From day 4 to 9, oval cells spread further into hepatic parenchyma, closely associated with stellate cells, fibronectin and laminin. Kupffer cells admixed with oval cells by day 6 and then decreased in the periportal zone. From day 12 to 15, most of hepatic stellate cells （HSCs）, laminin and fibronectin located around the small hepatocyte nodus, and minority of them appeared in the nodus. Kupffer cells were mainly limited in the pericentral sinusoids. After day 18, the normal liver Iobule structures began to recover.CONCLUSION： Local hepatic microenvironment may participate in the oval cell-mediated liver regeneration through the cell-cell and cell-matrix interactions.     

肝脏干细胞

引言近年来干细胞研究已成为世界生命科学领域的热点并取得了较大进展,目前研究认为,不仅胚胎组织含有干细胞,而且成年器官组织中也存在干细胞,如骨髓、中枢神经系统、皮肤、胰腺、胃肠、肝脏等都具有干细胞,本文将近年来肝脏干细胞的有关研究进行综述.     

A selective tropism of transfused oval cells for liver

AIM: To explore the biological behaviors of hepatic oval cells after transfused into the circulation of experimental animals.METHODS: Oval cells from male SD rat were transfused into the circulation of a female rat which were treated by a 2-AAF/CCl4 program, through caudal vein. Sex-determining gene sry which located on Y chromosome was examined by PCR and in situ hybridization technique in liver, kidney and spleen of the experimental animals, respectively.RESULTS: The results of the cell-transplant experiment showed that the srygene was detectable only in the liver but not in spleen and kidney of the experimental rats, and no signals could be detected in the control animals. It can be also morphologically proved that some exogenous cells had migrateci into the parenchyma of the liver and settled there.CONCLUSION: The result means that there are exogenous cells located in the liver of the experimental animal and the localization is specific to the liver. This indicates that some “signal molecules” must exist in the circulation of the rats treated by 2-AAF/CCl4. These “signal molecules” might play an important role in specific localization and differentiation of transfused oval cells.     

肝卵圆细胞分子标志物的研究进展

肝干细胞是一类具有自我更新与增殖分化能力的细胞,能产生表现型与基因型和自己完全相同的子细胞.起源于前肠内胚层,在胚胎发育过程中以肝细胞的形式存在,在成年哺乳动物肝中以小卵圆细胞存在,表现为核大而胞质小并具有特殊的细胞标记.正常情况下这类细胞处于静止期,增生分裂非常慢.当切除或药物损伤后,这类细胞开始活化增生,迅速从静止期进入增殖期.近年来的研究已经证实,肝卵圆细胞在肝细胞严重受损和分裂增生受抑制时呈现出向肝细胞和胆管上皮细胞双向分化的潜能,是一种肝脏的干细胞,目前已经成为热点.肝卵圆细胞不仅在急慢性肝功能不良、晚期肝硬化等肝脏病变,在胰腺病变引起的糖尿病等疾病研究中也开始引起兴趣.但如何发现和获得肝卵圆细胞始终是解决此类问题的关键.本文就肝卵圆细胞的分子标志物的研究进展作一综述.     

急性肝损伤大鼠肝卵圆细胞活化增殖的研究

目的　用D-氨基半乳糖 (D-galactosamine ,D-GalN)联合胆总管结扎 (CommonBiliaryDuctLigation ,CBDL)建立大鼠急性肝损伤模型 ,观察肝损伤后再生过程中肝卵圆细胞 (HepaticOvelCell,HOC)的活化和增殖。 方法　雄性SD大鼠 ,胆总管结扎离断术后予腹腔注射D-GalN 2 .0 g/kg ,对照组不做任何处理。处理后第 1、2、3、4、5及 6天 6个时间点测血清肝功能 ,取肝组织分别行苏木精 伊红染色、电镜、免疫组织化学及RT-PCR检测 ,并对符合HOC形态学特征且胞浆OV-6阳性染色的细胞进行计数。结果　肝功能损害以第 2天明显 (P <0 .0 1) ;对照组肝组织内未见HOC ,处理组各时间点均见有不同程度的HOC增殖反应 ,以第 3天HOC计数最多 (P <0 .0 5 ) ;HOC胞质AFP、OV 6染色阳性 ,胞核BrdU染色阳性 ;RT-PCR示模型组CGT mRNA表达明显增多。结论　用D GalN2 .0 g/kg联合CBDL可获得较满意的大鼠HOC增殖模型 ,在急性肝损伤时HOC被活化和不同程度的增殖 ,参与了肝再生过程     

Specific lectin bindings to oval cells and proliferated bile ductules

Histochemical evaluation of lectins was performed to examine the carbohydrate residues of oval cells induced by administration of α-naphthylisothiocyanate (ANIT), 2-acetylaminofluorene (2-AAF) and 3′-methyl-4-dimethylaminoazobenzene (3′-Me-DAB) in comparison with those of normal bile ducts and proliferated bile ductules induced by bile duct ligation. The normal bile ducts showed intense binding of Ricinus communis agglutinin, concanavalin A and wheat germ agglutinin, and weak binding of Ulex europaeus agglutinin I (UEA I). A few cells in the portal bile ducts showed binding of peanut agglutinin (PNA). Two different binding patterns were observed in oval cells and proliferated bile ductules. One group showed increased binding of PNA, while the other showed intense binding of UEA I. In both groups, binding of other lectins was similar to those of the normal bile duct. The first group included oval cells induced by 2-AAF and 3′-Me-DAB, and the second included both oval cells induced by ANIT and proliferated bile ductules induced by ligation. These results suggest that oval cells and proliferated bile ductules have their own specific carbohydrate residues and that oval cells induced by the carcinogens might be a cell population different from those induced by non-carcinogens and proliferated bile ductules by ligation. The authors wish to thank Dr. T. Itoshima and Dr. Y. Okada for their invaluable suggestions, and Mrs. T. Emi for her assistance in preparation of light microscopic examination.     

The origin and liver repopulating capacity of murine oval cells

The appearance of bipotential oval cells in chronic liver injury suggests the existence of hepatocyte progenitor/stem cells. To study the origin and properties of this cell population, oval cell proliferation was induced in adult mouse liver by 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) and a method for their isolation was developed. Transplantation into fumarylacetoacetate hydrolase (Fah) deficient mice was used to determine their capacity for liver repopulation. In competitive repopulation experiments, hepatic oval cells were at least as efficient as mature hepatocytes in repopulating the liver. In mice with chimeric livers, the oval cells were not derived from hepatocytes but from liver nonparenchymal cells. This finding supports a model in which intrahepatic progenitors differentiate into hepatocytes irreversibly. To determine whether oval cells originated from stem cells residing in the bone marrow, bone marrow transplanted wild-type mice were treated with DDC for 8 months and oval cells were then serially transferred into Fah mutants. The liver repopulating cells in these secondary transplant recipients lacked the genetic markers of the original bone marrow donor. We conclude that hepatic oval cells do not originate in bone marrow but in the liver itself, and that they have valuable properties for therapeutic liver repopulation.