ELF参与肝纤维化中星状细胞活化以及再生结节形成的机制研究
摘要
肝纤维化是各种原因所引起的慢性肝病向肝硬化发展的必经中间环节,是由损伤因素所引起的细胞外基质在肝脏内大量沉积为主要病理特征的疾病[1]。全世界有3.5亿乙肝患者,我国占1/3,而肝炎是导致肝纤维化,肝硬化,以及肝癌的重要原因。作为肝硬化必经的中间环节,肝纤维化的研究极为迫切。
在慢性肝脏损伤过程中,由于ECM (extracellular matrixc,细胞外基质)分泌的增加以及降解的减少,引起ECM大量沉积,最终导致肝纤维化的发生[2],而正常肝脏中,ECM的分泌和降解是受到精密调节的动态平衡过程。HSCs (hepatic stellate cell肝星状细胞)是产生ECM最主要的细胞,其位于肝细胞与肝窦内皮细胞之间的Disse间隙,形态不规则,胞体呈卵圆形,胞质富含类维生素A脂滴。正常时呈静息状态,其功能主要是储存和代谢维生素A,合成和分泌少量的ECM,并有一定的产生胶原酶的作用[3,4]。肝脏受损时HSC被激活,表现出特征性变化：类维生素A脂滴丢失,快速发生形态学改变；表达α-SMA (α-smooth muscle actin,α-平滑肌肌动蛋白)；具有收缩性；表达多种细胞因子及受体；细胞明显增殖,合成大量的ECM[5]。很多因素对HSC激活起促进作用,包括ECM成分和结构的改变,多种生长因子、细胞因子、趋化因子、氧化应激产物和其他可溶性因子等。其中,TGF-β1是目前已知的肝纤维化过程中最重要的促进因子。TGF-β1具有多重的生物学作用,包括细胞发育、生长、分化、凋亡、细胞黏附、迁移、ECM的沉着、免疫应答以及调节ECM蛋白的生成及降解。肝内多种细胞均可分泌TGF-β1,如HSCs、肝细胞、内皮细胞以及Kupffer细胞等。肝纤维化时,随着TGF-β1的激活,可以促进Ⅰ、Ⅲ型胶原基因的表达,引起胶原的沉积[6]。在TGF-β激活的过程中,TGF-β1二聚体首先与TβRⅡ细胞外段结合,TβRⅡ胞内段丝氨酸自身磷酸化并激活,进而与TβRⅠ结合形成异源四聚体,磷酸化TβRⅠ胞内近膜区的GS域的丝氨酸,使其活化。活化的TβRⅠ作用于胞浆Smads蛋白,启动信号转导。活化TβRⅠ首先磷酸化Smad2、3,使其与受体解离。Smad4与活化Smad2或Smad3结合形成复合物,共同转运到核内,直接或通过核内其他转录因子间接调节目的基因的转录.进一步研究发现,在此过程中,Smad3和Smad4的激活和结合需要某些特定的基因参与,包括ELF (embryonic liver fordin胚肝血影蛋白)、Sara、Filamin、Microtubule,其中ELF可能首先被TβR磷酸化,并与Smad3-TβR复合物相结合,通过影响Smad4核内的转运,进而影响后续基因表达的调控[7,8]。
ELF最早由Mishra等在胚胎小鼠肝脏中发现并鉴定,其位于小鼠11号染色体D11XRF到D11BIR6区之间。ELF是p血影蛋白家族的成员之一,它对于维持细胞形态、细胞极性、以及细胞膜上不同功能区域的形成有着重要的作用。ELF通过干扰Smad3的分布和激活,进而影响Smad4的分布和核内转运,从而参与TGF-β/Smad信号传导途径。既往的研究证实,ELF参与各组织器官的生长发育以及多种肿瘤的形成,在对肝癌,肺癌以及胃癌的研究中发现,ELF的表达与肿瘤形成密切相关[9-13]。
在本课题中,我们利用肝纤维化小鼠模型和原代分离的小鼠肝星状细胞研究ELF在肝纤维化过程中的作用机制。
Introduction
Liver fibrosis or cirrhosis, the ultimate pathological consequence of severe chronic liver damage, represents a major medical problem with significant morbidity and mortality worldwide.Liver cirrhosis is characterized by deposition of extracellular matrix (ECM), the distortion of the liver parenchyma replaced by regenerative nodules and altered blood flow.
In normal liver, ECM is a highly dynamic substratum with a precisely regulated balance between synthesis and degradation. During chronic liver injury, however,ECM production exceeds its degradation, and hepatic fibrosis develops as a result of the progressive thickening of fibrotic septae and chemical cross-linking of collagen. Moreover, these changes in ECM composition directly stimulate fibrogenesis Underlying this response is the activation of resident mesenchymal cells into contractile MF, primarily derived from HSCs, that generate scar, which encapsulates injury. HSCs are a resident mesenchymal cell type located in the subendothelial space of Disse, interposed between sinusoidal endothelium and hepatocytes. Following liver injury, HSCs become activated, which leads to the conversion of a resting vitamin A-rich cell [a quiescent HSC (qHSC)] to one that has lost vitamin A droplets, leading to increased proliferation and contraction and the release of proinflammatory, profibrogenic, and promitogenic cytokines. These activated cells are capable of enhanced migration and deposition of ECM components. HSC activation can be conceptually divided into two phases:initiation and erpetuation. Initiation, also known as the preinflammatory stage, refers to early changes in gene expression and phenotype. It is the result of primarily paracrine stimulation from damaged parenchymal cells. Maintenance of these stimuli leads to a perpetuation phase regulated by autocrine and paracrine stimuli. Perpetuation involves at least six distinct changes in HSC behavior, including proliferation, chemotaxis, fibrogenesis, contractility, matrix degradation, and retinoid loss (23).
Following liver injury, several cell types can secrete inflammatory cytokines; these cell types include KCs, hepatocytes, HSCs, natural killer (NK) cells, lymphocytes, and dendritic cells. Cytokines are a family of proteins that include chemokines [monocyte chemotactic protein 1 (MCP-1), RANTES, IL-8], interferons (IFN-a, IFN-y), interleukins (IL-1, IL-6, IL-10), growth factors, adipokines, Of cytokines involved in liver fibrogenesis, TGF-_1 is the most potent profibrogenic mediator [10,12-15].
TGF-β1 transforms HSCs into myofibroblasts, which results in up-regulation of many ECM proteins and down-regulation of their degradation by matrix metalloproteinases and tissue inhibitor of metalloproteinases. Blockade of the TGF-β1 signal by dominant negative typeⅡTGF receptor suppressed the development of dimethylnitrosamine-induced hepatic fibrosis [16,17]. ELF, aβ-spectrin, has been demonstrated to play a pivotal role in TGF-βsignalling [7,8]. It is involved in TGF-β/Smad signalling pathway as an adaptor [7,8] Previous studies had demonstrated the function of ELF during development and tumorigenesis. As showed in elf-/- mice brain,expression of cdk4 was increased and cell in brain was resistant to apoptosis. Loss of ELF in the liver leads the cancer formation by deregulated hepatocyte proliferation and stimulation of angiogenesis in early cancers.Study in lung cancer revealed that disruption in TGF-βsignaling mediated by loss of ELF leads to cell-cycle deregulation by modulating CDK4 and ELF highlights a key role of TGF-βadaptor protein in suppressing early lung cancer.
In view of the importance of TGF-βsignal in liver fibrosis, we hypothesize that ELF, an adaptor in TGF-βsignalling pathway may play a key role in liver cirrhosis. Therefore, we examined ELF expression in cirrhotic liver and evaluated the role of ELF in liver cirrhosis. In this study, we demonstrate that ELF is required for HSC activation and ECM deposition in activated HSCs cultured in vitro; in addition, interestingly, ELF down-regulation in regenerative hepatocytes is involved in the formation of regenerative nodules derived from hepatic progenitor cells (HPC). Thus, this study has identified, for the first time, a molecule participates in liver cirrhosis through the involvement of HSC activation and the formation of regenerative nodule.
在慢性肝脏损伤过程中,由于ECM (extracellular matrixc,细胞外基质)分泌的增加以及降解的减少,引起ECM大量沉积,最终导致肝纤维化的发生[2],而正常肝脏中,ECM的分泌和降解是受到精密调节的动态平衡过程。HSCs (hepatic stellate cell肝星状细胞)是产生ECM最主要的细胞,其位于肝细胞与肝窦内皮细胞之间的Disse间隙,形态不规则,胞体呈卵圆形,胞质富含类维生素A脂滴。正常时呈静息状态,其功能主要是储存和代谢维生素A,合成和分泌少量的ECM,并有一定的产生胶原酶的作用[3,4]。肝脏受损时HSC被激活,表现出特征性变化：类维生素A脂滴丢失,快速发生形态学改变；表达α-SMA (α-smooth muscle actin,α-平滑肌肌动蛋白)；具有收缩性；表达多种细胞因子及受体；细胞明显增殖,合成大量的ECM[5]。很多因素对HSC激活起促进作用,包括ECM成分和结构的改变,多种生长因子、细胞因子、趋化因子、氧化应激产物和其他可溶性因子等。其中,TGF-β1是目前已知的肝纤维化过程中最重要的促进因子。TGF-β1具有多重的生物学作用,包括细胞发育、生长、分化、凋亡、细胞黏附、迁移、ECM的沉着、免疫应答以及调节ECM蛋白的生成及降解。肝内多种细胞均可分泌TGF-β1,如HSCs、肝细胞、内皮细胞以及Kupffer细胞等。肝纤维化时,随着TGF-β1的激活,可以促进Ⅰ、Ⅲ型胶原基因的表达,引起胶原的沉积[6]。在TGF-β激活的过程中,TGF-β1二聚体首先与TβRⅡ细胞外段结合,TβRⅡ胞内段丝氨酸自身磷酸化并激活,进而与TβRⅠ结合形成异源四聚体,磷酸化TβRⅠ胞内近膜区的GS域的丝氨酸,使其活化。活化的TβRⅠ作用于胞浆Smads蛋白,启动信号转导。活化TβRⅠ首先磷酸化Smad2、3,使其与受体解离。Smad4与活化Smad2或Smad3结合形成复合物,共同转运到核内,直接或通过核内其他转录因子间接调节目的基因的转录.进一步研究发现,在此过程中,Smad3和Smad4的激活和结合需要某些特定的基因参与,包括ELF (embryonic liver fordin胚肝血影蛋白)、Sara、Filamin、Microtubule,其中ELF可能首先被TβR磷酸化,并与Smad3-TβR复合物相结合,通过影响Smad4核内的转运,进而影响后续基因表达的调控[7,8]。
ELF最早由Mishra等在胚胎小鼠肝脏中发现并鉴定,其位于小鼠11号染色体D11XRF到D11BIR6区之间。ELF是p血影蛋白家族的成员之一,它对于维持细胞形态、细胞极性、以及细胞膜上不同功能区域的形成有着重要的作用。ELF通过干扰Smad3的分布和激活,进而影响Smad4的分布和核内转运,从而参与TGF-β/Smad信号传导途径。既往的研究证实,ELF参与各组织器官的生长发育以及多种肿瘤的形成,在对肝癌,肺癌以及胃癌的研究中发现,ELF的表达与肿瘤形成密切相关[9-13]。
在本课题中,我们利用肝纤维化小鼠模型和原代分离的小鼠肝星状细胞研究ELF在肝纤维化过程中的作用机制。
Introduction
Liver fibrosis or cirrhosis, the ultimate pathological consequence of severe chronic liver damage, represents a major medical problem with significant morbidity and mortality worldwide.Liver cirrhosis is characterized by deposition of extracellular matrix (ECM), the distortion of the liver parenchyma replaced by regenerative nodules and altered blood flow.
In normal liver, ECM is a highly dynamic substratum with a precisely regulated balance between synthesis and degradation. During chronic liver injury, however,ECM production exceeds its degradation, and hepatic fibrosis develops as a result of the progressive thickening of fibrotic septae and chemical cross-linking of collagen. Moreover, these changes in ECM composition directly stimulate fibrogenesis Underlying this response is the activation of resident mesenchymal cells into contractile MF, primarily derived from HSCs, that generate scar, which encapsulates injury. HSCs are a resident mesenchymal cell type located in the subendothelial space of Disse, interposed between sinusoidal endothelium and hepatocytes. Following liver injury, HSCs become activated, which leads to the conversion of a resting vitamin A-rich cell [a quiescent HSC (qHSC)] to one that has lost vitamin A droplets, leading to increased proliferation and contraction and the release of proinflammatory, profibrogenic, and promitogenic cytokines. These activated cells are capable of enhanced migration and deposition of ECM components. HSC activation can be conceptually divided into two phases:initiation and erpetuation. Initiation, also known as the preinflammatory stage, refers to early changes in gene expression and phenotype. It is the result of primarily paracrine stimulation from damaged parenchymal cells. Maintenance of these stimuli leads to a perpetuation phase regulated by autocrine and paracrine stimuli. Perpetuation involves at least six distinct changes in HSC behavior, including proliferation, chemotaxis, fibrogenesis, contractility, matrix degradation, and retinoid loss (23).
Following liver injury, several cell types can secrete inflammatory cytokines; these cell types include KCs, hepatocytes, HSCs, natural killer (NK) cells, lymphocytes, and dendritic cells. Cytokines are a family of proteins that include chemokines [monocyte chemotactic protein 1 (MCP-1), RANTES, IL-8], interferons (IFN-a, IFN-y), interleukins (IL-1, IL-6, IL-10), growth factors, adipokines, Of cytokines involved in liver fibrogenesis, TGF-_1 is the most potent profibrogenic mediator [10,12-15].
TGF-β1 transforms HSCs into myofibroblasts, which results in up-regulation of many ECM proteins and down-regulation of their degradation by matrix metalloproteinases and tissue inhibitor of metalloproteinases. Blockade of the TGF-β1 signal by dominant negative typeⅡTGF receptor suppressed the development of dimethylnitrosamine-induced hepatic fibrosis [16,17]. ELF, aβ-spectrin, has been demonstrated to play a pivotal role in TGF-βsignalling [7,8]. It is involved in TGF-β/Smad signalling pathway as an adaptor [7,8] Previous studies had demonstrated the function of ELF during development and tumorigenesis. As showed in elf-/- mice brain,expression of cdk4 was increased and cell in brain was resistant to apoptosis. Loss of ELF in the liver leads the cancer formation by deregulated hepatocyte proliferation and stimulation of angiogenesis in early cancers.Study in lung cancer revealed that disruption in TGF-βsignaling mediated by loss of ELF leads to cell-cycle deregulation by modulating CDK4 and ELF highlights a key role of TGF-βadaptor protein in suppressing early lung cancer.
In view of the importance of TGF-βsignal in liver fibrosis, we hypothesize that ELF, an adaptor in TGF-βsignalling pathway may play a key role in liver cirrhosis. Therefore, we examined ELF expression in cirrhotic liver and evaluated the role of ELF in liver cirrhosis. In this study, we demonstrate that ELF is required for HSC activation and ECM deposition in activated HSCs cultured in vitro; in addition, interestingly, ELF down-regulation in regenerative hepatocytes is involved in the formation of regenerative nodules derived from hepatic progenitor cells (HPC). Thus, this study has identified, for the first time, a molecule participates in liver cirrhosis through the involvement of HSC activation and the formation of regenerative nodule.
引文
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