Pathobiology of Ito cells (hepatic stellate cells) with special reference to their myofibroblastic transformation in diseased livers

Ito 细胞（肝星状细胞）的病理生物学，特别是其在患病肝脏中的肌纤维母细胞转化

• 批准号: 10670162
• 负责人: ENZAN Hideaki
• 金额: $ 1.92万
• 依托单位: Kochi Medical School
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10670162/
• 关键词: liver fibrosis; Ito cell; hepatic stellate cell; myofibroblast; cellular transformation; TGF-β; α-smooth muscle actin; immunohistochemistry; TCF-β1; 病理学; 形質転換; 分子生物学TGF

We previously demonstrated that α-smooth muscle actin (ASMA) is a useful phenotypic marker for both normal and transformed Ito cells in the adult human liver. In this study, we examined the mechanism of myofibroblastic transformation of Ito cells in human fibrotic livers and obtained the following results ;1. In almost all types of liver fibrosis, such as hepatitic, posthepatitic, postnecrotic, alcoholic, cardiac and biliary fibrosis, the Ito cells in the areas of liver cell necrosis were always activated. They were swollen, proliferated actively and exhibited myofibroblastic transformation which were easily identified by the cytoplasmic overexpression of ASMA. These transformed Ito cells produced large amounts of collagen and other components of extracellular matrix, while the portal fibroblasts were not significantly associated with the development of liver fibrosis.2. The myofibroblastic transformation of Ito cells was a basic, but strictly localized reaction following liver cell necrosis and appeared to be an initial and key event in liver fibrosis.3. By innunohistochemistry and immunoelectron microscopy, we clear]y demonstrated the localization of transforming growth factor-β (TGF-β) and its latency-associated-peptide (LAP) and latent transforming growth factor binding protein (LTBP) in fibrotic human liver tissues, suggesting the close association of myofibroblastic transformation of Ito cells with the secretion of TGF-β and its activation.Further studies are necessary to elucidate of the mechanism of TGF-βl activation in vivo and the analysis of its receptor's expression.

我们以前证明，α-平滑肌肌动蛋白（ASMA）是一个有用的表型标记正常和转化的Ito细胞在成人肝脏。在本研究中，我们研究了人肝纤维化中Ito细胞肌纤维母细胞转化的机制，并获得了以下结果：1。在几乎所有类型的肝纤维化中，如肝炎性、肝炎后、坏死后、酒精性、心脏和胆道纤维化，肝细胞坏死区的Ito细胞总是被激活。细胞肿胀，增殖活跃，并表现出肌纤维母细胞转化，这很容易通过ASMA的胞质过表达来识别。这些转化的Ito细胞产生大量的胶原蛋白和其他细胞外基质成分，而门静脉成纤维细胞与肝纤维化的发生无明显相关性. Ito细胞的肌纤维母细胞转化是肝细胞坏死后的一种基本但严格局限的反应，似乎是肝纤维化的起始和关键事件.应用免疫组化和免疫电镜技术，明确了转化生长因子-β（TGF-β）及其潜伏相关肽（LTP）和潜伏转化生长因子结合蛋白（LTBP）在人肝纤维化组织中的定位。提示Ito细胞的肌纤维母细胞转化与TGF-β 1的分泌密切相关。TGF-β 1在体内的活化机制及其受体表达的分析有待于进一步研究。

项目成果

林 芳弘 他: "ヒト肝組織におけるtransforming growth factor-βおよびlatency-associated-peptideと潜在型TGF-β結合タンパク(LTBP)の局在"

Yoshihiro Hayashi 等人：“转化生长因子-β、潜伏相关肽和潜伏 TGF-β 结合蛋白 (LTBP) 在人肝组织中的定位”

Raicu V.,Saibara T.,Enzan H el al.: "Dielectric properties of rat liver in vivo.analysis by modeling hepatocytes in the tissue architecture." Bioelectrochemistry and Bioenergetics. 47. 333-342 (1998)

Raicu V.、Saibara T.、Enzan H 等人：“大鼠肝脏体内介电特性。通过组织结构中的肝细胞建模进行分析。”

M.Hiroi,et al.: "Mast cells and the activation of interstitial cells in rat liver fibrosis induced by ligation of common bile ducts"Cells of the Hepatic Sinusoid. 7. 181-182 (1999)

M.Hiroi 等人：“胆总管结扎诱导的大鼠肝纤维化中肥大细胞和间质细胞的活化”肝窦细胞。

T.Saibara,et al.: "Cationic amin acid teransporter in rat Ito cells"Cells of the Hepatic Sinusoid. 7. 30-31 (1999)

T.Saibara 等人：“大鼠 Ito 细胞中的阳离子氨基酸转运蛋白”肝窦细胞。

Y. Hayashi, H. Enzan et al: "Expression of transforming growth factor-β (TGF-β), its latency-associated-peptide (LAP) and latent TGF-β brinding protein (LTBP) in human liver tissue"Progress in Hepatic Sinusoidal Cell Studies. 11(in Japanese). 59-63 (1999)

Y. Hayashi、H. Enzan 等人：“转化生长因子-β (TGF-β)、其潜伏相关肽 (LAP) 和潜伏 TGF-β 结合蛋白 (LTBP) 在人肝组织中的表达”进展肝窦细胞研究 11（日文）59-63（1999）。