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The Role of Liver Sinusoidal Cells in Hepatocyte-Directed Gene Transfer

机译:肝窦细胞在肝细胞定向基因转移中的作用

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摘要

Hepatocytes are a key target for gene therapy of inborn errors of metabolism as well as of acquired diseases such as liver cancer and hepatitis. Gene transfer efficiency into hepatocytes is significantly determined by histological and functional aspects of liver sinusoidal cells. On the one hand, uptake of vectors by Kupffer cells and liver sinusoidal endothelial cells may limit hepatocyte transduction. On the other hand, the presence of fenestrae in liver sinusoidal endothelial cells provides direct access to the space of Disse and allows vectors to bind to receptors on the microvillous surface of hepatocytes. Nevertheless, the diameter of fenestrae may restrict the passage of vectors according to their size. On the basis of lege artis measurements of the diameter of fenestrae in different species, we show that the diameter of fenestrae affects the distribution of transgene DNA between sinusoidal and parenchymal liver cells after adenoviral transfer. The small diameter of fenestrae in humans may underlie low efficiency of adenoviral transfer into hepatocytes in men. The disappearance of the unique morphological features of liver sinusoidal endothelial cells in pathological conditions like liver cirrhosis and liver cancer may further affect gene transfer efficiency. Preclinical gene transfer studies should consider species differences in the structure and function of liver sinusoidal cells as important determinants of gene transfer efficiency into hepatocytes.
机译:肝细胞是基因疗法治疗先天性代谢异常以及诸如肝癌和肝炎等先天性疾病的关键目标。肝正弦细胞的组织学和功能方面 显着确定了基因向肝细胞的转移效率。一方面,库普弗细胞和肝窦内皮细胞摄取载体 可能会限制肝细胞的转导。另一方面,肝窦内皮细胞中窗孔的 的存在提供了 直接进入Disse的空间,并允许载体将 结合至受体在肝细胞的微绒毛表面。尽管如此, 窗扇的直径可能会根据其大小限制向量 的通过。根据不同物种的窗孔直径的传统手法测量 ,我们发现窗孔直径 影响转基因 DNA的分布腺病毒 转移后肝窦和肝实质细胞之间的关系人的小窗孔可能是男性腺病毒向肝细胞转移的效率低。 正弦波的独特形态特征的消失内皮细胞在诸如肝硬化和肝癌等病理状况下可能会进一步影响基因转移的效率。临床前基因转移研究应考虑 物种在肝窦形 细胞的结构和功能上的差异,这是决定基因向肝细胞转移效率的重要决定因素。 >

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  • 来源
    《American Journal of Pathology》 |2010年第1期|14-21|共8页
  • 作者单位

    From the Center for Molecular and Vascular Biology,Department of Molecular and Cellular Medicine, University of Leuven, Leuven, Belgium;

    and EM Unit Pathology Department and Department of Internal Medicine,University of Maastricht, Maastricht, The Netherlands;

    From the Center for Molecular and Vascular Biology,Department of Molecular and Cellular Medicine, University of Leuven, Leuven, Belgium;

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