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与肝细胞相比,肝窦内皮细胞的分子特征分析:关于哪种细胞类型应成为基因治疗靶点的思考

Molecular Profiling of Liver Sinusoidal Endothelial Cells in Comparison to Hepatocytes: Reflection on Which Cell Type Should Be the Target for Gene Therapy.

作者信息

El-Maarri Osman, Jamil Muhammad Ahmer, Oldenburg Johannes

机构信息

Institute of Experimental Hematology and Transfusion Medicine, University of Bonn, Bonn, Germany.

出版信息

Hamostaseologie. 2020 Nov;40(S 01):S26-S31. doi: 10.1055/a-1282-2286. Epub 2020 Nov 13.

Abstract

Human factor VIII (FVIII), which deficiency leads to hemophilia A, is largely synthesized and secreted by the liver sinusoidal endothelial cells (LSECs). However, the characteristics of these cells that secrete FVIII are not well known. We have previously reported that based on genome-wide expression and CpG methylation profiling, LSECs have a distinct molecular profile that distinguishes them from other endothelial cells. Hepatocytes are targeted by gene therapy protocols to treat hemophilia A. However, the hepatocyte is not the natural site for FVIII synthesis and current gene therapy protocols are eliciting immune responses that require immune suppression with corticosteroid therapy in a fairly high proportion of patients over a significant period of time. Cellular stress because of ectopic FVIII expression and codon optimization are discussed as potential underlying mechanisms. Here, we highlight the molecular differences between LSECs and hepatocytes.

摘要

人凝血因子VIII(FVIII)缺乏会导致甲型血友病,它主要由肝窦内皮细胞(LSEC)合成和分泌。然而,这些分泌FVIII的细胞的特性尚不清楚。我们之前曾报道,基于全基因组表达和CpG甲基化分析,LSEC具有独特的分子特征,使其有别于其他内皮细胞。肝细胞是治疗甲型血友病的基因治疗方案的靶点。然而,肝细胞并非FVIII合成的天然部位,目前的基因治疗方案正在引发免疫反应,相当一部分患者在相当长的一段时间内需要用皮质类固醇疗法进行免疫抑制。异位FVIII表达和密码子优化导致的细胞应激被认为是潜在的潜在机制。在此,我们强调LSEC与肝细胞之间的分子差异。

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