巨噬细胞在异种脱细胞肝基质体内重塑中表型转化及其分子机制研究

项目名称： 巨噬细胞在异种脱细胞肝基质体内重塑中表型转化及其分子机制研究

项目编号： No.81470873

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 窦科峰

作者单位： 中国人民解放军第四军医大学

项目金额： 67万元

中文摘要： 肝移植是从根本上治疗终末期肝病的方法，但受到供肝匮乏等多项限制，组织工程肝脏有望为肝移植提供理想的功能替代物。本项目组前期利用异种全肝脱细胞支架和自体间充质干细胞体外成功构建具有部分肝代谢功能的新型移植物，并发现其在体重塑结局可能与浸润巨噬细胞的极化密切相关。但巨噬细胞在新型复合移植物重塑过程的极化模式、调控途径和作用机制如何？目前均未见报道。本项目拟在前期研究巨噬细胞极化调控机制的基础上，利用形态学、免疫学和分子生物学等技术，①明确巨噬细胞极化在移植物重塑中的作用，寻找预测重塑结局的量化指标；②研究移植物重塑中调控巨噬细胞极化的关键因素和分子机制；③观察巨噬细胞极化方向对新型移植物主要重塑事件的作用和分子机制，探讨人工调节巨噬细胞极化方向对新型移植物重塑结局的影响。本项目旨在深入研究新型移植物体内重塑中巨噬细胞极化这一重要环节，为阐明移植物体内重塑机制、寻找预测和调控手段提供理论依据。

中文关键词： 细胞外基质；异种移植；重塑；巨噬细胞；极化

英文摘要： Orthotopic liver transplantation is the only available treatment for end-stage liver diiseases, but it is currently limited by organ shortage.Liver tissue engineering provides a promising alternative to liver transplantation in patients with acute and chronic hepatic failure. We demonstrate a novel approach to generate transplantable liver grafts using xenogenic decellularized liver matrix and autologous stem cells. This recellularized graft supports liver-specific function including albumin secretion, urea synthesis and cytochrome P450 expression in vitro. However, the host immune response and remodeling to the graft need to be further investigated for its fate and function in vivo. Macrophage was the major immune cell that infiltrated into grafts mainly constructed by the extracellular matrix. Recently, a clear association between macrophage phenotype and remodeling outcome exists and macrophage phenotype remains an important factor in the processing of ECM-based scaffolds. On the basis of our previous work on macrophage polarization, this research intends to study the following issues based on the use of morphology, immunology and other teshniques: ①the dynamic changes of macrophage polarization and related cytokines in the process of the graft remodeling, and whether macrophage phenotype works as a predictor of constructive remodeling following the implantation of graft; ②the effect and mechanism of graft-related microenvironment on macrophage polarization; ③ the mechanism of macrophage polarization on the main events of the graft remodeling and the effect of artificial-regulated macrophage polarization on the remodeling results of the implanted graft.

英文关键词： Extracellular matrix;Xenotransplantation;Remodeling;Macrophage;Polarization