Transplantation of Endothelial Cells

描述(由申请者提供)：肝脏导向细胞疗法对许多疾病具有巨大的潜力。肝细胞移植的研究为细胞治疗提供了新的见解，也为肝再生和干细胞生物学的基础研究提供了新的模式。我们现在希望确定其他类型的肝细胞的潜力，特别是内皮细胞，它们构成了主要的肝细胞间隔，并在细胞-细胞信号、凝血因子合成和免疫反应中发挥作用。我们的主要假设是肝窦状内皮细胞将在合适的受体的肝脏内植入和增殖。对肝内皮细胞这些特性的深入了解将为治疗特定疾病和调节其他类型肝细胞的行为提供各种应用。因此，我们建议在小鼠身上进行研究，以建立关于移植内皮细胞的存活、命运和功能的机制。我们的具体目标是首先建立转基因标记内皮细胞移植到同种移植受体肝脏的效率，包括在报告基因与病毒载体导入之后，并展示促进移植内皮细胞植入和/或增殖的特定机制。然后，我们将检查治疗基因是否可以在移植的内皮细胞中成功表达，以及这种操作是否可以改变肝脏疾病过程的自然历史。此外，我们将研究细胞与细胞之间的相互作用是否可以在活体环境中重现，以便通过内皮细胞的共移植来调节免疫缺陷动物移植的小鼠或人肝细胞的植入。此外，我们还将研究未受干扰的或转基因内皮肝细胞移植以及内皮干/祖细胞移植是否有助于改善小鼠的疾病。我们期望这些研究将有助于深入了解内皮细胞生物学，提供新的生物学模型，并有助于确定肝内皮细胞的治疗潜力。

DESCRIPTION (provided by applicant): Liver-directed cell therapy has significant potential for many disorders. Studies of hepatocyte transplantation provided insights into cell therapy, as well as novel models for basic studies concerning liver regeneration and stem cell biology. We now wish to define the potential of additional liver cell types, especially endothelial cells, which constitute a major liver cell compartment and contribute in cell-cell signaling, coagulation factor synthesis and immunological responses. Our major hypothesis is that sinusoidal liver endothelial cells will engraft and proliferate in the liver of suitable recipients. Insights into these properties of liver endothelial cells will offer ways to treat specific disorders and to modulate the behavior of other liver cell types for various applications. Therefore, we propose to conduct studies in mice for establishing mechanisms concerning the survival, fate and function of transplanted endothelial cells. Our specific objectives are to first establish the efficiency with which transgenically marked endothelial cells will engraft in the liver of congeneic recipients, including after the introduction of reporter genes with viral vectors, and demonstrate specific mechanisms that would facilitate engraftment and/or proliferation of transplanted endothelial cells. We will then examine whether therapeutic genes can be successfully expressed in transplanted endothelial cells and whether the natural history of hepatic disease processes could be altered by such manipulations. Furthermore, we will examine whether cell-cell interactions can be reproduced in the in vivo setting, such that engraftment of transplanted mouse or human hepatocytes could be modulated in immunodeficient animals by cotransplantation of endothelial cells. Also, we will examine whether transplantation of unperturbed or genetically modified endothelial liver cells and transplantation of endothelial stem/progenitor cells could help ameliorate disease in mice. We expect that these studies will generate insights into endothelial cell biology, offer novel biological models and help define the therapeutic potential of liver endothelial cells.