Transplantation of Endothelial Cells

描述（由申请人提供）：肝脏定向细胞疗法对许多疾病具有显著的潜力。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型。我们现在希望确定其他肝细胞类型的潜力，特别是内皮细胞，它们构成了主要的肝细胞区室，并有助于细胞-细胞信号传导、凝血因子合成和免疫反应。我们的主要假设是肝窦内皮细胞将在合适的受体肝脏中移植和增殖。深入了解肝内皮细胞的这些特性将为治疗特定疾病和调节其他肝细胞类型的行为提供方法。因此，我们建议在小鼠中进行研究，以建立有关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的内皮细胞将在同种受体的肝脏中移植的效率，包括在用病毒载体引入报告基因后，并证明促进移植的内皮细胞的移植和/或增殖的特定机制。然后，我们将研究治疗基因是否可以在移植的内皮细胞中成功表达，以及肝脏疾病过程的自然史是否可以通过这种操作来改变。此外，我们将研究细胞间的相互作用是否可以在体内环境中重现，这样移植的小鼠或人肝细胞的植入可以通过内皮细胞的共移植在免疫缺陷动物中进行调节。此外，我们还将研究移植未受干扰的或遗传修饰的内皮肝细胞和内皮干/祖细胞移植是否有助于改善小鼠的疾病。我们希望这些研究将产生对内皮细胞生物学的见解，提供新的生物学模型，并帮助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.