Transplantation of Endothelial Cells

肝脏导向细胞疗法对许多疾病具有显著的潜力。肝细胞移植的研究进展 提供了对细胞治疗的见解，以及关于肝脏再生的基础研究的新模型 和干细胞生物学。我们现在希望定义额外的肝细胞类型的潜力，特别是内皮细胞 细胞，构成主要的肝细胞隔室，在细胞-细胞信号转导中起作用，凝血因子 合成和免疫反应。我们的主要假设是正弦形肝内皮细胞将 在合适的受体的肝脏中移植和增殖。对肝内皮细胞这些特性的洞察 将提供治疗特定疾病的方法，并调节各种不同类型的肝细胞的行为 申请。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。我们的具体目标是首先建立 转基因标记的内皮细胞将移植到同种移植受体的肝脏的效率， 包括将报告基因与病毒载体一起导入后，并演示特定的机制 这将促进移植的内皮细胞的植入和/或增殖。然后我们将检查 治疗性基因能否在移植的内皮细胞中成功表达，以及 肝脏疾病过程的自然历史可以通过这样的操作来改变。此外，我们还将 检查细胞间的相互作用是否可以在活体环境中重现，以便植入 在免疫缺陷动物中，移植的小鼠或人肝细胞可以通过 内皮细胞共移植。此外，我们还将检查是否移植未受干扰的或 转基因内皮肝细胞和内皮干/祖细胞移植可能会有所帮助 改善小鼠的疾病。我们预计这些研究将对内皮细胞生物学产生深刻的影响， 提供新的生物学模型，并帮助确定肝内皮细胞的治疗潜力。

Liver-directed cell therapy has siginificant 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.