Endothelial cells in liver development and regeneration

描述（由申请人提供）：肝病影响着全球数百万人。肝细胞移植被认为是一种潜在的肝病治疗方法，也是等待肝移植患者的桥梁，但其应用受到肝细胞供应有限的阻碍。胚胎干（ES）细胞在培养物中形成多种分化细胞类型的能力为细胞替代疗法的可移植谱系和组织的产生提供了独特的模型系统。该项目的长期目标是确定调节ES细胞来源的内胚层向肝脏命运的特化以及成熟为能够重新填充患病肝脏的功能性肝细胞的机制。我们将测试的假设，内皮细胞支持胚胎干细胞衍生的内胚层细胞的生存，生长，肝规范和成熟过程中的肝脏发育，我们将随后确定这些细胞-细胞相互作用的机制。与正常肝脏发育期间发生的情况类似，肝移植再增殖需要高度协调的细胞-细胞相互作用。我们将确定内皮细胞和肝细胞之间串扰的重要分子参与者，这些分子可能与ES细胞衍生的肝细胞移植后促进肝再生有关。这些细胞-细胞相互作用的表征将为建立肝谱系的基础研究提供独特的模型，并为肝细胞替代疗法的临床前模型中的移植提供功能性肝细胞。 公共卫生相关性：肝细胞移植被认为是一种潜在的但尚未实现的肝病治疗方法。从胚胎干细胞（ES）培养产生的肝细胞可以为移植提供无限的细胞供应。我们将测试移植过程中内皮细胞和ES细胞衍生的肝细胞之间的相互作用促进成功的肝再生的假设。这些细胞-细胞相互作用的表征将提供对从ES细胞培养物建立肝谱系的深入了解，以及为肝细胞替代疗法的临床前模型提供功能性ES细胞衍生的肝细胞。

DESCRIPTION (provided by applicant): Liver disease affects millions of people worldwide. Hepatocyte transplantation is considered a potential treatment for liver diseases and a bridge for patients awaiting liver transplantation, but its application has been hampered by a limited supply of hepatocytes. The capacity of embryonic stem (ES) cells to form multiple differentiated cell types in culture provides a unique model system for the generation of transplantable lineages and tissues for cell replacement therapies. The long-term goal of this project is to define the mechanisms regulating the specification of ES cell-derived endoderm to a hepatic fate, and maturation to functional hepatocytes that are able to repopulate a diseased liver. We will test the hypothesis that endothelial cells support ES cell-derived endoderm cell survival, growth, hepatic specification and maturation during liver development and we will subsequently determine the mechanisms underlying these cell-cell interactions. Similar to what occurs during normal liver development, liver transplant repopulation requires highly orchestrated cell-cell interactions. We will identify the important molecular players in the crosstalk between endothelial cells and hepatic cells that could be relevant for promoting liver regeneration following transplantation with ES cell-derived hepatic cells. The characterization of these cell-cell interactions will provide a unique model for basic studies on the establishment of the hepatic lineage as well as provide functional hepatic cell for transplantation in pre-clinical models of liver cell replacement therapy. PUBLIC HEALTH RELEVANCE: Hepatocyte transplantation is considered a potential but unrealized treatment for liver diseases. Hepatocytes generated from embryonic stem (ES) cell cultures could provide an unlimited supply of such cells for transplantation. We will test the hypothesis that interactions between endothelial cells and ES cell-derived hepatic cells during transplantation promote successful liver regeneration. The characterization of these cell- cell interactions will provide insight into the establishment of the hepatic lineage from ES cell cultures, as well as provide functional ES cell-derived hepatic cells for pre-clinical models of liver cell replacement therapy.