Endothelial cells in liver development and regeneration

描述(申请人提供)：肝病影响全球数百万人。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，但由于肝细胞供应有限，其应用一直受到阻碍。胚胎干细胞在培养中形成多种分化细胞类型的能力为细胞替代疗法中可移植的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控ES细胞来源的内胚层对肝脏命运的规范以及成熟为能够重新填充病变肝脏的功能性肝细胞的机制。我们将验证内皮细胞支持ES细胞来源的内胚层细胞在肝脏发育过程中存活、生长、肝脏规格和成熟的假设，并随后确定这些细胞-细胞相互作用的机制。与正常肝脏发育过程中发生的情况类似，肝移植再繁殖需要高度协调的细胞-细胞相互作用。我们将确定在内皮细胞和肝细胞之间的串扰中可能与促进ES细胞来源的肝细胞移植后的肝再生相关的重要分子。这些细胞-细胞相互作用的特征将为建立肝脏谱系的基础研究提供独特的模型，并为肝细胞替代治疗的临床前模型中的移植提供功能性肝细胞。

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.