Endothelial cells in liver development and regeneration

描述（由申请人提供）：肝脏疾病影响全球数百万人。肝细胞移植被认为是肝脏疾病的潜在治疗方法，也是等待肝移植患者的桥梁，但由于肝细胞供应有限，其应用受到阻碍。胚胎干细胞（ES）在培养中形成多种分化细胞类型的能力为可移植谱系和细胞替代治疗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胚胎干细胞来源的内胚层向肝脏分化的调节机制，并使其成熟为能够重新填充病变肝脏的功能性肝细胞。我们将验证内皮细胞支持胚胎干细胞衍生的内胚层细胞在肝脏发育过程中的存活、生长、肝脏发育和成熟的假设，并随后确定这些细胞间相互作用的机制。与正常肝脏发育过程类似，肝移植的再生需要高度协调的细胞间相互作用。我们将确定内皮细胞和肝细胞之间的串扰中的重要分子，这些分子可能与胚胎干细胞来源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脏谱系的基础研究提供一个独特的模型，并为肝细胞替代治疗的临床前模型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. 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.