Endothelial cells in liver development and regeneration

内皮细胞在肝脏发育和再生中的作用

• 批准号: 8450908
• 负责人: VALERIE B GOUON-EVANS
• 金额: $ 33.6万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-20 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8450908
• 关键词: Affect; Biological Models; Cell Communication; Cell Culture Techniques; Cell Lineage; Cell Survival; Cell Transplantation; Cells; Data; Development; Ectoderm; Endoderm; Endoderm Cell; Endothelial Cells; Event; Generations; Germ Layers; Goals; Growth; Hepatic; Hepatocyte; Instruction; Knowledge; Link; Liver; Liver Regeneration; Liver diseases; Mediating; Mesoderm; Modeling; Molecular; Mus; Natural regeneration; Pathway interactions; Patients; Pre-Clinical Model; Process; Proliferating; Replacement Therapy; Role; Serum; Signal Transduction; Testing; Tissues; To specify; Transplantation; activin A; cell type; embryonic stem cell; in vivo; inhibitor/antagonist; insight; liver injury; liver transplantation; mouse model; progenitor; public health relevance; receptor; research study; stem cell differentiation

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.

描述（由申请人提供）：肝病影响全球数百万的人。肝细胞移植被认为是肝病的潜在治疗方法，也是等待肝移植的患者的桥梁，但其应用受到有限的肝细胞供应的阻碍。胚胎（ES）细胞在培养中形成多种分化细胞类型的能力为生成可移植谱系和细胞替代疗法组织的组织提供了独特的模型系统。该项目的长期目标是定义调节ES细胞衍生的内胚层规范到肝命运的机制，并成熟到能够重新填充患病肝脏的功能性肝细胞。我们将检验以下假设：内皮细胞支持ES衍生的内胚层细胞存活，生长，肝规范和肝发育过程中的成熟，随后我们将确定这些细胞相互作用的机制。与正常肝发育过程中发生的情况相似，肝移植重生需要高度精心策划的细胞 - 细胞相互作用。我们将确定内皮细胞和肝细胞之间串扰中的重要分子参与者，这些分子参与者与ES细胞衍生的肝细胞移植后可能有关促进肝脏再生。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，并在肝细胞替代疗法的临床前模型中提供功能性肝细胞进行移植。