Development of hepatocytes from ES cells

ES细胞发育成肝细胞

• 批准号: 7264009
• 负责人: VALERIE B GOUON-EVANS
• 金额: $ 12.95万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-15 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7264009
• 关键词: Acetoacetates; Activities of Daily Living; Address; Blood Vessels; Cell Differentiation process; Cell Separation; Cells; Characteristics; Condition; Data; Development; Ectoderm; Embryo; Endoderm; Exposure to; Generations; Germ Layers; Goals; Hematopoietic; Hepatic; Hepatocyte; Human; Hydrolase; Insulin; Intestines; Kinetics; Liver; Liver Failure; Lung; Mediating; Mesoderm; Modeling; Mus; Muscle; Neurons; Organ; Pancreas; Population; Pre-Clinical Model; Regulation; Replacement Therapy; Research Personnel; Serum; Staging; System; Thyroid Gland; Tissues; Translating; Translations; Transplantation; activin A; cell type; embryonic stem cell; human embryonic stem cell; mouse model; progenitor; programs; research study; stem

DESCRIPTION (provided by applicant): The development of definitive endoderm and its subsequent specification leads to the formation of many of the major organs including the liver, pancreas, lungs, thyroid, and intestines. Under appropriate culture conditions, mouse embryonic stem (ES) cells differentiate into embryoid bodies (EBs) that contain derivatives of all three germ layers. Most of these studies have focused on the development of mesoderm and ectoderm derivatives. The development of hematopoietic, vascular, muscle and neuronal lineages were found to parallel that in the early embryo, thus validating the ES system for early developmental studies. More recently, studies have provided evidence for endoderm development in ES differentiation cultures and demonstrated the generation of insulin expressing cells and cells with hepatocyte characteristics. ES studies have not yet established conditions for the efficient induction of endoderm or its specification to liver. This proposal addresses these issues by investigating specific steps of development including (1) induction of ES cells to an endoderm fate, (2) specification of endoderm into a hepatocyte progenitor, called the hepatoblast and (3) maturation of the hepatoblast into a functional hepatocyte. Thus, the liver is the focus in this application as an endoderm-derived tissue. Early endoderm fated cells as well as the hepatoblast will be characterized from ES cell cultures using cell sorting analysis. The liver repopulation potential of endoderm-derived cells will be analyzed in two mouse models of liver failure. The project will also seek to translate the murine ES cell differentiation program to optimize the generation of human hepatocytes. Therefore, the ultimate goal of these studies is to develop a feasible approach to generate functional hepatocytes from ES ells and to understand the mechanisms that orchestrate the hepatocyte development from ES cells.

描述（由申请人提供）： 确定性内胚层的发展及其后续规范导致形成许多主要器官，包括肝脏，胰腺，肺，甲状腺和肠道。在适当的培养条件下，小鼠胚胎茎（ES）细胞分化为包含所有三个胚芽层的衍生物的胚胎体（EB）。这些研究的大多数都集中在中胚层和外胚层衍生物的发展上。发现造血，血管，肌肉和神经元谱系的发展与早期胚胎相似，从而验证了ES系统的早期发育研究。最近，研究为ES分化培养物中的内胚层发育提供了证据，并证明了具有肝细胞特征的胰岛素表达细胞和细胞的产生。 ES研究尚未确定有效诱导内胚层或其对肝脏规范的条件。 该提案通过研究特定的发展步骤来解决这些问题，包括（1）将ES细胞诱导到内胚层命运，（2）内胚层将内胚层的规格指定为肝细胞祖细胞，称为肝细胞和（3）（3）将肝激素成熟为功能性肝细胞。因此，肝脏是该应用中作为内胚层衍生组织的重点。早期的内胚层命运细胞以及肝母细胞将通过ES细胞分析分析从ES培养物中表征。将在两种肝衰竭的小鼠模型中分析内胚层细胞的肝重生潜力。该项目还将寻求翻译鼠ES细胞分化程序，以优化人类肝细胞的产生。因此，这些研究的最终目标是开发一种可行的方法来从ES ELL产生功能性肝细胞，并了解从ES细胞中策划肝细胞发育的机制。