Mammalian Foregut and Liver Development

哺乳动物前肠和肝脏发育

• 批准号: 8204678
• 负责人: James M Wells
• 金额: $ 36.09万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-01-01 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8204678
• 关键词: Anterior; Bile fluid; Blood Proteins; Cardiac; Cell Adhesion; Cell Culture Techniques; Cells; Data; Defect; Development; Disease; Dose; Drug Metabolic Detoxication; Embryo; Embryonic Development; Endocrine; Endoderm; Event; Exhibits; Exocrine Glands; Fibroblast Growth Factor; Gastrula; Gene Expression; Generations; Genetic; Genetic Programming; Glucose; Glycogen; Goals; Hepatic; Hepatocyte; Hindgut; Human; In Vitro; Intestines; Knock-out; Knowledge; Lateral; Life; Ligands; Link; Liver; Liver diseases; Mammals; Mediating; Mesoderm; Methods; Modeling; Molecular; Morphogenesis; Mus; Operating System; Organ; Pathway interactions; Pattern; Phenotype; Primitive foregut structure; Publishing; Reporting; Repression; Research; Role; Signal Transduction; Site; Somites; Source; Staging; Testing; Time; Tissue Transplantation; Tissues; Translating; Undifferentiated; United States National Institutes of Health; Xenopus; cell type; embryonic stem cell; human disease; human embryonic stem cell; insight; liver transplantation; monolayer; mutant; progenitor; receptor; research study; response

ABSTRACT The long-term goal of this proposal is to elucidate the molecular mechanism controlling mammalian foregut and early liver development. The largest exocrine gland in the body the liver produces bile and is the primary site for detoxification. It also performs important endocrine functions by secreting homeostatic blood proteins and regulating glucose levels through glycogen storage. A recent trans-NIH report "Action Plan for Liver Disease Research (2004)" recognized that a better understanding of embryonic liver development would provide important insights into human liver disease and promote our ability to harness embryonic stem cells as a renewable source of tissue for transplantation. The mouse embryonic liver is induced from the ventral foregut endoderm by Fgf signals from the cardiac mesoderm. While we increasingly understand the genetic pathways regulating proliferation and differentiation of hepatoblasts after the liver bud has formed, the earlier events linking endoderm patterning to hepatic specification are less clear. In Xenopus we recently determined that differential Wnt/¿eta-catenin signaling regulates endoderm fates. Our data supports a model where during gastrula and early somite stages secreted Wnt- antagonists in the anterior endoderm establish foregut identity and initiate a molecular cascade leading to liver development. In contrast, the posterior endoderm has high ¿eta-catenin activity, due to Wnt ligands secreted from the lateral/axial mesoderm, which represses foregut fate and promotes intestinal development. We propose to test this hypothesis using mouse genetics and embryonic explants to characterize the underlying molecular mechanism. Moreover, we will investigate whether analogous pathways are important for liver development in humans using endoderm cultures derived from human embryonic stem cells. The results of this proposal will directly impact efforts to generate therapeutically useful endoderm tissue for the treatment of liver disease in humans. Aim 1. Determine if repression of ¿eta-catenin activity in the anterior endoderm is required for foregut and liver development using mouse genetics. Aim 2. Define when ¿eta-catenin needs to be repressed and examine how the temporally distinct Wnt and Fgf pathways interact during hepatic development, using mouse embryonic explant cultures. Aim 3. Investigate the role of Wnt signaling in promoting human foregut and liver lineages from HESCs

抽象的 该提议的长期目标是阐明控制哺乳动物的分子机制 和早期肝脏发育。 排毒的主要部位也通过分泌稳态来执行重要的内分泌功能 血蛋白和通过糖原储存来调节葡萄糖水平。 肝病研究计划（2004）“认识到对胚胎肝的更好理解 开发将为人类肝病提供重要的见解，并促进我们利用的能力 胚胎干细胞作为移植的可再生组织。 我们是由心脏中胚层的FGF信号从腹侧腹膜内诱导的 越来越了解调节肝类母细胞泛滥和差异的遗传途径 肝芽形成后，将内胚层构图与肝规范链接的早期事件是 在Xenopus中不太清楚。 Eta-catenin信号传导调节 内胚层的命运支持一个模型，在胃和早期阶段 前内胚层中的拮抗剂建立了前表面的启动物，一种分子级联反应，导致 相比之下，肝脏发育。 Eta-catenin活性，由于Wnt配体 从外侧/轴向中胚层分泌，它压抑了前肢命运并促进肠道 发展。 表征了基本的分子机制。 途径对于使用人类的内胚层培养物对人类肝脏发育很重要 胚胎干细胞。 有用的内胚层组织用于治疗人类肝病。 目标1。确定纠正是否前内胚层中的Eta-catenin活性是前面需要的， 使用小鼠遗传学发育。 目标2。定义何时� eta-催他氨酸宁宁宁宁宁需要暂时独特的wnt和 FGF途径在肝发育过程中使用小鼠胚胎外植体培养物相互作用。 目标3。研究Wnt信号传导在促进hESCS的人类和肝谱系中的作用

项目成果

Building additional complexity to in vitro-derived intestinal tissues.

• DOI: 10.1186/scrt362
• 发表时间: 2013
• 期刊: Stem cell research & therapy
• 影响因子: 7.5
• 作者: Brugmann SA;Wells JM
• 通讯作者: Wells JM

Generation of β cells from human pluripotent stem cells: are we there yet?

• DOI: 10.1111/nyas.12369
• 发表时间: 2014-04
• 期刊: Annals of the New York Academy of Sciences
• 影响因子: 5.2
• 作者: Schiesser JV;Wells JM
• 通讯作者: Wells JM