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

摘要 这项提案的长期目标是阐明控制哺乳动物前肠的分子机制 和早期肝脏发育。肝脏是人体内最大的外分泌腺，它产生胆汁， 解毒的主要场所。它还执行重要的内分泌功能， 血蛋白和通过糖原储存调节葡萄糖水平。最近的一份跨NIH报告"行动 肝病研究计划（2004年）"认识到，更好地了解胚胎肝脏 发展将为人类肝脏疾病提供重要的见解，并提高我们利用 胚胎干细胞作为移植组织的可再生来源。小鼠胚胎肝脏 通过来自心脏中胚层的FGF信号从腹侧前肠内胚层诱导。虽然我们 越来越多地了解调控成肝细胞增殖和分化的遗传途径 肝芽形成后，内胚层形成与肝特化的早期联系是： 不太清楚。在非洲爪蟾中，我们最近确定差异Wnt/β-连环蛋白信号调节 内胚层命运我们的数据支持一个模型，在原肠胚和早期体节阶段分泌Wnt- 前内胚层中的拮抗剂建立前肠身份并启动分子级联， 肝脏发育相反，由于Wnt配体，后内胚层具有高的β-连环蛋白活性， 从侧/轴向中胚层分泌，其抑制前肠命运并促进肠 发展我们建议使用小鼠遗传学和胚胎外植体来验证这一假设， 描述潜在的分子机制。此外，我们将研究是否类似 使用来源于人类的内胚层培养物， 胚胎干细胞这项提案的结果将直接影响到产生治疗效果的努力， 用于治疗人类肝病的内胚层组织。 目标1.确定前肠是否需要抑制前内胚层中的β-连环蛋白活性， 使用小鼠遗传学进行肝脏发育。 目标2.定义何时β-连环蛋白需要被抑制，并检查时间上不同的Wnt和 利用小鼠胚胎外植体培养研究肝发育过程中fgf通路的相互作用。 目标3.研究Wnt信号传导在促进人类前肠和肝脏谱系来自HESC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