Cooperative roles of Notch and biomechanics in biliary differentiation

Notch和生物力学在胆管分化中的协同作用

• 批准号: 9182390
• 负责人: Gregory H Underhill
• 金额: $ 7.48万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9182390
• 关键词: Acute; Alagille Syndrome; Area; Bile fluid; Biliary; Biochemical; Biological; Biomechanics; Biomedical Engineering; Cell Communication; Cell Count; Cells; Child; Cholestasis; Cirrhosis; Cues; Data; Degenerative Disorder; Development; Disease; Environment; Extracellular Matrix; Extracellular Matrix Proteins; Feedback; Fetal Liver; Functional disorder; Geometry; Goals; Gold; Hereditary Disease; Heterogeneity; Intrahepatic bile duct; Investigation; Lead; Life; Ligands; Link; Liver; Liver diseases; Malignant Neoplasms; Malignant neoplasm of liver; Maps; Mechanical Stress; Mechanics; Mediator of activation protein; Mesenchyme; Morphogenesis; Mutation; Natural regeneration; Nature; Neonatal Jaundice; Notch Signaling Pathway; Operative Surgical Procedures; Organ; Pathway interactions; Pattern; Play; Portal vein structure; Procedures; Process; Protocols documentation; Regulation; Research; Research Personnel; Role; Signal Pathway; Signal Transduction; Stem cells; Substrate Interaction; Technology; Testing; Tissue Engineering; Tissues; Transforming Growth Factor beta; Transplantation; Work; bile duct; cell fate specification; cellular engineering; combinatorial; disease mechanisms study; experience; insight; liver development; liver injury; liver transplantation; notch protein; novel strategies; novel therapeutics; prevent; progenitor; receptor; research study; response; standard care; stem cell differentiation; therapeutic development; tool

Project Summary The bipotential differentiation of liver progenitor cells is integral to liver development, regeneration, and diseases including bile duct paucity and liver cancer. The regionalization of biliary differentiation and morphogenesis near the portal region of the liver has suggested that spatially segregated microenvironmental signals govern this process. Accordingly, both TGFβ and Notch signaling have been demonstrated to be activated in the portal area, and both have been shown to be critical mediators of bile duct formation. We have recently developed a cell microarray platform that enabled the systematic analysis of liver progenitor fate specification within defined microenvironments, and in particular, facilitated the assessment of interactions between TGFβ, Notch, and other microenvironmental cues including extracellular matrix. Utilizing this approach, we additionally observed a reproducible gradient of biliary differentiation within the multicellular patterns of the array. Building on these findings, we hypothesize that mechanical signals play a role in progenitor function, and that spatial patterns of cell mechanotransduction and Notch signaling act together to regulate differentiation fate. We will exploit the tightly controlled and tunable microenvironments of the cell microarray platform to investigate the influence of multicellular geometry, cell-cell and cell-substrate interactions, and interrelated cell mechanical stress in biliary versus hepatocytic differentiation. Further, we will examine crosstalk between mechanical cues and Notch signaling, including the potential involvement of Hippo pathway effectors in these signaling interactions. We anticipate that these studies will reveal new insights into the combinatorial regulation of liver progenitor fate and will also establish this platform as a tool for studying disease mechanisms.

项目概要 肝祖细胞的双能分化对于肝脏的发育、再生和发育至关重要。 疾病包括胆管缺乏和肝癌。胆道分化的区域化和 肝脏汇管区附近的形态发生表明，空间隔离的微环境 信号控制这个过程。因此，TGFβ 和 Notch 信号传导均已被证明 在汇管区被激活，两者都被证明是胆管形成的关键介质。我们有 最近开发了一个细胞微阵列平台，可以对肝脏祖细胞命运进行系统分析 定义的微环境中的规范，特别是促进了相互作用的评估 TGFβ、Notch 和其他微环境线索（包括细胞外基质）之间的关系。利用这个 方法，我们还观察到多细胞内胆管分化的可重复梯度 阵列的模式。基于这些发现，我们假设机械信号在 祖细胞功能，以及细胞机械转导和 Notch 信号传导的空间模式共同作用 调节分化命运。我们将利用严格控制和可调节的细胞微环境 微阵列平台研究多细胞几何形状、细胞间和细胞基质的影响 胆汁与肝细胞分化中的相互作用和相互关联的细胞机械应力。此外，我们将 检查机械线索和 Notch 信号之间的串扰，包括 Hippo 的潜在参与 这些信号传导相互作用中的途径效应器。我们预计这些研究将揭示新的见解 肝脏祖细胞命运的组合调控，还将建立该平台作为研究工具 疾病机制。