Hedgehog Signaling and Adult Liver Regeneration

Hedgehog 信号传导和成人肝脏再生

• 批准号: 9753209
• 负责人: ANNA MAE ELIZABETH DIEHL
• 金额: $ 35.78万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9753209
• 关键词: Address; Adult; Amphiregulin; Cell Proliferation; Cells; Cellular Metabolic Process; Chronic; Cirrhosis; Coculture Techniques; Collaborations; Data; Development; Enzymes; Erinaceidae; Fibrosis; Genes; Genetic Transcription; Glycolysis; Goals; Growth; Hepatic Stellate Cell; Hepatitis; Hepatocyte; Human; Injury; Knowledge; Lead; Leptin; Link; Liver; Liver Regeneration; Liver diseases; Living Donor Liver Transplantation; Malignant neoplasm of liver; Mesenchymal Stem Cells; Metabolism; Metformin; Molecular; Myofibroblast; Natural regeneration; Obese Mice; Obesity; Partial Hepatectomy; Pathway interactions; Pericytes; Population; Population Sizes; Positioning Attribute; Process; Proliferating; Publications; Reporting; Research; Signal Pathway; Signal Transduction; Stem cells; To specify; Transforming Growth Factor beta; Translational Activation; Warburg Effect; Work; aerobic glycolysis; appendage; base; blastema; cell growth; cell type; cholangiocyte; experience; injured; liver injury; liver repair; member; morphogens; nerve stem cell; novel; prevent; progenitor; receptor; repaired; senescence; sensor; smoothened signaling pathway; stellate cell; success; therapy development; trait

ABSTRACT Liver regeneration enables living donor liver transplantation and is fundamental to repair after liver injury. However, aberrant repair processes, as in the setting of chronic injury due to hepatitis or obesity, can lead to cirrhosis and liver cancer. Considerable research effort, including our own, seeks to clarify fate relationships among cell types involved in liver regeneration, including hepatocytes, cholangiocytes, and stellate cells. However, key knowledge gaps persist regarding mechanisms controlling these cells' plasticity. Further, although an array of signaling pathways have been implicated in liver repair, how these are integrated to specify and maintain progenitor fate within the liver remains unknown. Our ultimate goal is to delineate the mechanisms that control liver regeneration so this knowledge can be applied to prevent and treat key consequences of mis-repair. Our work to date has shown that (1) the Hedgehog (Hh) pathway directs adult liver repair by controlling the size of liver progenitor and myofibroblast (MF) populations; (2) activating the pathway in Hh-responsive cells drives them to become more primitive (i.e., less differentiated, more glycolytic, proliferative, migratory, and fibrogenic), and silencing Hh signaling has the opposite effects; (3) hepatic stellate cells (HSC) are liver-resident members of a network of Hh-responsive perivascular cells (i.e., pericytes) that appear to retain mesenchymal stem cell traits (also reported by others); and (4) in extensive data underpinning our current proposal, Hh signaling interacts with the Hippo/YAP pathway, a distinct developmental pathway known to help control fate decisions in mesenchymal stem cells and to control adult liver growth by regulating liver progenitor population size. However, it is unknown how the Hh-YAP collaboration causes HSC reprogramming or why this is necessary for liver repair. Based on work by us and others, our hypothesis is that Hedgehog activates YAP in HSC to optimize accumulation of MF-HSC that enhance growth of cells with liver repopulating capacity, and this process requires Hh/YAP-dependent reprogramming of HSC through metabolism changes. Our aims will elucidate the functional consequences of Hh-YAP cross-talk on liver repair and will clarify energy-related mechanisms that coordinate this cross-talk. Each Aim addresses a key question: How do reprogrammed HSC control hepatocyte plasticity during liver repair? How does Hh reprogram HSC during liver repair? How does Hh interact with YAP to reprogram HSC into proliferative MF? Successful completion of these aims will deepen understanding of mechanisms that co-regulate Hedgehog and YAP/Hippo to achieve effective liver repair. This knowledge will clarify how this intricate process goes awry during human liver disease, and enable development of interventions to enhance appropriate regeneration. Our strong preliminary data and experienced and productive research team position us for success.

抽象的 肝再生使得活体肝移植成为可能，并且是肝损伤后修复的基础。 然而，异常的修复过程，如在肝炎或肥胖引起的慢性损伤的情况下，可能会导致 肝硬化和肝癌。大量的研究工作，包括我们自己的研究工作，都试图阐明命运关系 参与肝脏再生的细胞类型包括肝细胞、胆管细胞和星状细胞。 然而，关于控制这些细胞可塑性的机制，关键的知识差距仍然存在。更远， 尽管一系列信号通路与肝脏修复有关，但它们是如何整合到肝脏修复中的？ 指定和维持肝脏内祖细胞的命运仍然未知。我们的最终目标是划定 控制肝再生的机制，因此这些知识可以应用于预防和治疗关键 错误修复的后果。迄今为止我们的工作表明 (1) Hedgehog (Hh) 通路指导成人 通过控制肝祖细胞和肌成纤维细胞（MF）群体的大小来修复肝脏； (2) 激活 Hh 反应细胞中的通路促使它们变得更加原始（即分化程度较低、糖酵解程度较高、 增殖、迁移和纤维化），而沉默 Hh 信号则具有相反的效果； (3)肝星状 细胞 (HSC) 是 Hh 反应性血管周围细胞（即周细胞）网络的肝脏驻留成员， 似乎保留了间充质干细胞特征（其他人也报道过）； (4) 广泛的数据支持 我们目前的建议是，Hh 信号传导与 Hippo/YAP 途径（一种独特的发育途径）相互作用 已知有助于控制间充质干细胞的命运决定，并通过调节来控制成人肝脏的生长 肝脏祖细胞群的大小。然而，目前尚不清楚 Hh-YAP 协作如何导致 HSC 重新编程或为什么这对于肝脏修复是必要的。基于我们和其他人的工作，我们的假设是 Hedgehog 激活 HSC 中的 YAP，以优化 MF-HSC 的积累，从而促进细胞生长 肝脏再生能力，这个过程需要 Hh/YAP 依赖的 HSC 重编程 新陈代谢的变化。我们的目标是阐明 Hh-YAP 串扰对肝脏修复的功能影响 并将阐明协调这种串扰的能源相关机制。每个目标都解决一个关键问题： 重编程的HSC如何在肝脏修复过程中控制肝细胞可塑性？ Hh 如何重新编程 HSC 肝脏修复期间？ Hh 如何与 YAP 相互作用以将 HSC 重编程为增殖性 MF？成功的 完成这些目标将加深对共同监管刺猬和 YAP/Hippo实现有效的肝脏修复。这些知识将阐明这个复杂的过程是如何出错的 在人类肝脏疾病期间，并能够开发干预措施以增强适当的再生。 我们强大的初步数据和经验丰富、富有成效的研究团队为我们的成功奠定了基础。