Hedgehog Signaling and Adult Liver Regeneration

Hedgehog 信号传导和成人肝脏再生

基本信息

批准号：
7596424
负责人：
ANNA MAE ELIZABETH DIEHL
金额：
$ 33.15万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-04-01 至 2012-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7596424
关键词：
Adult Architecture Cell Count Cells Chronic Cirrhosis Clinical Complex Cytokeratin Data Development Endoderm Epithelial Epithelial Cells Equilibrium Erinaceidae Fibrosis Gene Targeting Health Hepatic Hepatic Stellate Cell Hepatocyte Hip region structure Immunofluorescence Immunologic Injury Intestines Keratin-19 Knowledge Ligands Liver Liver Regeneration Liver diseases Lung Mediating Mesenchymal Mesenchyme Natural regeneration Neoplasms Organ Organogenesis Pathway interactions Phenotype Play Population Prevention Production Proliferating Publishing Relative (related person)Research Role Signal Transduction Smooth Muscle Actin Staining Method Staining method Stains Stomach Stromal Cells System Tissues Work base bile ductular cell type disease diagnosis inhibitor/antagonist platelet-derived growth factor BB progenitor receptor reconstruction repaired response smoothened signaling pathway

项目摘要

DESCRIPTION (provided by applicant): The mechanisms that regulate repair of chronic liver injury are poorly understood. Mature hepatocytes proliferative capacity declines during chronic injury. To compensate for this, hepatic epithelial progenitor populations expand and differentiate to replace dying cells. Similar responses occur in the mesenchyme, enriching hepatic stellate cell (HSC) populations with proliferating myofibroblastic cells. Successful reconstruction of liver architecture occurs when mesenchymal-epithelial (M-E) interactions orchestrate balanced expansion and differentiation of both epithelial and mesenchymal cells. However, defective remodeling leads to disorganization of hepatic architecture, resulting in cirrhosis and neoplasia. M-E interactions that involve the Hedgehog (Hh) signaling pathway modulate repair of some adult tissues. We recently discovered that healthy adult livers contain cells that are capable of both producing and responding to Hh ligands. Interestingly, this Hh-reactive population includes immature liver epithelial cells and hepatic stellate cells. Both cell types play important roles in liver repair, suggesting the following HYPOTHESIS: Hedgehog signaling-mediated mesenchymal-epithelial interactions regulate regeneration of adult livers. We found that injury-related factors, such as PDGF-BB, promote the outgrowth of myofibroblastic cells that produce Sonic hedgehog (Shh) to auto-regulate their viability. Liver injury also expands populations of immature bile ductular cells that produce Indian hedgehog (Ihh), while significantly reducing hepatic expression of the Hh inhibitor, Hip. This is accompanied by expansion of stromal and epithelial cell populations that express Hh-target genes, such as Ptc and/or Gli. Double immunofluorescence staining reveals that Ihh expression is relatively restricted to bile ductular cells, while both epithelial and stromal cells express Hh-target genes. Progenitor populations seem to be relatively enriched with Hh-responsive cells. As liver damage resolves, fibrosis, myofibroblastic cells, and epithelial progenitors regress and Hh-pathway activity gradually subsides. These data support our hypothesis and justify further efforts to delineate mechanisms that control Hh activity in adult livers and clarify the role of the Hh pathway in regulating how adult livers respond to injury. Thus, our Aims are to determine: 1) how the activation of HSC alters the production of- and response to- Hh ligands; 2) if the phenotype of different types of liver epithelial cells influences their response to HSC-derived Hh ligands, or their ability to elicit HSC production of Hh ligands; and 3) if modulating Hh signaling activity alters regeneration following liver injury. PUBLIC HEALTH RELEVANCE: Results from this work will extend current understanding about the complex homeostatic mechanisms that maintain and restore liver architecture in adults. Such knowledge is likely to impact upon liver disease diagnosis, prevention and treatment and thus, has important clinical implications.

描述（由申请人提供）：人们对调节慢性肝损伤修复的机制知之甚少。慢性损伤期间成熟肝细胞增殖能力下降。为了弥补这一点，肝上皮祖细胞群会扩张并分化以取代垂死的细胞。类似的反应发生在间充质中，通过增殖的肌纤维母细胞丰富肝星状细胞（HSC）群体。当间充质-上皮（M-E）相互作用协调上皮细胞和间充质细胞的平衡扩张和分化时，肝脏结构的成功重建就会发生。然而，有缺陷的重塑会导致肝结构紊乱，导致肝硬化和肿瘤。涉及 Hedgehog (Hh) 信号通路的 M-E 相互作用可调节某些成人组织的修复。我们最近发现健康的成人肝脏含有能够产生 Hh 配体并对其做出反应的细胞。有趣的是，这个 Hh 反应群体包括未成熟的肝上皮细胞和肝星状细胞。这两种细胞类型在肝脏修复中都发挥着重要作用，提出以下假设：刺猬信号介导的间充质-上皮相互作用调节成年肝脏的再生。我们发现损伤相关因子，例如 PDGF-BB，可促进肌纤维母细胞的生长，从而产生 Sonic Hedgehog (Shh) 以自动调节其活力。肝损伤还会增加产生印度刺猬 (Ihh) 的未成熟胆管细胞数量，同时显着降低 Hh 抑制剂 Hip 的肝脏表达。这伴随着表达 Hh 靶基因（例如 Ptc 和/或 Gli）的基质细胞和上皮细胞群的扩张。双重免疫荧光染色显示，Ihh 表达相对局限于胆管细胞，而上皮细胞和基质细胞均表达 Hh 靶基因。祖细胞群似乎相对富含 Hh 反应细胞。随着肝损伤的消退，纤维化、肌纤维母细胞和上皮祖细胞消退，Hh 通路活性逐渐消退。这些数据支持我们的假设，并证明进一步努力描述控制成人肝脏中 Hh 活性的机制，并阐明 Hh 通路在调节成人肝脏如何应对损伤中的作用。因此，我们的目标是确定：1) HSC 的激活如何改变 Hh 配体的产生和响应； 2) 不同类型肝上皮细胞的表型是否影响其对 HSC 衍生的 Hh 配体的反应，或其引发 HSC 产生 Hh 配体的能力； 3) 调节 Hh 信号活性是否会改变肝损伤后的再生。公共健康相关性：这项工作的结果将扩展目前对维持和恢复成人肝脏结构的复杂稳态机制的理解。这些知识可能会影响肝病的诊断、预防和治疗，因此具有重要的临床意义。