Hedgehog Signaling and Adult Liver Regeneration

Hedgehog 信号传导和成人肝脏再生

• 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
• 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

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）：调节慢性肝损伤修复的机制知之甚少。在慢性损伤期间，成熟的肝细胞增殖能力下降。为了弥补这一点，肝上皮祖细胞种群扩展和区分以替代垂死的细胞。类似的反应发生在间质中，富集肝星细胞（HSC）群体具有增殖的肌纤维细胞。当间充质上皮（M-E）相互作用协调上皮细胞和间质细胞的平衡扩张和分化时，肝脏结构的成功重建发生。然而，有缺陷的重塑导致肝结构混乱，导致肝硬化和肿瘤。涉及刺猬（HH）信号通路调节某些成年组织的修复的M-E相互作用。我们最近发现，健康的成年肝含有能够产生和响应HH配体的细胞。有趣的是，这种HH反应性种群包括未成熟的肝上皮细胞和肝星状细胞。两种细胞类型在肝修复中都起着重要作用，这表明了以下假设：刺猬信号介导的间质上皮相互作用调节成年肝脏的再生。我们发现，与损伤相关的因素（例如PDGF-BB）促进产生声音刺猬（SHH）的肌纤维细胞的生长，以自动调节其生存能力。肝损伤还扩大了产生印度刺猬（IHH）的未成熟胆管型脱发细胞的种群，同时显着降低了HH抑制剂HIP的肝表达。这伴随着表达HH靶基因的基质和上皮细胞群的扩展，例如PTC和/或GLI。双重免疫荧光染色表明，IHH表达相对仅限于胆管细胞，而上皮细胞和基质细胞均表达HH-TARGET基因。祖细胞似乎相对富含HH响应性细胞。随着肝脏损伤的消退，纤维化，肌纤维细胞细胞和上皮祖细胞会逐渐消退，HH-Pathway活性逐渐消退。这些数据支持我们的假设，并证明了进一步的努力来描述控制成年肝脏中HH活性的机制，并阐明HH途径在调节成年肝脏对损伤方面的作用中的作用。因此，我们的目的是确定：1​​）HSC的激活如何改变配体HH配体的产生和反应； 2）如果不同类型的肝上皮细胞的表型会影响其对HSC衍生的HH配体的反应，或者其引起HSC产生HH配体的能力； 3）如果调节HH信号传导活性会在肝损伤后改变再生。公共卫生相关性：这项工作的结果将扩展对维持和恢复成人肝脏建筑的复杂稳态机制的当前理解。这种知识可能会影响肝病诊断，预防和治疗，因此具有重要的临床意义。