Hedgehog Signaling and Adult Liver Regeneration

调节慢性肝损伤修复的机制还知之甚少。成熟肝细胞 在慢性损伤过程中，增殖能力下降。为了弥补这一点，肝上皮祖细胞 种群扩张和分化以取代死亡的细胞。类似的反应也发生在间充质中， 用增殖的肌成纤维细胞丰富肝星状细胞(HSC)群体。成功 当间充质-上皮(M-E)相互作用协调时，肝脏结构重建发生 上皮细胞和间充质细胞的均衡扩增和分化。然而，有缺陷的 重塑导致肝脏结构紊乱，导致肝硬变和肿瘤形成。M-E 涉及Hedgehog(HH)信号通路的相互作用调节一些成体组织的修复。我们 最近发现，健康的成人肝脏含有能够产生和反应的细胞 HH配体。有趣的是，这种HH反应性群体包括未成熟的肝上皮细胞和肝星状细胞。 细胞。这两种细胞在肝脏修复中都扮演着重要的角色，并提出了以下假设：刺猬 信号介导的间充质-上皮相互作用调节成人肝脏的再生。我们发现 损伤相关因子，如PDGF-BB，促进产生Sonic的肌成纤维细胞的生长 刺猬(Shh)来自动调节它们的生存能力。肝损伤也会扩大未成熟胆管的数量 产生印度刺猬(IHH)的细胞，同时显著减少HH抑制物在肝脏的表达， 时髦。伴随而来的是表达HH靶基因的间质和上皮细胞群体的扩张， 例如PTC和/或GLi。双重免疫荧光染色显示IHH的表达相对受限 胆管上皮细胞和间质细胞均表达HH靶基因。祖代种群 似乎相对富含HH反应细胞。随着肝损伤的缓解，纤维化，肌成纤维细胞 细胞，上皮祖细胞退化，HH途径活性逐渐减弱。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活性的机制并澄清 HH通路在调节成人肝脏对损伤的反应中的作用。因此，我们的目标是确定：1) HSC的激活如何改变HH配体的产生和反应；2)如果不同的表型 肝上皮细胞的类型影响它们对HSC来源的HH配体的反应，或它们诱导HSC的能力 HH配体的产生；以及3)如果调节HH信号活性改变肝损伤后的再生。这项工作的结果将扩大目前对复杂的动态平衡机制的理解 维护和恢复成人的肝脏结构。这样的知识可能会对肝病产生影响。 因此，诊断、预防和治疗具有重要的临床意义。

The mechanisms that regulate repair of chronic liver injury are poorly understood. Mature hepatocyte 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. 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.