Signaling pathways and the fate of hepatic progenitor cells

描述（由申请人提供）：肝干细胞/祖细胞对严重肝损伤的反应能力依赖于祖细胞更新、扩增和分化的精细平衡。在肝脏中，包括hedgehog、wnt和notch系统在内的发育激活信号通路参与了肝祖细胞更新、组织修复和肝细胞癌发展的调控。到目前为止，缺乏特定的遗传工具来调节成年肝祖细胞中的这些途径，这妨碍了分析这些途径对祖细胞对肝损伤反应的特定贡献。我们发现翼螺旋转录因子Foxl1独特地标记了双潜能肝祖细胞，并衍生出Foxl1- cre和他莫昔芬诱导的Foxl1- creert2小鼠菌株，通过有条件地删除肝祖细胞中hedgehog， wnt和notch信号通路的单个组分来进行功能获得和功能丧失的研究。使用这种方法，我们将剖析复杂的自分泌和旁分泌信号事件，这些信号事件有助于祖细胞募集、分化和增殖，以及旁分泌对肝损伤组织修复过程中纤维形成的影响。我们提出了一个信号层次的存在，其中翼螺旋因子Foxl1介导了祖细胞更新和增殖所必需的hedgehog和wnt/b-catenin信号通路。我们预测Notch作用于wnt/b-catenin的下游，促进祖细胞向胆道谱系分化，也可能是胆道小管形态发生所必需的。了解肝祖细胞的生物学将对急性肝功能衰竭、慢性肝硬化和肝细胞癌的治疗方法的发展具有广泛的意义。

DESCRIPTION (provided by applicant): The ability of hepatic stem/progenitor cells to respond to severe liver injury is dependent upon a finely tuned balance of progenitor cell renewal, expansion and differentiation. In the liver, developmentally activated signaling pathways including the hedgehog, wnt and notch systems have been implicated in the regulation of hepatic progenitor cell renewal, tissue repair and the development of hepatocellular cancer. Until now, lack of specific genetic tools to modulate these pathways in adult hepatic progenitors has precluded the analysis of the specific contribution of these pathways to the progenitor cell response to liver injury. We have discovered that the winged helix transcription factor Foxl1 uniquely marks bipotential hepatic progenitor cells and have derived both Foxl1-Cre and tamoxifen inducible Foxl1-CreERT2 mouse strains to enable gain- and loss-of-function studies through the conditional deletion of individual components of the hedgehog, wnt and notch signaling pathways in hepatic progenitor cells. Using this approach, we will dissect the complex autocrine and paracrine signaling events that contribute to progenitor cell recruitment, differentiation and proliferation as well as paracrine effects on fibrogenesis during tissue repair in response to liver injury. We propose the existence of a signaling hierarchy in which the winged helix factor Foxl1 mediates the hedgehog and wnt/b-catenin signaling pathways necessary for progenitor cell renewal and proliferation. We predict that Notch acts downstream of wnt/b-catenin and promotes progenitor cell differentiation towards the biliary lineage and may also be required for biliary tubule morphogenesis. Understanding the biology of hepatic progenitor cells will have wide-ranging implications for the development of therapeutics for acute liver failure, chronic cirrhotic liver disease and hepatocellular carcinoma. PUBLIC HEALTH RELEVANCE: The studies proposed in this grant application will elucidate the signals that regulate hepatic progenitor cells and their response to acute or chronic liver injury. Understanding the biology of hepatic progenitor cells will have wide-ranging implications for the development of therapeutics for acute liver failure, chronic cirrhotic liver disease and hepatocellular carcinoma.