EDG receptor signaling in hepatic stem cell activation

描述（由申请人提供）：肝卵圆细胞（干细胞）的增殖和分化受多种因素调控，但尚未完全了解。溶血磷脂酸（LPA）和鞘氨醇-l-磷酸（S1P）是几种细胞类型的磷脂生长因子，可调节细胞增殖和分化，增加运动性，甚至提高存活率。LPA和S1P的细胞效应主要通过内皮分化基因（Endothelial Differentiation Genes， EDG）编码的g蛋白偶联受体介导。我们发现，肝损伤期间卵形细胞增殖的诱导与几种EDG受体的表达有关，主要在小卵形细胞中。因此，我们假设EDG表达谱和相应的细胞对EDG受体配体LPA和S1P的反应是不同分化阶段（到成熟肝细胞/胆管细胞）的肝干细胞所特有的。此外，我们提出EDG受体的差异表达可能是肝干细胞激活机制的必要组成部分。本项目的目标是探索肝脏EDG受体谱{在体内肝损伤期间}，以及{在体外确定LPA/S1P对卵形细胞的反应和EDG介导的信号传导}。这些目标将通过以下两个具体目标来实现：(1)表征小鼠慢性肝损伤不同阶段伴有肝卵圆细胞增殖的肝脏EDG受体的模式；(2)确定edg介导的LPA/S1P细胞信号传导如何调节肝卵圆细胞的激活、增殖和分化。研究结果将建立肝卵圆细胞增殖和分化过程中EDG受体的表达谱和定位，并确定LPA/S1P激活卵圆细胞的胞内信号通路。该项目的成功完成将为探索干细胞中脂质介质信号传递提供新的信息，对干细胞生物学的新认识具有重要价值。最后，我们相信在干细胞增殖和分化过程中脂质信号传导机制领域产生的数据可以用于生成R01，这将进一步扩大我们对干细胞生物学的理解。

DESCRIPTION (provided by applicant): Proliferation and differentiation of hepatic oval (stem) cells are regulated by a variety of factors, yet not completely understood. Lysophosphatidic acid (LPA) and sphingosine-l-phosphate (S1P) are {phospholipid growth factors}, which regulate cell proliferation and differentiation, increase motility, and even enhance survival in several cell types. Cellular effects of LPA and S1P are mediated mainly via G-protein coupled receptors encoded by Endothelial Differentiation Genes (EDG). We have found that induction of oval cell proliferation during liver damage was associated with the expression of several types of EDG receptors, predominantly in small oval cells. We, therefore, hypothesize that the EDG expression profiles and the corresponding cellular responses to EDG receptor ligands LPA and S1P are specific for hepatic stem cells at various stages of differentiation {to mature hepatocytes/cholangiocytes}. Moreover, we propose that differential expression of EDG receptors may be a necessary part of the mechanism responsible for the activation of hepatic stem cells. The goals of this project are to explore hepatic EDG receptor profiles {during liver injury in vivo}, and {determine oval cell responses and EDG-mediated signaling by LPA/S1P in vitro}. These goals will be achieved by pursuing two Specific Aims: (1) to characterize the pattern of hepatic EDG receptors at different stages of mouse chronic liver injury accompanied by proliferation of hepatic oval cells; and (2) To identify how EDG-mediated cell signaling by LPA/S1P will regulate hepatic oval cell activation, proliferation and differentiation in culture. The results will establish the expression profiles and localization of EDG receptors during hepatic oval cell proliferation and differentiation, and will determine intracellular signaling pathways of oval cell activation by LPA/S1P. Successful accomplishment of the project will provide novel information exploring lipid mediator signaling in stem cells, which will have a great value to develop new insights in stem cell biology. Finally, we believe that the data produced in the field of lipid signaling mechanisms during proliferation and differentiation of stem cells can be used to generate an R01, which will further expand our understanding of stem cell biology.