EDG receptor signaling in hepatic stem cell activation

描述(申请人提供)：肝卵圆(干细胞)细胞的增殖和分化受到多种因素的调节，但尚未完全了解。溶血磷脂酸(LPA)和鞘氨醇-L-磷酸(S1P)是磷脂生长因子，在多种类型的细胞中调节细胞的增殖和分化，增加活力，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(EDG)编码的G蛋白偶联受体介导。我们发现，肝损伤时卵圆细胞增殖的诱导与几种类型的EDG受体的表达有关，主要是在小的椭圆形细胞中。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的肝干细胞(成熟肝细胞/胆管细胞)所特有的。此外，我们认为EDG受体的差异表达可能是肝干细胞活化机制的必要组成部分。该项目的目标是探索肝脏EDG受体的分布(活体肝损伤时)，并在体外通过LPA/S1P确定卵圆细胞的反应和EDG介导的信号转导}。这些目标将通过追求两个特定的目标来实现：(1)在小鼠慢性肝损伤伴随肝卵圆细胞增殖的不同阶段，肝脏EDG受体的模式；(2)确定EDG通过LPA/S1P介导的细胞信号在培养中如何调节肝卵圆细胞的激活、增殖和分化。这些结果将为肝卵圆细胞增殖分化过程中EDG受体的表达和定位奠定基础，并将确定LPA/S1P激活卵圆细胞的细胞内信号通路。该项目的成功完成将为探索干细胞中的脂质中介信号提供新的信息，这将对干细胞生物学发展新的见解具有重要的价值。最后，我们相信干细胞增殖和分化过程中脂质信号机制领域产生的数据可以用来产生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.