EDG receptor signaling in hepatic stem cell activation

描述（由申请人提供）：肝卵圆（干）细胞的增殖和分化受多种因素调节，但尚未完全了解。溶血磷脂酸（LPA）和鞘氨醇-1-磷酸（S1 P）是{磷脂生长因子}，其调节细胞增殖和分化，增加运动性，甚至增强几种细胞类型的存活。LPA和S1 P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。我们已经发现，肝损伤期间卵圆细胞增殖的诱导与几种类型的EDG受体的表达有关，主要是在小卵圆细胞中。因此，我们假设EDG表达谱和对EDG受体配体LPA和S1 P的相应细胞反应对处于不同分化阶段（成熟肝细胞/胆管细胞）的肝干细胞具有特异性。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。本项目的目标是探索肝脏EDG受体谱{在体内肝损伤期间}，并{确定卵圆细胞反应和EDG介导的信号传导通过LPA/S1 P在体外}。这些目标将通过追求两个具体目标来实现：（1）表征伴有肝卵圆细胞增殖的小鼠慢性肝损伤不同阶段肝脏EDG受体的模式;和（2）确定LPA/S1 P介导的EDG介导的细胞信号传导如何调节培养物中肝卵圆细胞的激活、增殖和分化。本研究结果将建立肝卵圆细胞增殖分化过程中EDG受体的表达谱和定位，并将确定LPA/S1 P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脂质介导的信号转导提供新的信息，对开发干细胞生物学的新见解具有重要价值。最后，我们认为，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产生R 01，这将进一步扩展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.