Nguyen Thu Lan, Gasser Adelin, Nebigil Canan G
Centre National de la Recherche Scientifique (CNRS), Université de Strasbourg, UMR7242, Ecole Supérieure de Biotechnologie de Strasbourg, F-67412 Illkirch, France.
Recent address: Center of Research of Biomedicine in Strasbourg (CRBS), Regenerative Nanomedicine, UMR1260, INSERM, University of Strasbourg, 1 rue Eugéne Boeckel 67084 Strasbourg, France.
J Dev Biol. 2013 Jun 18;1(1):20-31. doi: 10.3390/jdb1010020.
G protein-coupled receptors (GPCRs) form a large class of seven transmembrane (TM) domain receptors. The use of endogenous GPCR ligands to activate the stem cell maintenance or to direct cell differentiation would overcome many of the problems currently encountered in the use of stem cells, such as rapid differentiation and expansion or rejection in clinical applications. This review focuses on the definition of a new GPCR signaling pathway activated by peptide hormones, called "prokineticins", in epicardium-derived cells (EPDCs) Signaling via prokineticin-2 and its receptor, PKR1, is required for cardiomyocyte survival during hypoxic stress. The binding of prokineticin-2 to PKR1 induces proliferation, migration and angiogenesis in endothelial cells. The expression of prokineticin and PKR1 increases during cardiac remodeling after myocardial infarction. Gain of function of PKR1 in the adult mouse heart revealed that cardiomyocyte-PKR1 signaling activates EPDCs in a paracrine fashion, thereby promoting vasculogenesis. Transient PKR1 gene therapy after myocardial infarction in mice decreases mortality and improves heart function by promoting neovascularization, protecting cardiomyocytes and mobilizing WT1 cells. Furthermore, PKR1 signaling promotes adult EPDC proliferation and differentiation to adopt endothelial and smooth muscle cell fate, for the induction of vasculogenesis. PKR1 is expressed in the proepicardium and epicardial cells derived from mice kidneys. Loss of PKR1 causes deficits in EPDCs in the neonatal mice hearts and kidneys and impairs vascularization and heart and kidney function. Taken together, these data indicate a novel role for PKR1 in heart-kidney complex via EPDCs.
G蛋白偶联受体（GPCRs）构成了一大类七跨膜（TM）结构域受体。利用内源性GPCR配体激活干细胞维持或指导细胞分化将克服目前在干细胞使用中遇到的许多问题，如临床应用中的快速分化、扩增或排斥反应。本综述重点关注一种由肽激素激活的新GPCR信号通路的定义，该肽激素称为“促胃动素”，存在于心外膜衍生细胞（EPDCs）中。通过促胃动素-2及其受体PKR1进行信号传导是缺氧应激期间心肌细胞存活所必需的。促胃动素-2与PKR1的结合可诱导内皮细胞增殖、迁移和血管生成。心肌梗死后心脏重塑过程中促胃动素和PKR1的表达增加。成年小鼠心脏中PKR1功能的获得表明，心肌细胞-PKR1信号以旁分泌方式激活EPDCs，从而促进血管生成。小鼠心肌梗死后进行短暂的PKR1基因治疗可降低死亡率并改善心脏功能，其机制是促进新生血管形成、保护心肌细胞和动员WT1细胞。此外，PKR1信号促进成年EPDC增殖和分化，使其向内皮细胞和平滑肌细胞命运转变，以诱导血管生成。PKR1在小鼠肾脏来源的前心外膜和心外膜细胞中表达。PKR1的缺失会导致新生小鼠心脏和肾脏中EPDCs的缺陷，并损害血管化以及心脏和肾脏功能。综上所述，这些数据表明PKR1通过EPDCs在心脏-肾脏复合体中发挥新作用。
