Physiological Roles Of ERK And SFRP1 During Placental Development And Trophoblast Cell Differentiation

The placenta is an important organ for the survival of the mammalian embryo in uterus,which is responsible for the exchange of gas,nutrients and waste excretion of the fetus between the mother and the fetus.Placental development is a process in which trophoblast stem cells self-renewal and differentiate into different trophoblast cell types.Many signaling molecules are involved in the process of trophoblast stem cells’ selfrenewal and placental development.Previous studies have found that the FGF/ERK signaling pathway plays an important role in the stem maintenance and self-renewal of mouse trophoblast stem cells,but the detailed regulatory mechanism is not clear.Recently established human trophoblast stem cells require EGF to maintain their stemness,since ERK is a key downstream signaling molecule of the EGF signaling pathway,so we speculate that the ERK signaling pathway may also play an important role in the stem maintenance and self-renewal of human trophoblast stem cells.In addition,studies have shown the Wnt signaling pathway participate in the regulation of placental development,but the role of Sfrpl,an inhibitory molecule in the Wnt signaling pathway,in the process of placental development has not been clearly defined.In this paper,using in vitro cultured human and mouse trophoblast stem cell line models,we found that the phosphorylated ERK in the cascade reaction of ERK signals was expressed in both trophoblast cells and was mainly located in the cytoplasm.Meanwhile,We also found that inhibition of the ERK signal significantly downregulated the expression of Cdx2,Eomes and other stem marker molecules in mouse trophoblast stem cells.In human trophoblast stem cells,inhibition of the ERK signal will affect the proliferation of trophoblast stem cells and down-regulate stem related molecules such as TP63.These results suggest that ERK signaling plays an important role in the process of stem maintenance and self-renewal of trophoblast stem cells.Another study,we found that Sfrp1,an inhibitor of Wnt signaling pathway presented a spatial-temporal specific expression pattern during placental development by situ hybridization.using Sfrp1 systemic knockout mice model,we found that under normal conditions placental development of Sfrp1 knockout mice is comparable to wild type mice.While,under hypoxic stress,the development of blood vessels in the labyrinth layer of the placenta and the development of the fetus in the knockout mice were much better than that in the wild type.These results indicated that Sfrp1 knockout mice resisted the adverse effects of hypoxic on the labyrinthic vascular development and increase the tolerance to hypoxic stress.These studies illustrate the role of ERK and Sfrp1,an inhibitor of Wnt signaling pathway in trophoblast stem maintenance and placental development,and will also help us understand the pathogenesis of diseases related to development of placenta and trophoblast cells.