The Function Of Shp2 In Endometrial Epithelial Cells During Labor

Labor disorders are very harmful,and there are about 15 million cases of prelabor worldwide each year,which is one of the important reasons for the high morbidity and mortality of newborns.Labor is the last step in the reproductive process,and it is a complex and requires multiple organizations to coordinate and cooperate.The labor process involves the participation of a variety of hormones(such as estrogen,progesterone,prostaglandin)and local secreted factors(inflammatory factors,growth factors),which requires the mother and fetus to cooperate with each other.Cause abortion,dystocia and prelabor.As a tyrosine phosphatase,Shp2 regulates cell migration,growth,differentiation,and death,mediates cellular reactions involving hormones,growth factors,and cytokines,and functions as a regulator in various metabolic diseases.Current research has found that Shp2 plays a role in reproduction It plays an important role in the process.It is involved in spermatogenesis in male reproduction and embryo implantation in the female uterus,which is closely related to the reproductive process.Earlier in our laboratory,it was found that PR-Cre knockout of Shp2 in uterine endometrium cells of mice caused the mice to lose their fertility and embryo attachment failed.Female mice knocked out Shp2 in uterine stromal cells with Amhr2-Cre Decreased,decidualization defects,which shows that Shp2 in the uterus is involved in guiding the process of early pregnancy,but the role of Shp2 in uterine epithelial cells is still unclear and needs further research.To clarify the role of Shp2 in endometrial epithelial cells in mouse reproductive processes,we used CretoLoxp system to activate Cre enzyme expression using Lactoferin(Ltf)as a promoter,and endometrial epithelial cells before mouse embryo implantation,And specific complete knockout of Shp2 in endometrial epithelial cells recovered after pregnancy D13.5.The mating experiment of knockout mice and WT male mice found that 86%of mice had an average labor delay of 3 days,and about 50%of them had dystocia,indicating that the uterine epithelial Shp2 is involved in the labor process of mice.Normal labor is indispensable,but the embryo implantation,decidualization process and embryo development in the first trimester of the mouse are not affected,indicating that the labor disorder is due to the lack of maternal uterine function in the second trimester;through embryo transfer,we found that the control mice were normal labor,knock-out mice have delayed labor and even dystocia,further confirming the above conclusions.Afterwards,we analyzed the labor process and found that:(1)abnormal hormone levels in mice:abnormally reduced levels of estrogen and prostaglandin,abnormally increased levels of progesterone;(2)defective expression of hormone synthase:prostaglandin synthase COX1/COX2 level did not change significantly with the progress of pregnancy,and there was no obvious increase in epithelial cells near labor,and the expression of progesterone synthetase StaR remained high before labor;(3)uterine contraction gene expression was blocked:uterine contraction activation in the myometrium The mRNA and protein levels of protein COX2 and CX43 were significantly reduced,and the uterine contraction failed;(4)The levels of inflammatory factors were significantly reduced:IL-1β,IL-6,IL-8 mRNA levels in uterine tissues and primary cells of uterine epithelium showed 2-5 times lower,and IL-1β in uterine epithelium did not show a significant surge before labor.In summary,the lack of Shp2 in the epithelial cells leads to labor disorders due to the impaired labor process,resulting in the failure of continuous labor reactions.It is speculated that the labor signal may have failed.Therefore,we verified in vitro by the human endometrial epithelial cell line ISHIKAWA in vitro,we found that after knocking out Shp2,the level of inflammatory factors in the cells decreased.significantly,and could not receive the IL-1β,IL-6 and SP-D cytokines After stimulation,the level of inflammatory factors did not show obvious changes.Compared with normal cells that showed a 5-10 fold increase after receiving stimulation,the gap was obvious.It further confirmed that the lack of Shp2 in the uterine epithelium led to the failure of labor signal delivery,which eventually led to labor disorders.A preliminary exploration of the mechanism of Shp2’s participation in labor and found that the lack of Shp2 led to the failure of P65/STAT3 phosphorylation in mouse uterine epithelium,indicating that Shp2 may regulate the labor process by attenuating P65/STAT3 phosphorylation.In summary,this experiment fully proves the important role of Shp2 in endometrial epithelial cells in the labor process of mice.After receiving the labor signal,the uterine epithelial cells amplify the labor signal through Shp2 and start the labor cascade reaction to complete the labor.Once Shp2 is missing The mouse uterus cannot receive the labor signal,and the continuous labor reaction cannot occur,resulting in labor failure.Therefore,the study of Shp2 in uterine epithelial cells provides new ideas for the clinical study of the labor process,provides a theoretical basis for the diagnosis of labor disorders,and also provides new targets for treatment of labor disorders.