PMID- 35025868 OWN - NLM STAT- MEDLINE DCOM- 20220217 LR - 20220217 IS - 1553-7404 (Electronic) IS - 1553-7390 (Print) IS - 1553-7390 (Linking) VI - 18 IP - 1 DP - 2022 Jan TI - Shp2 in uterine stromal cells critically regulates on time embryo implantation and stromal decidualization by multiple pathways during early pregnancy. PG - e1010018 LID - 10.1371/journal.pgen.1010018 [doi] LID - e1010018 AB - Approximately 75% of failed pregnancies are considered to be due to embryo implantation failure or defects. Nevertheless, the explicit signaling mechanisms governing this process have not yet been elucidated. Here, we found that conditional deletion of the Shp2 gene in mouse uterine stromal cells deferred embryo implantation and inhibited the decidualization of stromal cells, which led to embryonic developmental delay and to the death of numerous embryos mid-gestation, ultimately reducing female fertility. The absence of Shp2 in stromal cells increased the proliferation of endometrial epithelial cells, thereby disturbing endometrial epithelial remodeling. However, Shp2 deletion impaired the proliferation and polyploidization of stromal cells, which are distinct characteristics of decidualization. In human endometrial stromal cells (hESCs), Shp2 expression gradually increased during the decidualization process. Knockout of Shp2 blocked the decidual differentiation of hESCs, while Shp2 overexpression had the opposite effect. Shp2 knockout inhibited the proliferation of hESCs during decidualization. Whole gene expression profiling analysis of hESCs during the decidualization process showed that Shp2 deficiency disrupted many signaling transduction pathways and gene expression. Analyses of hESCs and mouse uterine tissues confirmed that the signaling pathways extracellular regulated protein kinases (ERK), protein kinase B (AKT), signal transducer and activator of transcription 3 (STAT3) and their downstream transcription factors CCAAT/enhancer binding protein beta (C/EBPbeta) and Forkhead box transcription factor O1 (FOXO-1) were involved in the Shp2 regulation of decidualization. In summary, these results demonstrate that Shp2 plays a crucial role in stromal decidualization by mediating and coordinating multiple signaling pathways in uterine stromal cells. Our discovery possibly provides a novel key regulator of embryo implantation and novel therapeutic target for pregnancy failure. FAU - Cheng, Jianghong AU - Cheng J AD - School of Pharmaceutical Sciences, State Key Laboratory of Cellular Stress Biology, Xiamen University, Xiamen, Fujian, China. FAU - Liang, Jia AU - Liang J AUID- ORCID: 0000-0002-6995-8028 AD - School of Pharmaceutical Sciences, State Key Laboratory of Cellular Stress Biology, Xiamen University, Xiamen, Fujian, China. FAU - Li, Yingzhe AU - Li Y AD - School of Pharmaceutical Sciences, State Key Laboratory of Cellular Stress Biology, Xiamen University, Xiamen, Fujian, China. FAU - Gao, Xia AU - Gao X AUID- ORCID: 0000-0002-3219-2858 AD - School of Pharmaceutical Sciences, State Key Laboratory of Cellular Stress Biology, Xiamen University, Xiamen, Fujian, China. FAU - Ji, Mengjun AU - Ji M AD - School of Pharmaceutical Sciences, State Key Laboratory of Cellular Stress Biology, Xiamen University, Xiamen, Fujian, China. FAU - Liu, Mengying AU - Liu M AUID- ORCID: 0000-0002-5987-1287 AD - School of Pharmaceutical Sciences, State Key Laboratory of Cellular Stress Biology, Xiamen University, Xiamen, Fujian, China. FAU - Tian, Yingpu AU - Tian Y AD - School of Pharmaceutical Sciences, State Key Laboratory of Cellular Stress Biology, Xiamen University, Xiamen, Fujian, China. FAU - Feng, Gensheng AU - Feng G AD - Department of Pathology, Division of Biological Sciences, University of California San Diego, La Jolla, California, United States of America. FAU - Deng, Wenbo AU - Deng W AD - Reproductive Medical Centre, The First Affiliated Hospital of Xiamen University, Xiamen, Fujian, China. AD - Fujian Provincial Key Laboratory of Reproductive Health Research, Medical College of Xiamen University, Xiamen, Fujian, China. FAU - Wang, Haibin AU - Wang H AUID- ORCID: 0000-0002-9865-324X AD - Reproductive Medical Centre, The First Affiliated Hospital of Xiamen University, Xiamen, Fujian, China. AD - Fujian Provincial Key Laboratory of Reproductive Health Research, Medical College of Xiamen University, Xiamen, Fujian, China. FAU - Kong, Shuangbo AU - Kong S AUID- ORCID: 0000-0002-7513-4041 AD - Reproductive Medical Centre, The First Affiliated Hospital of Xiamen University, Xiamen, Fujian, China. AD - Fujian Provincial Key Laboratory of Reproductive Health Research, Medical College of Xiamen University, Xiamen, Fujian, China. FAU - Lu, Zhongxian AU - Lu Z AUID- ORCID: 0000-0002-1682-7147 AD - School of Pharmaceutical Sciences, State Key Laboratory of Cellular Stress Biology, Xiamen University, Xiamen, Fujian, China. AD - Fujian Provincial Key Laboratory of Reproductive Health Research, Medical College of Xiamen University, Xiamen, Fujian, China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20220113 PL - United States TA - PLoS Genet JT - PLoS genetics JID - 101239074 RN - EC 3.1.3.48 (PTPN11 protein, human) RN - EC 3.1.3.48 (Protein Tyrosine Phosphatase, Non-Receptor Type 11) RN - EC 3.1.3.48 (Ptpn11 protein, mouse) SB - IM MH - Animals MH - Cell Line MH - Cell Proliferation MH - Decidua/*metabolism MH - Embryo Implantation MH - Female MH - Gene Deletion MH - Gene Expression Profiling MH - Humans MH - Mice MH - Pregnancy MH - Protein Tyrosine Phosphatase, Non-Receptor Type 11/*genetics/metabolism MH - Signal Transduction MH - Stromal Cells/cytology/metabolism MH - Uterus/*cytology/metabolism PMC - PMC8791483 COIS- The authors have declared that no competing interests exist. EDAT- 2022/01/14 06:00 MHDA- 2022/02/19 06:00 PMCR- 2022/01/13 CRDT- 2022/01/13 17:26 PHST- 2021/09/18 00:00 [received] PHST- 2022/01/05 00:00 [accepted] PHST- 2022/01/26 00:00 [revised] PHST- 2022/01/14 06:00 [pubmed] PHST- 2022/02/19 06:00 [medline] PHST- 2022/01/13 17:26 [entrez] PHST- 2022/01/13 00:00 [pmc-release] AID - PGENETICS-D-21-01259 [pii] AID - 10.1371/journal.pgen.1010018 [doi] PST - epublish SO - PLoS Genet. 2022 Jan 13;18(1):e1010018. doi: 10.1371/journal.pgen.1010018. eCollection 2022 Jan.