Piezo1 channel exaggerates ferroptosis of nucleus pulposus cells by mediating mechanical stress-induced iron influx.

To date, several molecules have been found to facilitate iron influx, while the types of iron influx channels remain to be elucidated. Here, Piezo1 channel was identified as a key iron transporter in response to mechanical stress. Piezo1-mediated iron overload disturbed iron metabolism and exaggerated ferroptosis in nucleus pulposus cells (NPCs). Importantly, Piezo1-induced iron influx was independent of the transferrin receptor (TFRC), a well-recognized iron gatekeeper. Furthermore, pharmacological inactivation of Piezo1 profoundly reduced iron accumulation, alleviated mitochondrial ROS, and suppressed ferroptotic alterations in stimulation of mechanical stress. Moreover, conditional knockout of Piezo1 (Col2a1-CreERT Piezo1flox/flox) attenuated the mechanical injury-induced intervertebral disc degeneration (IVDD). Notably, the protective effect of Piezo1 deficiency in IVDD was dampened in Piezo1/Gpx4 conditional double knockout (cDKO) mice (Col2a1-CreERT Piezo1flox/flox/Gpx4flox/flox). These findings suggest that Piezo1 is a potential determinant of iron influx, indicating that the Piezo1-iron-ferroptosis axis might shed light on the treatment of mechanical stress-induced diseases.

Placental trophoblast cell-derived exosomal microRNA-1290 promotes the interaction between endometrium and embryo by targeting LHX6.

Communication between the maternal uterus and the embryo is vital for a successful pregnancy. Exosomes, subtypes of extracellular vesicles comprising many bioactive factors, regulate the early stages of pregnancy, specifically during embryo implantation. Nevertheless, the mechanism by which exosomal microRNAs (miRNAs) derived from placental trophoblasts regulate embryo implantation remains elusive. We isolated and identified exosomes derived from placental trophoblast cells (HTR8/SVneo). Subsequently, we evaluated the loading miRNA in exosomes by small RNA sequencing. Consequently, we showed that trophoblast cell-derived exosomes could transfer to endometrial epithelial cells. Besides, these exosomes promoted the epithelial-mesenchymal transition (EMT) as well as migration of endometrial cells and were implicated in the regulation of inflammation. Further, the specific miRNAs were screened in exosomes, and as a result, miRNA (miR)-1290 was enriched specifically in exosomes. miR-1290 promoted the expression of inflammatory factors (interleukin [IL]-6 and IL-8) and migration of endometrial epithelial cells. In addition, exosomal miR-1290 promoted angiogenesis in vitro. More importantly, by targeting LHX6, trophoblast HTR8/SVneo cell-derived exosomal miR-1290 promoted the EMT process of endometrial epithelial cell HEC-1-A. Altogether, our findings provide novel insights into the mechanism of trophoblast cell-derived exosomes during embryo implantation.

Endometrial cell-derived small extracellular vesicle miR-100-5p promotes functions of trophoblast during embryo implantation.

Communication between maternal uterus and blastocyst occurs in the early stages of pregnancy, and the interaction influences the success of embryo implantation. Whereas small extracellular vesicles (sEVs) play an essential role in mediating intercellular communication in numerous biological processes, their role in embryo implantation during the window of implantation (WOI) remains poorly defined. Here, we report that endometrial epithelial cells (EECs) secrete sEVs during early pregnancy, which affects the trophoblast behaviors (migration, invasion, and proliferation), thus influencing embryo implantation. We show that microRNA (miR)-100-5p, sEVs containing microRNA (miRNA), activates both focal adhesion kinase (FAK) and c-Jun N-terminal kinase (JNK), as well as contributes to trophoblast migration and invasion. Furthermore, our findings indicate that the sEV miR-100-5p promotes angiogenesis during the implantation process. In conclusion, this study reveals a novel mechanism by which EEC-derived sEV miR-100-5p crosstalks with trophoblasts, leading to an enhanced ability for implantation.

MiR-183 impeded embryo implantation by regulating Hbegf and Lamc1 in mouse uterus.

Embryo implantation plays a decisive role in pregnancy. While in the process of implantation, microRNA (miRNA) is an important regulatory factor in the post transcriptional level. However, the role of many miRNAs in embryo implantation remained unknown. In this study, microRNA-183 (miR-183) was found differentially expressed in mouse uterus during implantation. In vivo treatment of miR-183 agomir in the uterine horn before implantation could eliminate the number of implantation site. The localization of miR-183 in mouse uteri gradually changed from epithelial to stromal layer in early pregnancy. Mice implantation models demonstrated that the decrease of miR-183 was mainly caused by maternal factors. Loss and gain function of miR-183 in endometrial cell lines showed that miR-183 could inhibit cell migration, invasion and apoptosis. MiR-183 could inhibit embryo implantation by binding Heparin-Binding EGF-like growth factor (Hbegf) and Laminin gamma one (Lamc1), which were key genes in embryo apposition and penetration. All these evidences indicate that miR-183 plays an important role during embryo implantation. This study provides new insights into the functions of miR-183 during embryo implantation and the development of contraceptive drugs in early pregnancy.

miR-192-5p suppresses uterine receptivity formation through impeding epithelial transformation during embryo implantation.

The establishment of uterine receptivity is a prerequisite for embryo implantation and begins with the transformation of the luminal epithelium. MicroRNAs (miRNAs) have been widely reported to be involved in the regulation of embryo implantation, but their roles in establishing uterine receptivity remain unclear. In this study, through small RNA sequencing analysis, we showed that a low level of miR-192-5p is essential for initiating implantation in mice, and transient upregulation of miR-192-5p led to implantation failure. In situ hybridization results revealed that miR-192-5p was primarily expressed in the endometrial epithelium, and dysregulation of miR-192-5p interfered with the performance of the luminal epithelium, resulting in inadequate receptivity. By manipulating miR-192-5p expression in mouse uterus and an endometrial epithelial cell line, we showed that miR-192-5p maintains cell polarity through stabilizing adherens junction protein E-cadherin, thereby preventing epithelial-mesenchymal transition. Furthermore, miR-192-5p preserved the pattern of microvilli as well as Muc1 expression on the apical membrane of epithelial cells, thereby avoiding embryo adhesion. Moreover, miR-192-5p was found to be regulated by ovarian steroids. Collectively, this study demonstrated that the physiological role of miR-192-5p in mouse uterus is to maintain the nonreceptive state of epithelial cells and prevent their transformation to the receptive state. Thus, a sustained high level of miR-192-5p is detrimental to embryo implantation. These findings help elucidate the mechanisms involved in miRNA-based regulation of uterine physiology in early pregnancy, and may even contribute to the diagnosis and treatment of infertility.

Identification of core genes in the progression of endometrial cancer and cancer cell-derived exosomes by an integrative analysis.

Endometrial cancer is one of the most prevalent tumors of the female reproductive system causing serious health effects to women worldwide. Although numerous studies, including analysis of gene expression profile and cellular microenvironment have been reported in this field, pathogenesis of this disease remains unclear. In this study, we performed a system bioinformatics analysis of endometrial cancer using the Gene Expression Omnibus (GEO) datasets (GSE17025, GSE63678, and GSE115810) to identify the core genes. In addition, exosomes derived from endometrial cancer cells were also isolated and identified. First, we analyzed the differentially expressed genes (DEGs) between endometrial cancer tissues and normal tissues in clinic samples. We found that HAND2-AS1, PEG3, OGN, SFRP4, and OSR2 were co-expressed across all 3 datasets. Pathways analysis showed that several pathways associated with endometrial cancer, including "p53 signaling pathway", "Glutathione metabolism", "Cell cycle", and etc. Next, we selected DEGs with highly significant fold change and co-expressed across the 3 datasets and validated them in the TCGA database using Gene Expression Profiling Interactive Analysis (GEPIA). Finally, we performed a survival analysis and identified four genes (TOP2A, ASPM, EFEMP1, and FOXL2) that play key roles in endometrial cancer. We found up-regulation of TOP2A and ASPM in endometrial cancer tissues or cells, while EFEMP1 and FOXL2 were down-regulated. Furthermore, we isolated exosomes from the culturing supernatants of endometrial cancer cells (Ishikawa and HEC-1-A) and found that miR-133a, which regulates expression of FOXL2, were present in exosomes and that they could be delivered to normal endometrial cells. The common DEGs, pathways, and exosomal miRNAs identified in this study might play an important role in progression as well as diagnosis of endometrial cancer. In conclusion, our results provide insights into the pathogenesis and risk assessment of endometrial cancer. Even so, further studies are required to elucidate on the precise mechanism of action of these genes in endometrial cancer.

MicroRNAs in Small Extracellular Vesicles Indicate Successful Embryo Implantation during Early Pregnancy.

Synchronous communication between the developing embryo and the receptive endometrium is crucial for embryo implantation. Thus, uterine receptivity evaluation is vital in managing recurrent implantation failure (RIF). The potential roles of small extracellular vesicle (sEV) miRNAs in pregnancy have been widely studied. However, the systematic study of sEVs derived from endometrium and its cargos during the implantation stage have not yet been reported. In this study, we isolated endometrium-derived sEVs from the mouse endometrium on D2 (pre-receptive phase), D4 (receptive phase), and D5 (implantation) of pregnancy. Herein, we reveal that multivesicular bodies (MVBs) in the endometrium increase in number during the window of implantation (WOI). Moreover, our findings indicate that CD63, a well-known sEV marker, is expressed in the luminal and glandular epithelium of mouse endometrium. The sEV miRNA expression profiles indicated that miR-34c-5p, miR-210, miR-369-5p, miR-30b, and miR-582-5p are enriched during WOI. Further, we integrated the RIF's database analysis results and found out that miR-34c-5p regulates growth arrest specific 1 (GAS1) for normal embryo implantation. Notably, miR-34c-5p is downregulated during implantation but upregulated in sEVs. An implication of this is the possibility that sEVs miR-34c-5p could be used to evaluate uterine states. In conclusion, these findings suggest that the endometrium derived-sEV miRNAs are potential biomarkers in determining the appropriate period for embryo implantation. This study also has several important implications for future practice, including therapy of infertility.

MicroRNA-183 in Cancer Progression.

MicroRNA-183(miR-183) is abnormally expressed in many kinds of tumors. It participates in the initiation and development of tumors. There are many pathways regulate the expression of miR-183. The action mechanism of miR-183 in cancer is very extensive, and contradictory conclusions are often drawn. It was upregulated in 18 kinds of cancer, downregulated in 6 kinds of cancer. In addition, there are seven types of cancer, both upregulated and downregulated reports can be found. Evidence showed that miR-183 can not only directly play the role of oncogene or antioncogene, but also regulate the expression of other oncogene or antioncogene in different cancer types. In this review, we discuss the regulator of miR-183 and summarized the expression of miR-183 in different cancers. We also counted the target genes of miR-183 and the functional roles they play. Furthermore, we focused on the roles of miR-183 in cell migration, cell invasion, epithelial-mesenchymal transition (EMT) and microangiogenesis, which play the most important roles in cancer processes. It sheds light on the likely reasons why miR-183 plays different roles in various cancers. In addition, miR-183 and its downstream effectors have the potential to be promising prognostic markers and therapeutic targets in cancer.