The functions of Sertoli cells in spermatogenesis have attracted much more attention recently. Normal spermatogenesis depends on Sertoli cells, mainly due to their influence on nutrient supply, maintenance of cell junctions, and support for germ cells’ mitosis and meiosis. Accumulating evidence in the past decade has highlighted the dominant functions of the MAPK, AMPK, and TGF-β/Smad signaling pathways during spermatogenesis. Among these pathways, the MAPK signaling pathway regulates dynamics of tight junctions and adherens junctions, proliferation and meiosis of germ cells, proliferation and lactate production of Sertoli cells; the AMPK and the TGF-β/Smad signaling pathways both affect dynamics of tight junctions and adherens junctions, as well as the proliferation of Sertoli cells. The AMPK signaling pathway also regulates lactate supply. These signaling pathways combine to form a complex regulatory network for spermatogenesis. In testicular tumors or infertile patients, the activities of these signaling pathways in Sertoli cells are abnormal. Clarifying the mechanisms of signaling pathways in Sertoli cells on spermatogenesis provides new insights into the physiological functions of Sertoli cells in male reproduction, and also serves as a pre-requisite to identify potential therapeutic targets in abnormal spermatogenesis including testicular tumor and male infertility.

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Primary ovarian insufficiency (POI) is a clinical syndrome of ovarian dysfunction characterized by premature exhaustion of primordial follicles. POI causes infertility, severe daily life disturbances and long-term health risks. However, the underlying mechanism remains largely unknown. We previously identified a Basonuclin 1 (BNC1) mutation from a large Chinese POI pedigree and found that mice with targeted Bnc1 mutation exhibit symptoms of POI. In this study, we found that BNC1 plays key roles in ovarian reserve and maintaining lipid metabolism and redox homeostasis in oocytes during follicle development. Deficiency of BNC1 results in premature follicular activation and excessive follicular atresia. Mechanistically, BNC1 deficiency triggers oocyte ferroptosis via the NF2-YAP pathway. We demonstrated that pharmacologic inhibition of YAP signaling or ferroptosis significantly rescues Bnc1 mutation-induced POI. These findings uncover a pathologic mechanism of POI based on BNC1 deficiency and suggest YAP and ferroptosis inhibitors as potential therapeutic targets for POI.

Background Thin endometrium is a primary cause of defective endometrial receptivity, resulting in infertility or recurrent miscarriage. Much effort has been devoted toward regenerating thin endometrium by stem cell-based therapies. The human placenta-derived mesenchymal stem cells (HP-MSCs) are emerging alternative sources of MSCs with various advantages. To maximize their retention inside the uterus, we loaded HP-MSCs with cross-linked hyaluronic acid hydrogel (HA hydrogel) to investigate their therapeutic efficacy and possible underlying mechanisms. Methods Ethanol was injected into the mice uterus to establish the endometrium-injured model. The retention time of HP-MSCs and HA hydrogel was detected by in vivo imaging, while the distribution of HP-MSCs was detected by immunofluorescence staining. Functional restoration of the uterus was assessed by testing embryo implantation rates. The endometrial morphological alteration was observed by H&E staining, Masson staining, and immunohistochemistry. In vitro studies were further conducted using EdU, transwell, tube formation, and western blot assays. Results Instilled HP-MSCs with HA hydrogel (HP-MSCs-HA) exhibited a prolonged retention time in mouse uteri than normal HP-MSCs. In vivo studies showed that the HP-MSCs-HA could significantly increase the gland number and endometrial thickness (P < 0.001, P < 0.05), decrease fibrous area (P < 0.0001), and promote the proliferation and angiogenesis of endometrial cells (as indicated by Ki67 and VEGF, P < 0.05, P < 0.05, respectively) in mice injured endometrium. HP-MSCs-HA could also significantly improve the embryo implantation rate (P < 0.01) compared with the ethanol group. Further mechanistic study showed the paracrine effects of HP-MSCs. They could not only promote the proliferation and migration of human endometrial stromal cells via the JNK/Erk1/2-Stat3-VEGF pathway but also facilitate the proliferation of glandular cells via Jak2-Stat5 and c-Fos-VEGF pathway. In turn, the increased VEGF in the endometrium promoted the angiogenesis of endothelial cells. Conclusion Our study suggested the potential therapeutic effects and the underlying mechanisms of HP-MSCs-HA on treating thin endometrium. HA hydrogel could be a preferable delivery method for HP-MSCs, and the strategy represents a promising therapeutic approach against endometrial injury in clinical settings. Graphical abstract

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Increasing evidences showed ovulatory dysfunction, possibly caused by luteinized unruptured follicular follicle syndrome(LUFS), is one of the reasons for endometriosis-related infertility. The present study was conducted to explore the potential effect of elevated progesterone in follicular fluid (FF) on ovulation in endometriosis. A prospective study including 50 ovarian endometriosis patients and 50 control patients with matched pairs design was conducted with alterations in FF and peritoneal fluid (PF) components identified by metabolomics analyses and differentially expressed genes in granulosa cells (GCs) identified by transcriptome analysis. Patients with endometriosis exhibited a significantly higher progesterone level in serum, FF and PF. GCs from endometriosis patients revealed decreased expression of HPGD, COX-2 and suppressed NF-кB signaling. Similarly, progesterone treatment in vitro down-regulated HPGD and COX2 expression and suppressed NF-кB signaling in granulosa tumor-like cell line KGN (Bena culture collection, China) and primarily cultured GCs, as manifested by decreased expressions of IL1R1, IRAK3, reduced pIкBα/IкBα ratio and nucleus translocation of p65. On the contrary, TNF-α treatment increased expression of IL1R1, IRAK3, pIкBα, p65 and HPGD in GCs. One potential p65 binding site was identified in the promoter region of HPGD by chromatin immunoprecipitation. In conclusion, we found intrafollicular progesterone might down-regulate HPGD and COX-2 in GCs via suppressing the NF-кB signaling pathway, shedding light on the mechanism underlying the endometriosis related ovulatory dysfunction.

Background: Endometriosis can affect the systemic metabolic indicators, including body mass index, glucose metabolism and lipid metabolism, while the association between metabolic indexes and the occurrence and ART outcome of endometriosis is unclear. We aimed to evaluate the characteristics of systemic metabolic indexes of endometriosis patients with infertility and their effects on pregnancy outcome after ART treatment. Methods:A retrospective cohort study involve 412 endometriosis patients and 1551 controls was conducted. Primary outcome was metabolic indexes, and secondary measures consisted of the influence of metabolic indexes on the number of retrieved oocytes and ART outcomes, as well as the relation between blood glucose and prevalence of GDM. Results:Endometriosis patients had higher INS [6.90(5.10-9.50) vs 6.50(4.80-8.90) μU/mL, P = 0.005]. A prediction model for endometriosis combining the number of previous pregnancies, CA125, fasting blood Glu and INS, had a sensitivity of 73.9%, specificity of 67.8% and area AUC of 0.77. There were no significant differences in ART outcomes and complications. The levels of Glu were associated with GDM both in endometriosis group (aOR 12.95, 95% CI 1.69–99.42; P = 0.014) and in control group (aOR 4.15, 95% CI 1.50–11.53; P = 0.006). Conclusions: Endometriosis patients had abnormal metabolic indexes, in which serum Glu and serum INS are related to the occurrence of endometriosis, the number of retrieved oocytes and the occurrence of GDM. A prediction model based on metabolic indexes was established, representing a promising non-invasive method to predict endometriosis patients with known pregnancy history.