Background: Umbilical cord-derived mesenchymal stem cell (UCMSCs) transplantation has been widely studied in premature ovarian failure (POF). However, the underlying mechanism remains elusive. This study aims to investigate the protective properties and mechanisms of heme oxygenase-1 (HO-1) expressed in UCMSCs in restoring the ovarian function of POF mice. Methods: In in vitro and in vivo experiments, mice were treated with the presence or absence of the HO-1/shHO-1-transfected UCMSCs, and the administration of SP600125 or anisomycin, the inhibitor or activator of JNK. The viability and apoptosis of granulosa cells (GCs) at different time points of co-cultivation were assessed in vitro. In in vivo experiments, mouse ovarian function was assessed by detecting the serum levels of hormone and observing the ovarian morphological changes. Multiple molecular indices of JNK/Bcl-2 signal pathway were performed. And the autophagy changes in GCs were assessed by detecting the associated cytokines and observing the intracellular autophagosome accumulation. Additionally, the spleen levels of CD8⁺CD28⁻ T cells and serum levels of interleukin 10 (IL-10) were tested to evaluate the immune mechanisms involved. Results: UCMSCs transfected with shHO-1 or treated with SP600125 inhibited GCs’ viability and promoted its apoptosis in a time-dependent manner in vitro. In in vivo experiments, mice in both groups showed little therapeutic efficiency which presented as the increased extent of ovarian fibrosis with decreased number of functional follicles, and disordered hormone production. Additionally, the JNK/Bcl-2-associated cytokines were obviously declined. The inhibited autophagy-related cytokines, the chromatin condensation and abound vacuolar autophagosome in GCs, and weakened fluorescence intensity by MDC were observed. The downregulated levels of CD8⁺CD28⁻ T cells and serum levels of IL-10 were also detected. The damages above can be alleviated with HO-1-MSCs treatment or anisomycin administration. Conclusions: HO-1 expressed in UCMSCs is critical in restoring the ovarian function in POF mice with UCMSC transplantation, which is mediated by the activation of JNK/Bcl-2 signal pathway-regulated autophagy and upregulating the circulating of CD8⁺CD28⁻ T cells.

If fertilization does not occur for a prolonged period in vivo or in vitro, the postovulatory oocytes will deteriorate, which called the postovulatory aging. This process disrupts the developmental competence. In the present study, we showed that the reactive oxygen species (ROS) was accumulated in oocytes during the postovulatory aging. ROS inhibited Sirt1 expression, and then increased oxidative stress by downregulating the intracellular Sirt1-FOXO3a-SOD2 axis. Moreover, the inhibited Sirt1 expression was related to the decreased mitochondrial function and the lowered level of autophagy. The mitochondrial-related apoptosis was increased by inhibiting the AKT and ERK1/2 pathways, due to the accumulation of ROS in the postovulatory oocytes. The mitochondrial pyruvate dehydrogenase kinase-4 (PDK4) can reduce ROS by inhibiting the tricarboxylic acid (TAC) cycle. We found that PDK4 was significantly decreased in the postovulatory aging oocytes. Putrescine, one of the abundant biogenic amines, ameliorated the effects of ROS and therefore improved the quality of the postovulatory aging oocytes by increasing the expression of PDK4. When PDK4 was downregulated using siRNAs, the effects of putrescine were significantly receded. We concluded that putrescine delayed the aging process of postovulatory oocytes by upregulating PDK4 expression and improving mitochondrial activity.

With the global epidemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the increasing number of infections, little is known about how SARS-CoV-2 affects the male reproductive system during infection or after recovery. Based on the existing research data, we reviewed the effects of SARS-CoV-2 on the male reproductive system and discussed its possible mechanism of action. SARS-CoV-2 enters host cells through the angiotensin-converting enzyme 2 (ACE2)/transmembrane serine protease 2 (TMPRSS2) pathway, and males are more susceptible than females. After infection, immunopathological damage is noticed in the testicles, and the semen index is significantly reduced. Second, abnormalities of serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), and testosterone (T) levels were also observed, suggesting that there may be dysfunction of the hypothalamic–pituitary–gonadal (HPG) axis. Even after recovery, the effect of SARS-CoV-2 on the male reproductive system can last for at least a period. There are still many unresolved questions about the effect of SARS-CoV-2 infection on the male reproductive tract. Other receptors involved during the invasion of human cells by SARS-CoV-2 remain to be identified. Will the mutation of SARS-CoV-2 increase the diversity of receptors? How does SARS-CoV-2 affect the HPG axis? The long-term effects of SARS-CoV-2 on the male reproductive system remain to be evaluated. SARS-CoV-2 infection can affect male reproductive function. Standard treatment strategies should be developed in time to protect the fertility of infected patients. For recovered patients with fertility requirements, fertility assessments should be performed and professional fertility guidance should be provided at the same time.

Umbilical cord-derived mesenchymal stem cell (UCMSC) transplantation has been deeply explored for premature ovarian insufficiency (POI) disease. However, the associated mechanism remains to be researched. To explore whether and how the microRNA 21 (miR-21) functions in POI mice with UCMSCs transplantation, the autoimmune-induced POI mice model was built up, transplanted with or without UCMSCs transfect with the LV-hsa-miR-21-5p/LV-hsa-miR-21-5p-inhibition, with the transfection efficiency analyzed by QRT-PCR. Mice hormone secretion and the anti-Zona pellucida antibody (AZPAb) levels were analyzed, the ovarian morphological changes and folliculogenesis were observed, and the ovarian apoptosis cells were detected to evaluate ovarian function. The expression and localization of the PTEN/Akt/FOXO3a signal pathway-related cytokines were analyzed in mice ovaries.Additionally, the spleen levels of CD8 + CD28-T cells were tested and qualified with its significant secretory factor, interleukin 10 (IL-10). We found that with the LV-hsa-miR-21-5p-inhibition-UCMSCs transplantation, the mice ovarian function can be hardly recovered than mice with LV-NC-UCMSCs transplantation, and the PTEN/Akt/FOXO3a signal pathway was activated. The expression levels of the CD8 + CD28-T cells were decreased, with the decreased levels of the IL-10 expression. In contrast, in mice with the LV-hsa-miR-21-5p-UCMSCs transplantation, the injured ovarian function can be reversed, and the PTEN/AKT/FOXO3a signal pathway was detected activated, with the increased levels of the CD8 + CD28-T cells, and the increased serum levels of IL-10. In conclusion, miR-21 improves the ovarian function recovery of POI mice with UCMSCs transplantation, and the mechanisms may be through suppressing the PTEN/AKT/FOXO3a signal pathway and up-regulating the circulating of the CD8 + CD28-T cells.