Background Premature ovarian insufficiency (POI) is one of the major causes of infertility. We previously demonstrated that transplantation of menstrual blood-derived stromal cells (MenSCs) effectively improved ovarian function in a murine model of POI. Recent studies indicated that mesenchymal stem cell-derived exosomes were important components in tissue repair. In this study, we investigated the therapeutic effects of MenSCs-derived exosomes (MenSCs-Exos) in a rat model of POI and its mechanism in restoring ovulation. Methods Ovaries of 4.5-day-old Sprague Dawley rats (SD rats) were cultured in vitro to evaluate the effects of MenSCs-Exos exposure on early follicle development. Furthermore, POI in rats was induced by intraperitoneal administration of 4-vinylcyclohexene diepoxide (VCD). Forty-eight POI rats were randomly assigned to four groups, each receiving a different treatment: PBS, MenSCs, MenSCs-Exos, and Exo-free culture supernatant of MenSCs. Estrous cyclicity, ovarian morphology, follicle dynamics, serum hormones, pregnancy outcomes, and molecular changes were investigated. Results Exposure to MenSCs-Exos promoted the proliferation of granulosa cells in primordial and primary follicles in vitro and increased the expression of early follicle markers Deleted In Azoospermia Like (DAZL) and Forkhead Box L2 (FOXL2) while inhibiting follicle apoptosis. In vivo, MenSCs-Exos transplantation effectively promoted follicle development in the rat model of POI and restored the estrous cyclicity and serum sex hormone levels, followed by improving the live birth outcome. In addition, transplantation of MenSCs-Exos regulated the composition of the ovarian extracellular matrix and accelerated the recruitment of dormant follicles in the ovarian cortex and increased proliferation of granulosa cells in these follicles. Conclusion MenSCs-Exos markedly promoted follicle development in vitro and in vivo and restored fertility in POI rats, suggesting a restorative effect on ovarian functions. The therapeutic effect of MenSCs-Exos transplantation was sustainable, consistent with that of MenSCs transplantation. Our results suggested that MenSCs-Exos transplantation may be a promising cell-free bioresource in the treatment of POI.
Intrauterine adhesion (IUA) is caused by endometrial damage and leads to the formation of scar fibrosis and repair disorders. We compared four different rat IUA modelling procedures in order to establish a stable animal model suitable for investigating IUA. Twenty female Sprague–Dawley rats were randomly divided into four groups. IUA was induced on one side of each rat uterus by ethanol instillation, heat stripping, mechanical injury or mechanical injury with infection (dual-injury); the other side of the uterus was left intact as a control. After 8 days the rats were sacrificed, their uteri were examined for histomorphology and expression of endometrial markers was checked using immunohistochemistry. All four IUA modelling procedures resulted in visual pathophysiological changes in the rat uterus, including stenosis, congestion and loss of elasticity. Endometrial thinning, shrinkage of glands and formation of fibrotic hyperplasia were also observed. All four procedures resulted in the downregulation of cytokeratin 18 and vimentin expression compared with control tissues, as well as the upregulation of collagen I expression. After mechanical injury and dual-injury the expression of interleukin 6 was significantly increased. Overall, our results suggest that ethanol instillation is the most stable IUA modelling procedure. Mechanical injury reliably yielded inflammatory indicators.
MenSCs-sEVs safely and effectively enhanced endometrial restoration, suggesting a promising non-cellular therapy for endometrial regeneration and a key role in MenSC-mediated IUA treatment.
BACKGROUNDIntrauterine adhesion (IUA) can cause serious damage to women's reproductive health, yet current treatment methods are difficult to achieve satisfactory results. In our previous studies, we demonstrated that menstrual-derived stromal stem cells (MenSCs), with high proliferative capacity and self-renewal ability, have a powerful therapeutic effect in patients with severe IUA. However, safety assessment of MenSCs transplantation is essential for its further application. AIMTo evaluate the short-, medium-, and long-term biosafety of MenSCs via intrauterine transplantation in a rat model of IUA, with a focus on toxicity and tumorigenicity. METHODSMenSCs were injected into the sub-serosal layer of the uterus in an IUA rat model, for 3 d, 3 mo, and 6 mo separately, to monitor the corresponding acute, sub-chronic, and chronic effects. Healthy rats of the same age served as negative controls. Toxicity effects were evaluated by body weight, organ weight, histopathology, hematology, and biochemistry tests. Tumorigenicity of MenSCs was investigated in Balb/c-nu mice in vivo and by colony formation assays in vitro. RESULTSCompared with the same week-old control group, all of the IUA rats receiving MenSC transplantation demonstrated no obvious changes in body weight, main WJSC https://www.wjgnet.com May 26, 2020 Volume 12 Issue 5 Institutional Animal Care of Shengjing Hospital Affiliated to China Medical University and were conducted in accordance with the AAALAC and IACUC guidelines.
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