Exosomes Derived From CTF1-Modified Bone Marrow Stem Cells Promote Endometrial Regeneration and Restore Fertility.

Background: Thin endometrial tissue is a leading cause of embryo transfer failure, potentially contributing to sustained infertility and associated adverse outcomes. The application of exosomes derived from autologous or allogeneic bone marrow-derived stem cells (BMSCs) has been used to promote uterine repair following injury, and there is also prior evidence that stem cell transplantation can bolster fertility. Genetic modifications represent a primary approach to enhancing exosomal therapy strategies. The present study thus explored the effects of Cardiotrophin-1 (CTF1)-modified BMSCs-exo on fertility-related outcomes. Methods: An adenoviral vector was used to generate CTF1-overexpressing BMSCs (C-BMSCs), after which exosomes were isolated from control BMSCs (BMSC-exos) and C-BMSCs (C-BMSC-exos). The angiogenic effects of C-BMSC-exo treatment were assessed through analyses of endothelial cell proliferation and tube formation. Model rats exhibiting endometrial thinning were administered C-BMSCs-exo, after which the effects of such treatment were assessed through H&E staining, Masson's trichrome staining, and immunofluorescence analyses. The mechanistic basis for the proangiogenic effects of CTF1 as a driver of endometrial regeneration was additionally explored. Results: C-BMSC-exo treatment of HUVECs was associated with enhanced neovascularization, as evidenced by improved in vitro proliferation, migration, and tube formation. Importantly, such treatment was also linked to tissue regeneration, neovascularization, and the suppression of localized tissue fibrosis in vivo. Regenerated endometrial tissue exhibited higher embryo receptivity and was associated with higher birth rates in treated rats. The upregulation of the JAK/PI3K/mTOR/STAT3 signaling pathways in C-BMSC-exo-treated rats may underscore the mechanistic basis whereby CTF1 can positively impact endometrial angiogenesis and regeneration. Conclusion: Our data suggest that exosomes produced by CTF1-modified BMSCs can more effectively promote the regeneration of endometrial and myometrial tissues, driving neovascularization in a manner that improves endometrial receptivity in a rat model system, highlighting the therapeutic promise of this approach for patients diagnosed with endometrial thinning.

Effect of previous wedge resection for interstitial pregnancy on pregnancy and neonatal outcomes following frozen-thawed embryo transfer (FET) cycles of IVF/ICSI: a retrospective study.

OBJECTIVE: The present study aimed to evaluate pregnancy and neonatal outcomes in women, with a previous history of wedge resection for interstitial pregnancy, in frozen-thawed embryo transfer (FET) cycles of IVF/ICSI. METHODS: The present study involved a retrospective case-control assessment of 75 cases and 375 control subjects over 6 years in a single center. To compare pregnancy and neonatal outcomes between cases, treated using wedge resection, and controls without any previous history of ectopic pregnancy, propensity score matching (1:5) was utilized. The study also compared subgroups in the case group. RESULTS: Women with previous wedge resection exhibited higher rates of ectopic pregnancy and uterine rupture rate as compared to control subjects (9.1% vs 1.3%, P = 0.025 and 4.5% vs 0%, P = 0.035, respectively). No statistically significant differences were recorded between the two cohorts with regard to clinical pregnancy rate, live birth rate, and neonatal outcomes. For pregnancy type subgroup analysis, Z-score and rates of large for gestational age were recorded to be significantly lower in twin pregnancy subgroup when compared with singleton pregnancy subgroup (0.10 (- 0.59, 0.25) vs 0.50 (- 0.97, 1.39), P = 0.005; 4.5% vs 26.1%, P = 0.047, respectively). CONCLUSION: The results of the present study indicated that previous wedge resection correlated to a higher risk of ectopic pregnancy and uterine rupture. However, it might not be related to an increased risk of adverse neonatal outcomes. The study recommended cesarean section in these patients. Further studies are required to verify the validity of current recommendations.

Microenvironment-Protected Exosome-Hydrogel for Facilitating Endometrial Regeneration, Fertility Restoration, and Live Birth of Offspring.

Thin endometrium is a primary cause of failed embryo transfer, resulting in long-term infertility and negative family outcomes. While hormonal treatments have greatly improved fertility results for some women, these responses remain unsatisfactory due to damage and infection of the complex endometrial microenvironment. In this study, a multifunctional microenvironment-protected exosome-hydrogel is designed for facilitating endometrial regeneration and fertility restoration via in situ microinjection and endometrial regeneration. This exosome hydrogel is formulated via Ag+ -S dynamic coordination and fusion with adipose stem cell-derived exosomes (ADSC-exo), yielding an injectable preparation that is sufficient to mitigate infection risk while also possessing the antigenic contents and paracrine signaling activity of the ADSC source cells, enabling regeneration of the endometrial microenvironment. In vitro, this exosome-hydrogel exerts an outstanding neovascularization-promoting effect, increased human umbilical vein endothelial cell proliferation and tube formation for 1.87 and 2.2 folds. In vivo, microenvironment-protected exosome-hydrogel also reveals to promote neovascularization and tissue regeneration while suppressing local tissue fibrosis. Importantly, regenerated endometrial tissue is more receptive to give embryos and birth to a healthy newborn. This microenvironment-protected exosome-hydrogel system offers a convenient, safe, and noninvasive approach for repairing thin endometrium and fertility restoration.

Adverse effects of pre-pregnancy maternal underweight on pregnancy and perinatal outcomes in a freeze-all policy.

BACKGROUND: Underweight and overweight may affect reproduction and interfere with treatment of infertility. In the present retrospective analysis, we sought to evaluate the effect of low body mass index (BMI) on pregnancy and perinatal outcomes in frozen-thawed embryo transfer (FET) cycles. METHODS: This study involved 8755 FET cycles in a single IVF center during the period from January 2009 to December 2018. Both pregnancy and perinatal outcomes were assessed in women who were underweight, normal weight, and overweight as defined based on a respective BMI < 18.5 kg/m2, ≥ 18.5 BMI < 24.9 kg/m2, and BMI ≥ 25 kg/m2. RESULTS: Being underweight was linked to reduced implantation rates as compared to a normal weight (33.56% vs. 37.26%). Similarly, when comparing outcomes in underweight women to those in normal weight women, rates of clinical pregnancy (48.14% vs. 53.85%) and ongoing pregnancy (43.04% vs. 50.47%) were reduced. Rates of miscarriage were markedly reduced in the normal weight group relative to the overweight group (10.73% vs. 13.37%). Perinatal outcomes were largely comparable for all groups, with the exception of very low birth weight rates (normal weight:0.58% vs. overweight: 2.03%), very small for gestational age rates (normal weight:1.31% vs. overweight:3.55%) and very preterm delivery rates (normal weight:0.82% vs. overweight: 2.03%), which were significantly elevated for overweight mothers. CONCLUSIONS: These results indicate that being underweight is linked to negative pregnancy outcomes when undergoing FET-based IVF.