Stem cell therapy in the treatment of organic and dysfunctional endometrial pathology.

BACKGROUND: Intrauterine adhesions caused by postpartum curettage, spontaneous abortions, interrupted pregnancies, endometrial ablations, infections and inflammations, can lead to a loss of endometrial function, with consequent hypomenorrhea and infertility in women of reproductive age. In a non-negligible percentage of cases, the available surgical methods and hormone therapy, with sequential administration of estrogen and progesterone, are ineffective. In fact, severe damage to the basal layer of the endometrium causes the loss of endometrial cell precursors and leads to the failure of regeneration of the functional layer to which the endometrium is cyclically exposed. Today, many researchers are evaluating the use of stem cells of different origins as a potential therapy to restore endometrial function. METHODS: Our interest has been focused on adipose-derived stromal/stem cells (ADSCs) obtained by collecting subcutaneous adipose tissue and subsequently treating it with the MilliGraft® method. This procedure produces a cell suspension, the stromal vascular fraction (SVF), which includes ADSCs and soluble factors such as proteins and extracellular vesicles (exosomes). The SVF thus obtained was characterized in its cellular composition and its functional factors. Our clinical protocol for the future use of adipose tissue in endometrial regeneration in its different phases is presented. RESULTS: The data obtained, even though they still require further support and implementation, show the regenerative properties of SVF obtained from adipose tissue using a mechanical method. CONCLUSIONS: These findings can contribute to the development of cell therapies using stem cells of different derivations which are increasingly being utilized in the treatment of endometrial lesions from adherent or dysfunctional pathologies.

Extracellular Vesicle-Derived microRNAs of Human Wharton's Jelly Mesenchymal Stromal Cells May Activate Endogenous VEGF-A to Promote Angiogenesis.

Despite low levels of vascular endothelial growth factor (VEGF)-A, the secretome of human Wharton's jelly (WJ) mesenchymal stromal cells (MSCs) effectively promoted proangiogenic responses in vitro, which were impaired upon the depletion of small (~140 nm) extracellular vesicles (EVs). The isolated EVs shared the low VEGF-A profile of the secretome and expressed five microRNAs, which were upregulated compared to fetal dermal MSC-derived EVs. These upregulated microRNAs exclusively targeted the VEGF-A gene within 54 Gene Ontology (GO) biological processes, 18 of which are associated with angiogenesis. Moreover, 15 microRNAs of WJ-MSC-derived EVs were highly expressed (Ct value ≤ 26) and exclusively targeted the thrombospondin 1 (THBS1) gene within 75 GO biological processes, 30 of which are associated with the regulation of tissue repair. The relationship between predicted microRNA target genes and WJ-MSC-derived EVs was shown by treating human umbilical-vein endothelial cells (HUVECs) with appropriate doses of EVs. The exposure of HUVECs to EVs for 72 h significantly enhanced the release of VEGF-A and THBS1 protein expression compared to untreated control cells. Finally, WJ-MSC-derived EVs stimulated in vitro tube formation along with the migration and proliferation of HUVECs. Our findings can contribute to a better understanding of the molecular mechanisms underlying the proangiogenic responses induced by human umbilical cord-derived MSCs, suggesting a key regulatory role for microRNAs delivered by EVs.

Metformin reduces risk of ovarian hyperstimulation syndrome in patients with polycystic ovary syndrome during gonadotropin-stimulated in vitro fertilization cycles: a randomized, controlled trial.

OBJECTIVE: To test whether metformin administration reduces the incidence of ovarian hyperstimulation syndrome (OHSS) in infertile high-risk patients with polycystic ovary syndrome (PCOS) who have been treated with gonadotropins for IVF. DESIGN: Parallel, randomized, double-blind, placebo-controlled clinical trial. SETTING: Academic departments, general hospital, and IVF centers. PATIENT(S): One hundred twenty patients with PCOS at high risk for OHSS. INTERVENTION(S): Gonadotropins ovarian stimulation for IVF and metformin (500 mg three times daily) or placebo tablets (three times daily). MAIN OUTCOME MEASURE(S): The primary end point of the current clinical trial was the rate of OHSS. Anthropometric and reproductive data were evaluated. RESULT(S): The total OHSS and cancellation rates were significantly reduced in patients treated with metformin. The relative risk for OHSS was of 0.28 (95% confidence interval, 0.11-0.67). With metformin the stimulation length and the total amount of gonadotropins used were significantly increased, whereas the peak E(2) levels were significantly reduced. CONCLUSION(S): In patients with PCOS who are at high risk for OHSS and who have been stimulated with gonadotropins for IVF cycles, metformin reduces the risk of OHSS by modulating the ovarian response to the stimulation. REGISTRATION ID NUMBER FROM CLINICALTRIALS.GOV: NCT01233206.