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Background Human amniotic epithelial cells (hAECs) exhibit a strong capability to restore ovarian function in chemotherapy-induced premature ovarian failure (POF). However, the therapeutic efficacy of hAECs is usually affected by the limited number and proliferative ability of grafted hAECs in target organs. The transplantation of stem cells encapsulated in sodium alginate-bioglass (SA-BG) composite hydrogel has recently been shown to be an effective strategy for tissue regeneration. The current study aims to investigate the therapeutic potential of hAECs or hAEC-derived conditioned medium (CM) encapsulated in SA-BG in mice with chemotherapy-induced POF. Methods C57BL/6 mice were intraperitoneally injected with chemotherapy drugs to induce POF. hAECs or CM were harvested and encapsulated in SA-BG composite hydrogel, which were transplanted onto the injured ovaries of mice with POF. Follicle development, granulosa cell function, and ovarian angiogenesis were evaluated by morphological methods. To further elucidate the effect of SA-BG-encapsulated hAECs/CM on vascularization, the tube formation of human umbilical vein epithelial cells (hUVECs) was conducted in vitro. Cytokine array and ELISA were used to analyze and quantify the effects of bioactive components released by SA-BG on the secretion of angiogenic factors by hAECs. Results The transplantation of SA-BG-encapsulated hAECs/CM restored follicle development, repaired granulosa cell function, and enhanced ovarian angiogenesis in POF mice. The further study showed that SA-BG significantly promoted the tube formation of hUVECs in vitro. Moreover, encapsulating hAECs could facilitate the effect of SA-BG on inducing the formation of the capillary tube in a paracrine manner. In addition, we found that SA-BG extracts significantly enhanced the viability of hAECs and stimulated the secretion of pro-angiogenic factors of hAECs. Notably, compared with SA-BG/CM, SA-BG/hAECs achieve better therapeutic effects, possibly because stimulation of BG enhanced the viability and paracrine capacity of hAECs. Conclusions The present study initially demonstrates that SA-BG-encapsulated hAECs or CM can exert a therapeutic effect on chemotherapy-induced POF mainly by protecting granulosa cell function and enhancing ovarian vascularization, which might provide a novel strategy for the delivery of hAECs for treating POF.

BackgroundPrimary ovarian insufficiency (POI) is gaining awareness as its prevalence increases and its effect on patients is extremely negative. To date, several therapies have been designed to treat POI, but the conclusions are conflicting, in part, due to inconsistent evaluation methods. Thus, we explore a multi-index of ovarian function assessment methods to evaluate the recovery of ovarian function after various therapies in order to evaluate effectiveness in a more comprehensive manner.AimThe purpose of this review is to assess the effectiveness of various therapies to recover ovarian function in patients with POI. The primary outcome measures were anti-Müllerian hormone (AMH) levels, follicle stimulating hormone (FSH) levels, and antral follicle count (AFC). The secondary outcomes included the change of mean ovarian volume, menstruation recovery, and pregnancy rate.MethodsOur systematic searching including PubMed, Web of Science, Cochrane, and Embase databases was conducted to find all human clinical trial articles published from January 2000 to April 2021 and related to POI treatment, including the keywords: POI, AFC, and hormones. All prospective and retrospective studies exploring ovarian function recovery that include AFC, AMH levels, and FSH levels evolution throughout treatment were included. All patients included in the studies met the POI criteria described by the European Society for Human Reproductive Embryology (ESHRE) guideline.ResultsSix studies were selected based on the criteria: one randomized controlled trial and five observational studies. Among them, two studies focused on the intraovarian platelet-rich plasma (PRP) infusion treatment, two studies focused on dehydroepiandrosterone (DHEA) supplements, one study focused on hormone replacement therapy (HRT), and one study focused on autologous adipose-derived stromal cells (ADSCs) treatment. There was insufficient scientific evidence that any approach could help ovarian function recovery in patients with POI because the ovarian function markers in each study had inconsistent changes with 26 patients (6.2%) reporting spontaneous pregnancy.ConclusionSerum AMH levels, FSH levels, and AFC are sensitive indicators and reflect the evolution of ovarian function. Large randomized controlled trials are necessary, and the data on ovarian function should be collected comprehensively to evaluate the effectiveness of a variety of treatments.