Abstract
BackgroundChemotherapy can induce premature ovarian insufficiency (POI) and reduce fertility in young female patients. Currently, there is no effective therapy for POI. Human amnion-derived mesenchymal stem cells (hAD-MSCs) may be a promising seed cell for regenerative medicine. This study investigated the effects and mechanisms of hAD-MSC transplantation on chemotherapy-induced POI in rats.MethodsChemotherapy-induced POI rat models were established by intraperitoneal injection of cyclophosphamide. Seventy-two female SD rats were randomly divided into control, POI, and hAD-MSC-treated groups. hAD-MSCs were labeled with PKH26 and injected into the tail veins of POI rats. To examine the underlying mechanisms, the differentiation of transplanted hAD-MSCs in the POI ovaries was analyzed by immunofluorescent staining. The in vitro expression of growth factors secreted by hAD-MSCs in hAD-MSC-conditioned media (hAD-MSC-CM) was analyzed by ELISA. Sixty female SD rats were divided into control, POI, and hAD-MSC-CM-treated groups, and hAD-MSC-CM was injected into the bilateral ovaries of POI rats. After hAD-MSC transplantation or hAD-MSC-CM injection, serum sex hormone levels, estrous cycles, ovarian pathological changes, follicle counts, granulosa cell (GC) apoptosis, and Bcl-2, Bax, and VEGF expression in ovaries were examined.ResultsPKH26-labeled hAD-MSCs mainly homed to ovaries after transplantation.hAD-MSC transplantation reduced ovarian injury and improved ovarian function in rats with POI. Transplanted hAD-MSCs were only located in the interstitium of ovaries, rather than in follicles, and did not express the typical markers of oocytes and GCs, which are ZP3 and FSHR, respectively. hAD-MSCs secreted FGF2, IGF-1, HGF, and VEGF, and those growth factors were detected in the hAD-MSC-CM. hAD-MSC-CM injection improved the local microenvironment of POI ovaries, leading to a decrease in Bax expression and an increase in Bcl-2 and endogenous VEGF expression in ovarian cells, which inhibited chemotherapy-induced GC apoptosis, promoted angiogenesis and regulated follicular development, thus partly reducing ovarian injury and improving ovarian function in rats with POI.ConclusionshAD-MSC transplantation can improve ovarian function in rats with chemotherapy-induced POI at least partly through a paracrine mechanism. The presence of a paracrine mechanism accounting for hAD-MSC-mediated recovery of ovarian function might be attributed to the growth factors secreted by hAD-MSCs.
Highlights
Chemotherapy can induce premature ovarian insufficiency (POI) and reduce fertility in young female patients
The presence of a paracrine mechanism accounting for Human amnion-derived mesenchymal stem cell (hAD-mesenchymal stem cell (MSC))-mediated recovery of ovarian function might be attributed to the growth factors secreted by hAD-MSCs
The results showed that compared to the Premature ovarian insufficiency (POI) group, the percentages of rats with irregular estrous cycles were lower in the hAD-MSC-Conditioned media (CM)-treated group from the second week after hAD-MSC-CM injection (Fig. 7a), and the levels of anti-Müllerian hormone (AMH) and E2 were significantly greater in the hAD-MSC-CM-treated group starting from the fourth week after hAD-MSC-CM injection (P < 0.05; Fig. 7b, d), while the Follicle-stimulating hormone (FSH) level was significantly lower (P < 0.05; Fig. 7c)
Summary
Chemotherapy can induce premature ovarian insufficiency (POI) and reduce fertility in young female patients. This study investigated the effects and mechanisms of hAD-MSC transplantation on chemotherapy-induced POI in rats. Premature ovarian insufficiency (POI) is a clinical syndrome characterized by oligomenorrhea or amenorrhea for at least 4 months, elevated follicle-stimulating hormone levels (FSH, > 25 mIU/ml on two occasions > 4 weeks apart) and low estradiol (E2) levels in women before the age of 40 years [1,2,3]. It has been estimated and reported that there are approximately 1,000,000 new cancer diagnoses annually in adolescents and young adults (AYAs) aged 15 to 39 years worldwide [5]. Chemotherapy is a common method used to treat various malignancies and could induce ovarian failure and reduce fertility in young female patients [7]. It is important to examine and/or improve the treatment strategies for POI
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