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Abstract
IntroductionPremature ovarian failure and insufficiency are significant long-term side-effects of chemotherapy for female cancer patients. Recently, stem cell transplantation has been identified as a promising treatment for premature ovarian failure and insufficiency. We have previously demonstrated that human amniotic epithelial cells (hAECs) migrate into injured tissue and promote the recovery of ovarian function in chemoablated mice. However, the molecular mechanism guiding this process remains unclear.MethodsTo further investigate the effect of hAECs on chemotherapy-induced apoptosis, cultured primary hAECs were injected intravenously into mice treated with cyclophosphamide and busulphan. Apoptosis of granulosa cells was observed by TUNEL staining, and apoptosis-related gene expression was performed on ovarian tissue by real-time PCR and Western blot 7 days after hAEC transplantation. Additionally, the ovarian function and fertility of mice were assessed via counts of follicles and mating experiments at 4 weeks after hAEC transplantation.ResultshAECs significantly inhibited tumor necrosis factor-alpha-mediated granulosa cell apoptosis induced by chemotherapeutics and reduced the inflammatory reaction in ovaries at 7 days after transplantation. In addition, 4 weeks after transplantation, hAECs promoted the development of follicles and increased the number of cumulus oocyte complexes in chemoablated mice. Furthermore, hAECs improved ovarian mass and increased the number of follicles compared to those of the chemoablated group, and hAEC transplantation partially rescued the fertility of chemoablated mice.ConclusionshAEC transplantation promotes ovarian function by inhibiting tumor necrosis factor-alpha-mediated cell apoptosis and reducing inflammation in chemotherapy-induced premature ovarian failure. These results suggest a potential molecular mechanism for the effective therapy of hAEC transplantation in chemotherapy-induced premature ovarian failure and insufficiency.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-015-0148-4) contains supplementary material, which is available to authorized users.
Highlights
Premature ovarian failure and insufficiency are significant long-term side-effects of chemotherapy for female cancer patients
Results: Human amniotic epithelial cell (hAEC) significantly inhibited tumor necrosis factor-alpha-mediated granulosa cell apoptosis induced by chemotherapeutics and reduced the inflammatory reaction in ovaries at 7 days after transplantation
4 weeks after transplantation, hAECs promoted the development of follicles and increased the number of cumulus oocyte complexes in chemoablated mice
Summary
Premature ovarian failure and insufficiency are significant long-term side-effects of chemotherapy for female cancer patients. Stem cell transplantation has been identified as a promising treatment for premature ovarian failure and insufficiency. Chemotherapy is commonly used to treat both malignant neoplasms and disorders of the immune system, and its use is accompanied by a host of side-effects. The use of chemotherapy can lead to irreversible premature ovarian failure and insufficiency (POF/POI). There is no effective treatment for POF/POI, and medical reversal can be challenging. Stem cells have indefinite proliferative capacity and multi-directional differentiation potential, and hold great promise in tissue engineering for regenerative. Clinical applications of stem cells are quite limited at the present time, partly due to the low quantities available for use and research
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