Human embryonic stem cell-derived mesenchymal stem cells improved premature ovarian failure

Abstract

BACKGROUND Premature ovarian failure (POF) affects many adult women less than 40 years of age and leads to infertility. According to previous reports, various tissue-specific stem cells can restore ovarian function and folliculogenesis in mice with chemotherapy-induced POF. Human embryonic stem cells (ES) provide an alternative source for mesenchymal stem cells (MSCs) because of their similarities in phenotype and immunomodulatory and anti-inflammatory characteristics. Embryonic stem cell-derived mesenchymal stem cells (ES-MSCs) are attractive candidates for regenerative medicine because of their high proliferation and lack of barriers for harvesting tissue-specific MSCs. However, possible therapeutic effects and underlying mechanisms of transplanted ES-MSCs on cyclophosphamide and busulfan-induced mouse ovarian damage have not been evaluated. AIM To evaluate ES-MSCs vs bone marrow-derived mesenchymal stem cells (BM-MSCs) in restoring ovarian function in a mouse model of chemotherapy-induced premature ovarian failure. METHODS Female mice received intraperitoneal injections of different doses of cyclophosphamide and busulfan to induce POF. Either human ES-MSCs or BM-MSCs were transplanted into these mice. Ten days after the mice were injected with cyclophosphamide and busulfan and 4 wk after transplantation of the ES-MSCs and/or BM-MSCs, we evaluated body weight, estrous cyclicity, follicle-stimulating hormone and estradiol hormone concentrations and follicle count were used to evaluate the POF model and cell transplantation. Moreover, terminal deoxynucleotidyl transferase mediated 2-deoxyuridine 5-triphosphate nick end labeling, real-time PCR, Western blot analysis and immunohistochemistry and mating was used to evaluate cell transplantation. Enzyme-linked immunosorbent assay was used to analyze vascular endothelial growth factor, insulin-like growth factor 2 and hepatocyte growth factor levels in ES-MSC condition medium in order to investigate the mechanisms that underlie their function. RESULTS The human ES-MSCs significantly restored hormone secretion, survival rate and reproductive function in POF mice, which was similar to the results obtained with BM-MSCs. Gene expression analysis and the terminal deoxynucleotidyl transferase mediated 2-deoxyuridine 5-triphosphate nick end labeling assay results indicated that the ES-MSCs and/or BM-MSCs reduced apoptosis in the follicles. Notably, the transplanted mice generated new offspring. The results of different analyses showed increases in antiapoptotic and trophic proteins and genes. CONCLUSION These results suggested that transplantation of human ES-MSCs were similar to BM-MSCs in that they could restore the structure of the injured ovarian tissue and its function in chemotherapy-induced damaged POF mice and rescue fertility. The possible mechanisms of human ES-MSC were related to promotion of follicular dev...

Bone marrow mesenchymal stem cells derived from juvenile macaques reversed ovarian ageing in elderly macaques

“…Our results showed that Prog, Testo, PRL, and E2 were significantly increased after BMMSC treatment, while FSH, LH, and AMH were not significantly different before and after BMMSC treatment. These results are consistent with previous studies reporting the ability of MSCs to restore ovarian structure and sex hormone secretion [ 22 , 27 , 28 ]. Furthermore, previous studies have demonstrated that the number of MSCs in different cell cycle stages can be adjusted by adjusting the concentrations of sex hormones [ 29 , 30 ], suggesting that after BMMSCs restore the secretion of sex hormones, sex hormones may in turn regulate the biological function of MSCs.…”

“…Follicular atresia is related to the apoptosis of granulosa cells, which are large in ovarian follicles; previous studies showed that MSCs improved the apoptosis [ 21 , 22 ]. TUNEL assay was performed to analyse apoptosis, with red staining indicating apoptotic cells (Fig.…”

Menstrual blood CD146+ mesenchymal stem cells reduced fibrosis rate in the rat model of premature ovarian failure

“…36 In line with this statement, Bahrehbar and colleagues showed that human amniotic fluid MSCs improved ovarian function and folliculogenesis in POF mice. 37 Likewise, in a similar study conducted by Li et al, authors noted that transplantation of human umbilical cord-derived MSCs into the ovaries of menopausal rats improved ovarian reserve, function and resistance to ovarian aging. 38 All of these studies showed an improved ovarian function after the transplantation of different MSC types in the POF models.…”

Mesenchymal Stem Cells in Preclinical Infertility Cytotherapy: A Retrospective Review

“…POF refers to amenorrhea caused by ovarian follicular degeneration or dysfunction before the age of 40. In most cases, decreased ovarian function and premature ovarian failure are associated with chemotherapy, autoimmune diseases, and operation of the ovary, among other conditions [ 92 ]. Decreased ovarian function not only leads to female infertility, but also affects long-term fertility ability and pregnancy outcomes [ 93 ].…”

“…Notably, the transplanted mice generated new offspring. [ 108 ]. This outcome will serve as an important foundation for MSCs in stem cell therapy in infertility cytotherapy.…”