Abstract
BackgroundClinical use of mesenchymal stem cells (MSCs) requires a uniform cell population, and their harvesting is invasive and produces a limited number of cells. Human embryonic stem cell-derived MSCs (hESC-MSCs) can differentiate into three germ layers and possess immunosuppressive effects in vitro. Anticancer treatment is a well-known risk factor for premature ovarian failure (POF). In this study, we investigated the effect of hESC-MSC on recovery of ovarian function in cisplatin-induced POF in mice.MethodsFemale mice received intraperitoneal cisplatin for 10 days. On day 12, CHA15-derived hESC-MSCs were transplanted into the mice by tail vein injection. An injection of PBS served as the negative control. Ovaries were removed 28 days after transplantation for assessment of ovarian histology, immunostaining, and fertility testing by superovulation and in vitro fertilization. hESC-MSC transplantation into mice with cisplatin-induced damage restored body weight and ovary size.ResultsMean primary and primordial follicle counts in the hESC-MSC group were significantly improved compared to the PBS group (P < 0.05), and counts of zona pellucida remnants, an apoptotic sign in ovarian follicles, were significantly reduced (P < 0.05). TUNEL assays and cleaved PARP immunostaining indicated apoptosis, which led to loss of ovarian stromal cells in negative control mice, while Ki-67 was higher in the hESC-MSC group and in non-cisplatin-treated controls than in the PBS group. Ovulation was reduced in the PBS group but recovered significantly in the hESC-MSC group. Rates of blastocyst formation from ovulated eggs and live births per mouse also recovered significantly in the hESC-MSC group.ConclusionshESC-MSC restored structure and function in the cisplatin-damaged ovary. Our study provides new insights into the great clinical potential of human hESC-MSC in treating POF.
Highlights
Clinical use of mesenchymal stem cells (MSCs) requires a uniform cell population, and their harvesting is invasive and produces a limited number of cells
We evaluated for the first time the restorative effects of intravenously injected Human embryonic stem cells (hESCs)-MSCs on structure and function in mouse ovaries previously injured by cisplatin
Establishment of a murine model of cisplatin-induced premature ovarian failure (POF) and hESC-MSC transplantation Animals were weighed before treatment with either cisplatin at 2.0 mg/kg or saline
Summary
Clinical use of mesenchymal stem cells (MSCs) requires a uniform cell population, and their harvesting is invasive and produces a limited number of cells. Anticancer treatment is a well-known risk factor for premature ovarian failure (POF). We investigated the effect of hESC-MSC on recovery of ovarian function in cisplatin-induced POF in mice. Premature ovarian failure (POF) after chemotherapy is a major long-term adverse effect of anticancer treatment. The impact of chemotherapy on ovarian function varies with patient age at the time of treatment, anticancer drug type, and dose. Chemotherapy may be especially problematic for young women, because loss of ovarian reserve is strongly related to the risk of infertility. The preservation of fertility and ovarian function should be a major consideration for chemotherapy in women of reproductive age. More studies are required to evaluate feasibility, safety, and efficacy of fertility-preserving methods, and improved therapeutic strategies to prevent chemotherapy-induced gonadal toxicity are needed for these patients
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