Prevention of chemotherapy-induced premature ovarian insufficiency in mice by scaffold-based local delivery of human embryonic stem cell-derived mesenchymal progenitor cells

Abstract

Background Premature ovarian insufficiency (POI) is one of the most serious side effects of chemotherapy in young cancer survivors. It may not only reduce fecundity but also affect lifelong health. There is no standard therapy for preserving ovarian health after chemotherapy. Recently, administration of embryonic stem cell-derived mesenchymal progenitor cells (ESC-MPCs) has been considered a new therapeutic option for preventing POI. However, the previous method of directly injecting cells into the veins of patients exhibits low efficacy and safety. This study aimed to develop safe and effective local delivery methods for the prevention of POI using two types of bioinspired scaffolds. Methods Female mice received intraperitoneal cisplatin for 10 days. On day 11, human ESC-MPCs were delivered through systemic administration using intravenous injection or local administration using intradermal injection and intradermal transplantation with a PLGA/MH sponge or hyaluronic acid (HA) gel (GEL) type of scaffold. PBS was injected intravenously as a negative control. Ovarian function and fertility were evaluated 4 weeks after transplantation. Follicle development was observed using hematoxylin and eosin staining. The plasma levels of sex hormones were measured using ELISA. Expression levels of anti-Müllerian hormone (AMH) and ki-67 were detected using immunostaining, and the quality of oocytes and embryos was evaluated after in vitro fertilization. The estrous cycles were observed at 2 months after transplantation. Results The local administration of human ESC-MPCs using the bioinspired scaffold to the backs of mice effectively prolonged the cell survival rate in vivo. The HA GEL group exhibited the best recovered ovarian functions, including a significantly increased number of ovarian reserves, estrogen levels, and AMH levels and decreased apoptotic levels. Furthermore, the HA GEL group showed improved quality of oocytes and embryos and estrous cycle regularity. Conclusions HA GEL scaffolds can be used as new delivery platforms for ESC-MPC therapy, and this method may provide a novel option for the clinical treatment of chemotherapy-induced POI.

Bone marrow mesenchymal stem cells in premature ovarian failure: Mechanisms and prospects

“…However, transplanting cells directly into the core of the ovaries may lead to ovarian injury resulting from needle puncture. Shin EY et al effectively avoid the disadvantage through subcutaneous transplanted MSCs using hyaluronic acid gel scaffold, and at the same time, the method effectively prolongs the survival rate of transplanted cells and significantly recovers ovarian functions in POF rats, too (178). Moreover, Mao AS et al found that biomaterial encapsulation of BMSCs into programmable microencapsulation using a microfluidic device could partly reduce donor rejection and efficiently increase retention in vivo after intravenous injection, which substantially sustained BMSCs survival and enhanced overall immunomodulatory capacity of BMSCs in a model of allogeneic transplantation (179).…”

Serum Anti-Müllerian Hormone Levels and Risk of Premature Ovarian Insufficiency in Female Childhood Cancer Survivors: Systematic Review and Network Meta-Analysis

“…Gonadal function should be regularly tested during the long-term follow-up of female CCS [ 11 , 29 ]. However, it is difficult to evaluate ovarian function in childhood due to the nondiagnostic levels of serum gonadotropin and estradiol concentrations before the start of the puberty [ 30 ].…”

“…The use of oral contraceptives and menopausal hormone therapy (MHT) leads to several difficulties in the interpretation of FSH and female sex steroids levels for gonadal status. In addition, the ovarian function needs to be significantly decreased to have a critical raise of FSH levels, which cannot be used as a sentinel for anticipating premature menopause [ 11 , 12 ]. Because AFC (the cumulative amount of the growing follicles between 2 and 10 mm in diameters from both the ovaries) seems to correlate well with the primordial follicle pool, this method is currently the most often preferred way to predict ovarian reserves [ 13 ].…”

Biomaterials and advanced technologies for the evaluation and treatment of ovarian aging

“… Wenlin Jiao [ 228 ] 2022 A combination of UCMSCs and HA gel 4-Vinylcyclohexene diepoxide -induced POI mouse model Improved follicular survival. Eun-Young Shin [ 229 ] 2021 HA gel scaffolder Cisplatin-induced POI mouse model Restored the ovarian structure and function and improved the quality of oocyte and embryo as well as the regularity of estrus cycle. Guangfeng Zhao [ 230 ] 2015 HA Immunosuppressive drug-induced POI-like rat model Prevented chemotherapy-induced ovarian damage.…”

“…The authors demonstrated that transplantation of hUCMSCs combined with HA gel could improve follicular survival by activating the PI3K-AKT pathway. Shin et al transplanted embryonic stem cell-derived mesenchymal progenitor cells (ESC-MPCs) into cisplatin-induced POI mouse models by using HA gel scaffolds [ 229 ]. This method could effectively restore the ovarian structure and function of POI mice and improve the quality of oocytes and embryos, as well as the regularity of the estrus cycle.…”