Advances in assisted reproductive technologies (ART) have provided significant hope for preserving fertility in cancer patients undergoing gonadotoxic chemotherapy or women experiencing premature ovarian failure.
Currently, the most reliable method for fertility preservation is pre-chemotherapy fertility treatment cycles using ART to cryopreserve oocytes for future use. However, low referral rates for ART prior to chemotherapy and reduced success rates of ART cycles with autologous oocytes in cancer survivors pose significant challenges.
Moreover, mutations in certain genes associated with cancer risk are also linked to premature ovarian insufficiency, further complicating the situation.
Beyond infertility, premature ovarian insufficiency results in estrogen deficiency, leading to various health consequences, including accelerated bone loss, increased sexual dysfunction, and higher cardiovascular mortality rates among cancer survivors.
Hormone replacement therapy (HRT) is commonly used to restore hormonal balance in these patients. However, concerns about potential long-term health risks, such as secondary malignancies, have prompted the need for alternative approaches to preserve or restore ovarian function.
In this study, a groundbreaking cell-based approach is proposed for treating infertility and restoring endocrine function in patients with premature ovarian insufficiency or failure. The method involves using mouse granulosa cell-derived, induced pluripotent stem cells (iPSCs) to generate ovarian endocrine tissue and functional oocytes. These iPSCs can be patient-specific, ensuring isogenicity with the individual.
Generation of Ovarian Endocrine Tissue from iPSCs
Previous research has demonstrated the differentiation of embryonic stem cells (ESCs) and iPSCs into steroidogenic ovarian tissue capable of producing physiologic concentrations of estrogen and progesterone. The study suggests that iPSCs generated from mouse granulosa cells preferentially differentiate into ovarian cell types due to their epigenetic memory.
The differentiation process is enhanced by using human follicular fluid (HFF), which promotes oocyte maturation. The resulting stem cell-derived ovarian cells demonstrate normal endocrine behavior and exhibit the capacity to generate oocytes and form ovarian follicles.
Restoring Fertility in Animal Models
In animal experiments, the injection of AMHR2+ enriched mGriPSCs into subfertile mice exposed to gonadotoxic chemotherapy restored ovarian function. The stem cell-derived oocytes displayed the ability to be fertilized and activated, leading to the generation of healthy offspring.
Orthotopic injection of differentiated iPSCs into subfertile nude mice also restored fertility, with these mice successfully delivering healthy pups derived from the stem cells. This was further validated through genetic analysis confirming the iPSC lineage of subsequent generations.
The Role of Anti-Müllerian Hormone (AMH)
The study suggests that AMH, a reproductive glycoprotein exclusively synthesized by granulosa cells during early follicular development, may play a crucial role in mediating the observed restoration of ovarian function. AMH is known to protect against follicular atresia and apoptosis, and its synthesis was found to increase in the presence of differentiated stem cells.
Conclusion and Future Directions
The presented autologous iPSC system for generating functional oocytes and restoring ovarian function holds immense potential for therapeutic applications in patients with premature ovarian failure or chemotherapy-induced infertility. Patient-specific iPSCs could be differentiated into steroidogenic tissue for synthesizing bioidentical hormones, facilitating hormone replacement therapy. Furthermore, the ovarian tissue and primordial gametes derived from these iPSCs may be used for in vitro egg maturation in ART procedures.
While the study highlights the promise of this approach, several limitations remain, such as the need to explore the use of different iPSC types and evaluate their genetic normalcy. Future research efforts will focus on addressing these aspects and refining the cell-based therapies to revolutionize fertility preservation and restoration in women facing reproductive challenges.
The potential to provide patients with their own cells for restoring ovarian function and fertility offers new hope for addressing infertility caused by premature ovarian insufficiency or cancer treatment, significantly impacting women’s reproductive health and quality of life.
reference link :https://www.thelancet.com/journals/ebiom/article/PIIS2352-3964(23)00280-3/fulltext#secsectitle0220