iPSC-Derived Ovarian Tissue Restores Ovarian Function in Subfertile Mice After Gonadotoxic Chemotherapy

Many oncologic therapies given to young women are gonadotoxic and associated with diminished ovarian reserve, increased risk of permanent sterility, and premature menopause. Previously, we reported the derivation of steroidogenic ovarian cells from induced pluripotent and embryonic stem cells. Derived cells not only produced reproductive hormones, but also displayed markers of ovarian tissue and primordial gametes. Here, we describe that human follicular fluid, when added to our stem cell differentiation system, enhances the steroidogenic potential of derived cells and increases the subpopulation of cells that differentiate to express the ovarian and germ cell markers GJA1 and ZP1, respectively. More importantly, using an in vivo model of chemotherapy-induced premature ovarian insufficiency in subfertile nude mice, we demonstrate that orthotopic implantation of these derived cells restores ovarian hormonal production and produces functional stem cell-derived germ cells. Collectively, these data support the hypothesis that stem cell-derived steroidogenic ovarian tissue could be used to promote neo-gametogenesis and treat premature menopause.