Rescue of ovarian functionstem cells and regenerative factors

Abstract

Aging, as well as other acquired damaging conditions lead to impaired ovarian function. Nevertheless, even when the ovaries lose their ability to ovulate, they might contain a residual pool of quiescent follicles that could be rescued. Soluble factors secreted by stem cells could provide an adequate ovarian environment to maintain and promote follicular growth. Therefore, the present study aimed to assess the regenerative effects of different sources of stem cell-secreted factors on mice models of ovarian damage induced by chemotherapy and physiological aging. Mouse models of Diminished Ovarian Reserve (DOR) and Premature Ovarian Insufficiency (POI) were established by chemotherapy, and animals were treated with peripheral blood plasma (PB plasma), plasma rich in bone marrow-derived stem cell-secreted factors (BMDSC plasma), or plasma rich in umbilical cord stem cell-secreted factors (UCB plasma). We also evaluated the effects of the additional growth factors enclosed in platelets released through activation of plasmas. BMDSC and UCB plasma induced microvessel formation and cell proliferation, and reduced apoptosis in ovarian tissue, rescuing follicular development and fertility in DOR and POI models. Activation of these plasmas further enhanced these effects. Activated BMDSC (aBMDSC) plasma was the most potent treatment, inducing ovarian rescue in both models. Due to the differences between mouse and human ovaries, we validated the most beneficial plasma treatment, aBMDSC plasma, in human tissue from poor responder patients xenografted in mice. This plasma promoted human follicle development and regenerated the ovarian stroma, corroborating the effects observed in mice. Although our DOR and POI models are useful for evaluating treatments, an increasing number of women are delaying the age of childbearing, suffering age-related infertility. To evaluate the effects of new therapies on these patients, preclinical studies in appropriate animal models are needed. Thus, we characterized a physiological reproductive aging mouse model of different stages of women's reproductive life. We observed that follicular activation, growth, and stromal status reduce as age increases, leading to impaired oocyte and embryo quantity and quality. Moreover, in our initial studies, we tested the plasmas by systemic administration for two weeks, a regimen that would prove challenging in a future clinical setting. Thus, we aimed to evaluate if a single intraovarian injection of the most beneficial treatment could improve ovarian function. We observed that an intraovarian injection of aBMDSC promoted follicle activation and development. Further, aBMDSC rescued fertility in older mice by enhancing the quantity and quality of oocytes and supporting embryo development. In conclusion, our results suggest that plasmas rich in stem cell-secreted factors could positively impact the fertility treatment of patients with impaired ovarian function and few reproductive options.