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Single intraovarian dose of stem cell- and platelet-secreted factors mitigates age-related ovarian infertility in a murine model.

Published:January 24, 2023DOI:https://doi.org/10.1016/j.ajog.2023.01.018
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      ABSTRACT

      Background

      Systemic administration of soluble factors from bone marrow-derived stem cells combined with activated platelet-rich plasma (SC-PRP) restored ovarian function, mediated through paracrine signaling, in murine models of chemotherapy-induced ovarian damage and human tissue from poor responder patients. However, the effects against age-related infertility and the efficacy of local administration have not yet been evaluated.

      Objective

      To assess whether a single intraovarian dose of SC-PRP can recover ovarian function, oocyte quality and developmental competence in older mice.

      Study design

      The effects of SC-PRP against age-related infertility were assessed following controlled ovarian stimulation, in an aging murine model reproducing three physiological stages of women´s reproductive life: young, advanced maternal age (AMA), and menopausal (n=12 animals per group). Female mice were randomized to receive a single intraovarian injection (10 μL/ovary) of saline, activated platelet-rich plasma (PRP), or SC-PRP. Seven days later, mice were stimulated, naturally mated, and sacrificed to harvest their ovaries for histological assessment and molecular analysis, and oviducts to evaluate oocyte maturation and assess early embryo development.

      Results

      A single intraovarian injection of SC-PRP promoted follicle activation and development in young, advanced maternal age, and old mice. Further, SC-PRP rescued fertility in older mice, by enhancing the quantity and quality of ovulated mature oocytes and supporting early embryo development to the blastocyst stage in all the evaluated ages. These fertility outcomes were positively associated with mitochondrial quality, with treatment increasing mitochondrial DNA copy numbers and reducing oxidative damage and apoptosis. Finally, the effects observed by histological analysis were supported at the proteomic level. Functional proteomic analysis revealed molecular mechanisms involved in oocyte maturation and quality, mitochondrial function, and recovery of the ovarian stroma.

      Conclusions

      SC-PRP is a promising treatment with the potential to improve the reproductive outcomes of women with age-related infertility, exceeding the restorative effects of PRP alone. Although further research in human ovarian samples is still required, the autologous nature of stem cell factors collected by non-invasive mobilization, their combination with PRP, and the local administration route, suggest that SC-PRP treatment could be a potentially effective and safe application for future clinical practice.

      Keywords

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