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Original Research: Gynecology|Articles in Press

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

      Publication history

      Accepted: January 14, 2023
      Received in revised form: January 13, 2023
      Received: September 28, 2022

      Publication stage

      In Press Journal Pre-Proof

      Footnotes

      Disclosures: The authors report no conflict of interest.

      Funding:

      This work was supported by grants from the Regional Valencian Ministry of Education (CIPROM/2021/058 [A.P]); Spanish Ministry of Science, Innovation and Universities (FPU17/01495 [M.M.] and FPU19/0496 [N.M.]); Instituto de Salud Carlos III (ISCIII; PI21/00170 [S.H.] co-funded by European Union, CP19/00141 [S.H.], and CD20/00116 [A.B.], co-funded by European Social Fund (ESF)"Investing in your future").

      Paper presentation information: This paper was partially presented as an oral at the 69th Annual Meeting of the Society for Reproductive Investigation (SRI), March 15-19, 2022, in Denver, CO, USA.

      Author contributions:

      M.M.: Conceptualization, formal analysis, investigation, visualization, and writing A.B.: methodology, support, review, and editing; N.R.: support and investigation; J.M.: investigation and resources; N.P.: investigation, support, review, and editing; A.P.: conceptualization, funding acquisition, supervision, and review; S.H.: conceptualization, funding acquisition, methodology, project administration, supervision, visualization, writing, review, and editing.

      Condensation: Intraovarian injection of stem cell-secreted- and platelet-enclosed growth factors restores ovarian function and improves oocyte developmental competence in a murine model of physiological ovarian aging.

      AJOG at a glance:

      A. Why was the study conducted? To find an alternative treatment for patients affected by age-related infertility, who have few reproductive options.

      B. What are the key findings? In a murine model, the synergy of stem cell- and platelet-secreted factors improved reproductive outcomes by enhancing the quantity and quality of aged oocytes retrieved following stimulation, restoring ovarian stroma and long-lasting folliculogenesis, while decreasing oxidative damage and apoptosis.

      C. What does this study add to what is already known? A single intraovarian injection, combining the paracrine properties of stem cell- and platelet- soluble factors has the potential to become an effective treatment to rescue fertility of aged patients.

      Identification

      DOI: https://doi.org/10.1016/j.ajog.2023.01.018

      Copyright

      © 2023 Elsevier Inc. All rights reserved.

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