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

Data de publicació: 24/01/2023 Data Ahead of Print: 24/01/2023

Autors de IIS La Fe

Autors aliens a IIS La Fe

Marchante, Maria
Ramirez-Martin, Noelia

Grups d'Investigació

Biología Reproductiva y Bioingeniería en Reproducción Humana

Leader

Nicolás Garrido Puchalt
Medicina Reproductiva

Investigador Principal

José Morales Roselló

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.

Dades de la publicació

ISSN/ISSNe:: 0002-9378, 1097-6868
Tipus:: Article
Pàgines:: -
DOI:: 10.1016/j.ajog.2023.01.018
PubMed:: 36706857
Factor d'Impacte:: 2,948 SCImago ℠
Quartil:: Q1 SCImago ℠

Documents

No hi ha documents

Mètriques

Filiacions

Marchante, Maria:: IVI Foundation, Valencia, Spain

Department of Pediatrics, Obstetrics and Gynecology, Faculty of Medicine, University of Valencia, Valencia, Spain
Buigues, Anna:: IVI Foundation, Valencia, Spain

Instituto de Investigación. Reproductive Medicine Research Group, Instituto Investigación Sanitaria La Fe (IIS la Fe), Valencia, Spain
Ramirez-Martin, Noelia:: IVI Foundation, Valencia, Spain

Instituto de Investigación. Reproductive Medicine Research Group, Instituto Investigación Sanitaria La Fe (IIS la Fe), Valencia, Spain
Martinez, Jessica:: IVI Foundation, Valencia, Spain

Instituto de Investigación. Reproductive Medicine Research Group, Instituto Investigación Sanitaria La Fe (IIS la Fe), Valencia, Spain
Pellicer, Nuria:: Instituto de Investigación. Reproductive Medicine Research Group, Instituto Investigación Sanitaria La Fe (IIS la Fe), Valencia, Spain
Pellicer, Antonio:: Instituto de Investigación. Reproductive Medicine Research Group, Instituto Investigación Sanitaria La Fe (IIS la Fe), Valencia, Spain

IVI-RMA Valencia, Valencia, Spain

IVI-RMA Rome, Rome, Italy
Herraiz, Sonia:: IVI Foundation, Valencia, Spain

Instituto de Investigación. Reproductive Medicine Research Group, Instituto Investigación Sanitaria La Fe (IIS la Fe), Valencia, Spain

Keywords

Ovarian aging; age-related infertility; early embryo development; fertility rescue; intraovarian administration; mitochondrial function; oocyte; platelet activation; platelet-rich plasma; stem cell secreted factors