Growth factor-loaded ovarian extracellular matrix hydrogels promote in vivo ovarian niche regeneration and enhance fertility in premature ovarian insufficiency preclinical models

Autores de IIS La Fe

• Emilio Francés Herrero

  Autor

• Clara Bueno Fernández

  Autor

• Adolfo Rodríguez Eguren

  Autor

• María Gómez Álvarez

  Autor

• Amparo Faus Esteve

  Autor

• Ana Buigues Lafuente

  Autor

• Sonia Herraiz Raya

  Autor

• Irene Cervelló Alcaraz

  Autor

Participantes ajenos a IIS La Fe

• Soto-Prado, A
• Pellicer, A

Grupos

• Biología Reproductiva y Bioingeniería en Reproducción Humana

• Medicina Fetal y Reproductiva

Abstract

Premature ovarian insufficiency (POI) means menopause before 40 years of age affecting about 1 % of women. Approaches based on cell therapy and the paracrine effects of stem cells or bioproducts such as platelet-rich plasma have been proposed, but concerns remain about undesired systemic effects, as well as the need to optimize delivery methods through bioengineering methods. This study explores the efficacy of decellularized bovine ovarian cortex extracellular matrix (OvaECM) hydrogels alone and as a growth factor (GF) carrier (OvaECM + GF) in a chemotherapy-induced POI murine model. In vitro assays showed a gradual release of GF from the OvaECM sustained for two weeks. Chemotherapy drastically reduced follicle numbers, but OvaECM + GF treatment restored pre-antral follicle development. Moreover, this treatment notably regenerated the ovarian microenvironment by increasing cell proliferation and microvessel density while reducing chemotherapy-induced apoptosis and fibrosis. Whole-ovary RNA sequencing and gene set enrichment analysis revealed an upregulation of regeneration-related genes and a downregulation of apoptotic pathways. The OvaECM + GF treatment also yielded significantly better outcomes following ovarian stimulation and in vitro fertilization. After two consecutive crossbreeding cycles, OvaECM + GF-treated mice showed normal reproductive function. This research showcases the biocompatibility and efficacy of OvaECM to reverse POI in mice, setting a foundation to explore innovative bioengineering-based POI therapies. (c) 2024 The Authors. Published by Elsevier Ltd on behalf of Acta Materialia Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/ )

Keywords

• Ovarian extracellular matrix hydrogel; Growth factors; Premature ovarian insufficiency; Regeneration; Fertility