2. Academic Validation
  3. Ex vivo removal of pro-fibrotic collagen and rescue of metabolic function in human ovarian fibrosis

Ex vivo removal of pro-fibrotic collagen and rescue of metabolic function in human ovarian fibrosis

  • iScience. 2025 Feb 13;28(3):112020. doi: 10.1016/j.isci.2025.112020.
Julieta S Del Valle 1 2,  Ruben W Van Helden 1 2,  Ioannis Moustakas 1 2 3,  Fu Wei 1 2,  Joyce D Asseler 4 5 6,  Jeroen Metzemaekers 7,  Gonneke S K Pilgram 7,  Christine L Mummery 1 2,  Lucette A J van der Westerlaken 7,  Norah M van Mello 4 5 6,  Susana M Chuva de Sousa Lopes 1 2 8
Affiliations

Affiliations

  • 1 Department of Anatomy and Embryology, Leiden University Medical Center, 2333 ZC Leiden, the Netherlands.
  • 2 The Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW), Leiden University Medical Center, Leiden 2333 ZC, the Netherlands.
  • 3 Sequencing Analysis Support Core, Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden 2333 ZC, the Netherlands.
  • 4 Department of Obstetrics and Gynecology, Amsterdam University Medical Center, Amsterdam 1105 AZ, the Netherlands.
  • 5 Amsterdam UMC, Centre of Expertise on Gender Dysphoria, Amsterdam 1081 HV, the Netherlands.
  • 6 Amsterdam Reproduction and Development Research Institute, Amsterdam 1081 HV, the Netherlands.
  • 7 Department of Gynecology, Leiden University Medical Center, Leiden 2333 ZA, the Netherlands.
  • 8 Ghent-Fertility and Stem Cell Team (G-FAST), Department of Reproductive Medicine, Ghent University Hospital, 9000 Ghent, Belgium.
PMID: 40104066 DOI: 10.1016/j.isci.2025.112020
Abstract

Tissue fibrosis, with the excessive accumulation of extracellular matrix, leads to organ dysfunction. The ovary shows signs of fibrosis from an early age, creating a permissive environment for ovarian Cancer. A robust culture-platform to study human ovarian fibrosis would enable screens for antifibrotic drugs to prevent or even reverse this process. Based on previous results showing that androgen therapy can induce ovarian fibrosis, we characterized the fibrotic state of ovaries from transmasculine donors of reproductive age. Anti-inflammatory and antioxidant drugs, such as Pirfenidone, Metformin, and Mitoquinone, could reduce and revert the excess collagen content of the ovarian cortical tissue during culture. We demonstrated that Metformin exerts an antioxidant role and prevents a glycolytic metabolic shift in non-immune ovarian stromal cells in the human ovary, while promoting early folliculogenesis during culture. These results may contribute to develop strategies to manage pro-tumorigenic fibrotic ovarian stroma in advanced age and metabolic disorders.

Keywords

cancer; fibrosis; pathophysiology.

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