Adipose tissue-derived stem cells protect the primordial follicle pool from both direct follicle death and abnormal activation after ovarian tissue transplantation

Cacciottola, Luciana;Courtoy, Guillaume;Nguyen, Thi Yen Thu;Hossay, Camille;Dolmans, Marie-Madeleine;et.al.
(2021) Journal of Assisted Reproduction and Genetics — Vol. 38, n° 1, p. 151-161 (2021)

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Authors
  • Cacciottola, LucianaUCLouvain
    Author
  • Courtoy, GuillaumeUCLouvain
    Author
  • Nguyen, Thi Yen ThuUCLouvain
    Author
  • Hossay, Camilleorcid-logoUCLouvain
    Author
  • Donnez, JacquesUCLouvain
    Author
  • Dolmans, Marie-Madeleineorcid-logoUCLouvain
    Author
  • et. al.
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Abstract
(en) PURPOSE: To investigate whether adipose tissue-derived stem cells (ASCs) protect the primordial follicle pool, not only by decreasing direct follicle loss but also by modulating follicle activation pathways. METHODS: Twenty nude mice were grafted with frozen-thawed human ovarian tissue from 5 patients. Ten mice underwent standard ovarian tissue transplantation (OT group), while the remaining ten were transplanted with ASCs and ovarian tissue (2-step/ASCs+OT group). Ovarian grafts were retrieved on days 3 (n = 5) and 10 (n = 5). Analyses included histology (follicle count and classification), immunohistochemistry (c-caspase-3 for apoptosis and LC3B for autophagy), and immunofluorescence (FOXO1 for PI3K/Akt activation and YAP for Hippo pathway disruption). Subcellular localization was determined in primordial follicles on high-resolution images using structured illumination microscopy. RESULTS: The ASCs+OT group showed significantly higher follicle density than the OT group (p = 0.01). Significantly increased follicle atresia (p < 0.001) and apoptosis (p = 0.001) were observed only in the OT group. In primordial follicles, there was a significant shift in FOXO1 to a cytoplasmic localization in the OT group on days 3 (p = 0.01) and 10 (p = 0.03), indicating follicle activation, while the ASCs+OT group and non-grafted controls maintained nuclear localization, indicating quiescence. Hippo pathway disruption was encountered in primordial follicles irrespective of transplantation, with nuclear YAP localized in their granulosa cells. CONCLUSION: We demonstrate that ASCs exert positive effects on the ovarian reserve, not only by protecting primordial follicles from direct death but also by maintaining their quiescence through modulation of the PI3K/Akt pathway.
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Cacciottola, L., Courtoy, G., Nguyen, T. Y. T., Hossay, C., Donnez, J., Dolmans, M.-M., & et al. (2021). Adipose tissue-derived stem cells protect the primordial follicle pool from both direct follicle death and abnormal activation after ovarian tissue transplantation. Journal of Assisted Reproduction and Genetics, 38(1), 151-161. https://doi.org/10.1007/s10815-020-02005-z (Original work published 2021)