Human umbilical cord mesenchymal stem cells alleviate chemotherapy-induced premature ovarian insufficiency mouse model by suppressing ferritinophagy-mediated ferroptosis in granulosa cells

Wenjie Dai; Bo Xu; Liyang Ding; Zhen Zhang; Hong Yang; Tiantian He; Ling Liu; Xiuying Pei; Xufeng Fu

doi:10.1016/j.freeradbiomed.2024.04.229

Human umbilical cord mesenchymal stem cells alleviate chemotherapy-induced premature ovarian insufficiency mouse model by suppressing ferritinophagy-mediated ferroptosis in granulosa cells

Free Radic Biol Med. 2024 Apr 25:220:1-14. doi: 10.1016/j.freeradbiomed.2024.04.229. Online ahead of print.

Authors

Wenjie Dai¹, Bo Xu¹, Liyang Ding¹, Zhen Zhang¹, Hong Yang¹, Tiantian He¹, Ling Liu¹, Xiuying Pei², Xufeng Fu³

Affiliations

¹ Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, 750004, China.
² Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, 750004, China. Electronic address: peixiuying@163.com.
³ Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, 750004, China. Electronic address: fuxufeng100@163.com.

PMID: 38677487
DOI: 10.1016/j.freeradbiomed.2024.04.229

Abstract

Primary ovarian insufficiency (POI) in younger women (under 40) manifests as irregular periods, high follicle-stimulating hormone (FSH), and low estradiol (E2), often triggered by chemotherapy. Though mesenchymal stem cell (MSC) therapy shows promise in treating POI, its exact mechanism remains unclear. This study reveals that human umbilical cord-derived MSCs (hUC-MSCs) can protect ovarian granulosa cells (GCs) from cyclophosphamide (CTX)-induced ferroptosis, a form of cell death driven by iron accumulation. CTX, commonly used to induce POI animal model, triggered ferroptosis in GCs, while hUC-MSCs treatment mitigated this effect, both in vivo and in vitro. Further investigations using ferroptosis and autophagy inhibitors suggest that hUC-MSCs act by suppressing ferroptosis in GCs. Interestingly, hUC-MSCs activate a protective antioxidant pathway in GCs via NRF2, a stress-response regulator. Overall, our findings suggest that hUC-MSCs improve ovarian function in CTX-induced POI by reducing ferroptosis in GCs. This study not only clarifies the mechanism behind the benefits of hUC-MSCs but also strengthens the case for their clinical use in treating POI. Additionally, it opens up a new avenue for protecting ovaries from chemotherapy-induced damage by regulating ferroptosis.

Keywords: Ferritinophagy; Ferroptosis; Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs); Nuclear factor erythroid 2-related factor 2 (NRF2); Ovarian granulosa cells; Premature ovarian insufficiency.