Research Laboratory in Human Reproduction, Faculty of Medicine, Université Libre de Bruxelles (ULB), Brussels, Belgium.
Sci Rep. 2022 Jun 27;12(1):10863. doi: 10.1038/s41598-022-14926-z.
Pharmacological approaches offer a non-invasive and promising option for fertility preservation in young female cancer patients undergoing gonadotoxic therapy. The GnRH-agonists are the only clinically available drugs in this indication, but their use and mechanisms of protection are still controversial. Recently, we have investigated new targeted drugs based on microRNA (miRNA) replacement therapy, and have identified the let-7a miRNA as candidate for fertility preservation strategies. Here, the effect of let-7a replacement during chemotherapy exposure on follicular growth and oocyte maturation capacity was investigated using a mouse ovarian-kidney transplantation model. Newborn mouse ovaries were cultured under different conditions; control, chemotherapy exposure (4-hydroperoxycyclophosphamide, 4-HC), and co-treatment with 4-HC and let-7a mimic transfection (4-HC + let-7a). The ovaries were then transplanted under the kidney capsule of recipient mice and follicular growth, survival, and oocyte in vitro maturation were assessed after 3 weeks. The results showed that the follicular pool was highest in the control group but higher in the 4-HC + let-7a group than the 4-HC group. DNA-damage/apoptosis ratios were higher in all 4-HC-exposed groups compared to control but were reduced in the 4-HC + let-7a group. In addition, the post-transplantation oocyte in vitro maturation rate was higher in the 4-HC + let-7a group compared to the 4-HC group, suggesting better oocyte quality. These results provide new information regarding the beneficial effects of let-7a replacement against chemotherapy-induced ovarian damage and open new perspectives for future in vivo applications.
药物治疗为接受性腺毒性治疗的年轻女性癌症患者提供了一种非侵入性且有前景的生育力保存选择。 GnRH 激动剂是该适应证中唯一临床可用的药物，但它们的使用和保护机制仍存在争议。最近，我们研究了基于 microRNA (miRNA) 替代疗法的新型靶向药物，并将 let-7a miRNA 鉴定为生育力保存策略的候选物。在这里，我们使用小鼠卵巢-肾移植模型研究了化疗暴露期间 let-7a 替代对卵泡生长和卵母细胞成熟能力的影响。在不同条件下培养新生小鼠卵巢；对照组、化疗暴露（4-羟环磷酰胺，4-HC）和化疗暴露加 let-7a 模拟物转染（4-HC+let-7a）。然后将卵巢移植到受体小鼠的肾包膜下，并在 3 周后评估卵泡生长、存活和卵母细胞体外成熟情况。结果表明，对照组的卵泡池最高，但 4-HC+let-7a 组比 4-HC 组更高。与对照组相比，所有 4-HC 暴露组的 DNA 损伤/凋亡比值均升高，但在 4-HC+let-7a 组中降低。此外，与 4-HC 组相比，4-HC+let-7a 组移植后卵母细胞体外成熟率更高，提示卵母细胞质量更好。这些结果为 let-7a 替代对化疗引起的卵巢损伤的有益作用提供了新的信息，并为未来的体内应用开辟了新的视角。
