In vivo and in vitro activation of dormant primordial follicles by EGF treatment in mouse and human

摘要

In the mammalian ovaries, dormant primordial follicles represent the reproductive reserve of individual females. Recently, stimulating the activation of primordial follicles in vitro has been practiced, making the utilization of those dormant follicles to treat female infertility possible. However, there are still lacks of effective upstream molecule and strategy to elevate follicle activation in vivo. In the current study, we revealed that growth factor EGF improved a transiently primordial follicle activation in mice by elevating the CDC42‐PI3K signaling activity, and EGF treatment also improved the activation and development of human follicles in ovarian cortical pieces. Using a liquid‐solid phase transition bio‐gel as a carrier, an efficient in vivo activation system was established by ovarian topical EGF administration to living mice. We found that EGF treatment led to an increase of primordial follicle activation in short time but had no effect on long‐term fertility in females. By establishing an inducible premature ovarian insufficiency (POI) mouse model through selectively ablating growing follicles in Zp3‐Cre;iDTR mice, we further revealed that our in vivo EGF treatment system improved primordial follicle activation and ovulation of POI ovaries significantly. Taken together, our results revealed that in situ ovarian EGF administration could improve the activation of primordial follicles in living animals, and manipulating activation and development of primordial follicles in vivo might be an efficient approach to improve reproductive health in women. Zhang et al. reveal that EGF is a physiological stimulator of dormant primordial follicle activation in both mouse and human. Using EGF as an activator, the current study established an efficient and ovarian non‐invasive in vivo activation system to improve the dormant follicle development in living animals. In this system, the ovarian surface is covered by the bio‐gel with EGF through a topical administration, then the dormant follicles on the cortical region are stimulated to active and develop. The experimental data shows that the system is efficient in both normal and primary ovarian insufficient females.