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

Abstract

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.

The combined induction of liver progenitor cells and the suppression of stellate cells by small molecules reverts chronic hepatic dysfunction

“…Notably, native hepatocytes exhibited a marked increase in Ki67 + expression in the liver following HACY administration, thus showing a potential benefit by stimulating hepatic regeneration in the host. Other studies have shown that in vivo EGF treatment can reestablish the balance between growing follicles and dormant follicles following an acute change of ovarian microenvironment 25 . Similarly, the internal administration of HACY may reestablish a balance favoring liver regeneration, thus providing a clinically effective approach for the treatment of chronic liver disease.…”

HDAC6 regulates primordial follicle activation through mTOR signaling pathway

“…During the process, the decline of HDAC6 may be transient because the levels of HDAC6 elevates in primary follicles soon. According to previous studies, short-term activation treatment with one of the activators of either AKT, CDC42, or SIRT1 promotes the activation of mouse primordial follicles in vitro 9 , 11 , 12 , 17 , 31 , 32 . Therefore, the transition of primordial follicles from the dormant state to the activated state may be a very short process.…”

In Vitro Activation Early Follicles: From the Basic Science to the Clinical Perspectives

“…The importance of PI3K/Akt pathway in primordial follicle activation has been well-established [ 6 , 7 , 8 , 9 ]. This pathway has been shown to be modulated by numerous intraovarian growth factors including Kit ligand (KL), insulin-like growth factor I, platelet-derived growth factor, and EGF [ 7 , 38 , 39 ]. On the other hand, phosphatase and tensin homolog deleted on chromosome 10 (PTEN), a lipid phosphatase converting phosphatidylinositol-3,4,5-triphosphate (PIP3) back to phosphatidylinositol biphosphate (PIP2), negatively regulates the PI3K/Akt pathway [ 6 ].…”

“…The recent experiment suggested that EGF could be an alternative agent to activate the primordial follicle through elevating CDC42-PI3K signaling and PI3K/Akt pathway in both murine and human ovarian tissue. After treatment of mouse ovaries with EGF by in vitro culture together with in vivo topical administration of EGF dissolved in the Matrigel into ovarian bursa, the histological results demonstrated an increase in the percentage of growing follicles in EGF-treated ovaries compared to controls [ 39 ]. In human tissues, similar results were observed by culturing ovarian cortical fragments with EGF [ 39 ].…”