Hippo signaling, actin polymerization, and follicle activation in fragmented human ovarian cortex

Abstract

The Hippo pathway has been associated with regulation of early follicle growth. Studies of murine ovaries suggest that changes in the actin cytoskeleton, caused by fragmentation, result in inhibition of the Hippo pathway, and in turn, may activate follicle growth. In humans, the connections between fragmentation, the actin cytoskeleton, and follicle activation are yet to be confirmed. In this study, we investigated the impact in vitro fragmentation of a human ovarian cortex on (a) actin polymerization, (b) components of the Hippo pathway, and (c) follicle growth in vivo. The results showed that the ratio between globular and filamentous actin remained unchanged at all timepoints (0, 10, 30, 60, 120, and 240 min) following tissue fragmentation. Neither was the Hippo pathway effector protein YES‐associated protein upregulated nor was gene expression of the downstream growth factors CCN2, CCN3, or CCN5 increased at any timepoint in the fragmented cortex. Furthermore, the number of growing follicles was similar in fragmented and intact cortex pieces after 6 weeks' xenotransplantation. However, the total number of surviving follicles was considerably lower in the fragmented cortex compared with intact tissue, suggesting detrimental effects of fragmentation on tissue grafting. These results indicate that fragmentation is likely to be ineffective to activate follicle growth in the human ovarian cortex.

In-vitro fragmentation of ovarian tissue activates primordial follicles through the Hippo pathway

“…Tissue preparation for cryopreservation includes the removal of the medulla by scraping with a scalpel to prepare the cortical tissue to the required thickness of 1 mm. This most probably results physical removal of secondary and early pre-antral follicles, mostly situated on the dissection plane as previously demonstrated ( De Roo et al , 2017 ; Herraiz et al , 2020 ; Lunding et al , 2020 ), but also in an unintended activation and burnout of residing follicles of all maturation stages in the cortex fragments. If so, ovarian tissue preparation for cryopreservation might benefit by keeping the medulla (partially) intact.…”

In vitro activation of ovarian cortex and autologous transplantation: A novel approach to primary ovarian insufficiency and diminished ovarian reserve

“…Recently, a study conducted on human ovaries could not prove the relevance of drug-free IVA technique, since it did not find a relationship between the fragmentation of the ovarian tissue and actin polymerization, nor between the fragmentation and the effectors of the Hippo pathway; also it did not show an increase in the number of growing follicles from the fragmented tissue ( Lunding et al , 2020 ). However, this trial was limited to nine women and does not rule out a transient effect on this pathway what is difficult to assay, as demonstrated by other authors ( Grosbois and Demeestere, 2018 ).…”

Regulation of Transcription Factor YAP-TEAD by Non-coding RNA LINC00857 and the Inhibitory Effects on Ovarian Cancer Cell Proliferation

“…However, it decreased with the extension of culture time (P< 0.05), indicating that the Hippo signaling pathway regulates the proliferation of cancer cells by acting on target genes. Another study suggested that CCN1 has the effect of promoting YAP-TEAD expression activity, which is opposite to the effect of CCN2 (36,37).To prove the inhibitory effects of non-coding RNA LINC00857 on cell proliferation, the cell apoptosis rate of the response group and the control group was determined byCCK8. It was found that After 12, 24, 36, and 48 hours, the apoptosis rates of the response group were higher versus the control group, and the difference was notable (P<0.01).…”