Cumulus cells accelerate oocyte aging by releasing soluble Fas Ligand in mice

Abstract

Although previous studies have suggested that cumulus cells (CCs) accelerate oocyte aging by secreting soluble and heat-sensitive paracrine factors, the factors involved are not well characterized. Because Fas-mediated apoptosis represents a major pathway in induction of apoptosis in various cells, we proposed that CCs facilitate oocyte aging by releasing soluble Fas ligand (sFasL). In this study, we reported that when the aging of freshly ovulated mouse oocytes were studied in vitro, both the apoptotic rates of CCs and the amount of CCs produced sFasL increased significantly with the culture time. We found that oocytes expressed stable levels of Fas receptors up to 24 h of in vitro aging. Moreover, culture of cumulus-denuded oocytes in CCs-conditioned CZB medium (CM), in CZB supplemented with recombinant sFasL, or in CM containing sFasL neutralizing antibodies all showed that sFasL impaired the developmental potential of the oocytes whereas facilitating activation and fragmentation of aging oocytes. Furthermore, CCs from the FasL-defective gld mice did not accelerate oocyte aging due to the lack of functional FasL. In conclusion, we propose that CCs surrounding aging oocytes released sFasL in an apoptosis-related manner, and the released sFasL accelerated oocyte aging by binding to Fas receptors.

Single-cell analysis of differences in transcriptomic profiles of oocytes and cumulus cells at GV, MI, MII stages from PCOS patients

“…Interaction of the FAS receptor with its ligand accelerates oocyte aging63. And SOD1 expression is increased in CCs from infertile women64.…”

The timing of cumulus cell removal for intracytoplasmic sperm injection influences the capability of embryonic development

“…Although many studies have attempted to determine an optimal time for cumulus cell removal in ICSI procedures, there is currently no consensus. According to a recent report on the culture of murine COCs, long‐term culture of oocytes with intact cumulus cells induces apoptotic changes . Therefore, oocyte denudation should be completed as soon as possible after oocyte retrieval.…”

“…Based on the outcomes of previous murine studies on oocyte aging accelerated by cumulus cells, we hypothesized that the oocytes denuded immediately after oocyte retrieval (Group A) would have higher capability of embryonic development. However, the results of the present study showed that the percentage of good quality blastocyst was significantly higher in Group B than Group A (Table ), which may have resulted from the difference in the site and stage of the retrieved oocytes.…”

“…For example, Wakayama et al reported negative effects of temperature change on mouse oocyte aging, while Goud et al indicated that the production of reactive oxygen species significantly enhanced oocyte aging. Also, cumulus cells can reportedly accelerate the aging progression of both in vivo‐ and in vitro‐matured oocytes . On the contrary, Takahashi et al reported that cumulus cells partly prevent poor embryonic development during in vitro aging.…”

“…The focus of the present study is the effect of cumulus cells on the oocyte aging process, as these cells play important roles in oocyte maturation and subsequent embryonic development . Although preincubation of oocytes before ICSI is carried out without removal of cumulus cells in some facilities, a recent study of the murine cumulus cell‐oocyte complex (COC) reported that prolonged culture of oocytes with intact cumulus cells induces apoptotic changes, suggesting that oocyte denudation should be performed as soon as possible after oocyte retrieval. Although some researchers have investigated the optimal timing of cumulus cell removal in ICSI procedures, there is yet no consensus.…”