Abstract
Women with cancer and low ovarian reserves face serious challenges in infertility treatment. Ovarian tissue cryopreservation is currently used for such patients to preserve fertility. One major challenge is the activation of dormant ovarian follicles, which is hampered by our limited biological understanding of molecular determinants that activate dormant follicles and help maintain healthy follicles during growth. Here, we investigated the transcriptomes of oocytes isolated from dormant (primordial) and activated (primary) follicles under in vivo and in vitro conditions. We compared the biological relevance of the initial molecular markers of mature metaphase II (MII) oocytes developed in vivo or in vitro. The expression levels of genes involved in the cell cycle, signal transduction, and Wnt signaling were highly enriched in oocytes from primary follicles and MII oocytes. Interestingly, we detected strong downregulation of the expression of genes involved in mitochondrial and reactive oxygen species (ROS) production in oocytes from primordial follicles, in contrast to oocytes from primary follicles and MII oocytes. Our results showed a dynamic pattern in mitochondrial and ROS production-related genes, emphasizing their important role(s) in primordial follicle activation and oocyte maturation. The transcriptome of MII oocytes showed a major divergence from that of oocytes of primordial and primary follicles.
Highlights
Laparoscopic ovariectomy and subsequent cryopreservation of ovarian tissue is a standard procedure for female cancer patients undergoing potentially sterilizing chemotherapy and/or radiotherapy
We extended our in vivo and in vitro analysis to include morphological, transcriptomic, and biochemical analyses of metaphase II oocytes
Sox11, Atp4a, Galnt7, Lemd2, Dnajc24, Gemin2, Gstm6, Ildr2, and Oaf were determined to be slightly interrelated, and Gm27027 showed no connections in either metaphase II (MII) oocytes or oocytes from primary follicles (Figures 5C,D). These results suggested that significantly differentially expressed genes (SDEGs) in MII oocytes showed higher overlap with those in oocytes from primordial follicles, the interconnection of the proteins encoded by overlapping SDEGs between MII oocytes and oocytes from primary follicles was more similar than that of overlapping SDEGs between MII oocytes and oocytes from primordial follicles in the in vivo and in vitro groups
Summary
Laparoscopic ovariectomy and subsequent cryopreservation of ovarian tissue is a standard procedure for female cancer patients undergoing potentially sterilizing chemotherapy and/or radiotherapy. FOXO3a, as a downstream effector, inhibits primordial follicle activation by suppressing this pathway (Castrillon et al, 2003) Despite this molecular knowledge, attempts to use AKT stimulators and PTEN inhibitors were deleterious for follicle quality (Maidarti et al, 2020), and inhibition of PTEN increased DNA damage and reduced the DNA repair response in bovine oocytes (Maidarti et al, 2019). Attempts to use AKT stimulators and PTEN inhibitors were deleterious for follicle quality (Maidarti et al, 2020), and inhibition of PTEN increased DNA damage and reduced the DNA repair response in bovine oocytes (Maidarti et al, 2019) This pharmacological inhibition of PTEN during the in vitro development of human follicles revealed that primordial follicles were activated, their growth was compromised (McLaughlin et al, 2014). To obtain high-quality oocytes from in vitro development, we must elucidate the molecular mechanisms that underlie this complex activation step of primordial follicles in vivo and compare them to those in vitro
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