Abstract
The serpin peptidase inhibitor, clade E, member 2 (SERPINE2) inhibits urokinase-type plasminogen activator (PLAU) and tissue-type plasminogen activator. Higher SERPINE2 expression levels were detected in cumulus cells of human immature oocytes than in those of mature oocytes. The objective of this study was to evaluate whether high SERPINE2 levels in cumulus cells are associated with oocyte immaturity. Using the mouse cumulus–oocyte complex as an experimental model, the effects of elimination and overexpression of SERPINE2 in cumulus cells on cumulus expansion and oocyte maturation were assayed by in vitro maturation. Serpine2 and PLAU transcripts were the most highly expressed serpins and plasminogen activators, respectively. Their expression was coordinately regulated in cumulus cells during gonadotropin-induced oocyte maturation. Silencing of Serpine2 expression using small interfering RNAs or blockage of SERPINE2 protein using a specific antibody had no effect on oocyte maturation. However, overexpression of Serpine2 or exogenous supplementation with high levels of SERPINE2 impaired cumulus expansion and oocyte maturation, probably by decreasing hyaluronan synthase 2 (Has2) and versican (Vcan) mRNA expression. Amiloride, a specific PLAU inhibitor, also suppressed these processes. PLAU supplementation of the oocyte in vitro maturation medium caused earlier and more extensive expansion of cumulus cells and oocyte maturation that may be mediated by increased Has2 mRNA expression. However, these effects were neutralized by coincubation with SERPINE2 or amiloride and PLAU. In conclusion, SERPINE2 and PLAU are involved in cumulus expansion and oocyte maturation. High SERPINE2 levels impair these processes, probably by decreasing cumulus matrix gene expression as well as reducing cumulus hyaluronan contents and inhibiting PLAU activity. These findings may explain why cumulus cells surrounding immature human oocytes express high SERPINE2 levels.
Highlights
The structural integrity of the cumulus cell extracellular matrix (ECM) is essential for oocyte maturation
Considerably more SERPINE2 protein was detected in cumulus cells from immature human oocytes at the GV and metaphase I (MI) stages (Figure 1C, a and b, respectively) than in those from mature MII oocytes or with the control staining of MII oocytes (Figure 1C, c and d, respectively)
SERPINE2 overexpression in mouse cumulus–oocyte complexes (COCs) or its exogenous addition to In vitro maturation (IVM) medium remarkably impaired cumulus expansion, with the COCs exhibiting a compact morphology with a high proportion of GV and MI oocytes, leading to a significant reduction in oocyte maturation (Figure 4 and Table S3)
Summary
The structural integrity of the cumulus cell extracellular matrix (ECM) is essential for oocyte maturation. Several cumulus proteins linked to ECM hyaluronan, e.g., heavy chain of inter-alphatrypsin inhibitor (ITIH) [1], pentraxin-3 (PTX3) [2,3], tumor necrosis factor alpha-induced protein 6 (TNFAIP6) [4], and versican (VCAN) [5], are required for regulating cumulus integrity, ensuring cumulus expansion and oocyte maturation [2,6,7]. PAs are involved in tissue remodeling by converting abundant extracellular plasminogen into active protease plasmin, which degrades almost all matrix proteins [20]. Understanding how serpins modulate PLAT/PLAU proteolytic activities is considerably important in developing therapeutic strategies for PA-involved tissue remodeling
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
