Journal of Fertilization: In Vitro - IVF-Worldwide, Reproductive Medicine, Genetics & Stem Cell Biol
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The Aspect of Cumulus Cells in Fertilization Procedure

Bipin Singh Irom^{* *}Correspondence: Bipin Singh Irom, Department of Biotechnology, Chandigarh University, India, Email:

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During ovulation process, cumulus cells produced and accumulated hyaluronan (HA) rich matrix within cumulus cell layers, called as cumulus expansion. The expanded cumulus oocyte complex is ovulated from follicle, and then fertilized in oviduct. It has been known that the fertilization rate of oocyte in vitro is higher when expanded COCs are used for in vitro fertilization as compared with that in denuded oocyte. However, the positive roles of cumulus cells in fertilization process were remained unclear. Using mutant mouse models, the functional relevance of HA and HA binding proteins has been documented by a wealth of biochemical data and physiological studies. Specifically, the level of Tnfaip6 mRNA was significantly lower in mice null for either Ptgs2 (prostaglandin synthase 2, also known as COX-2) or Ptger2 (prostaglandin E2 receptor 2 known as EP2) than in their wild type littermates [1,2], indicating that Tnfaip6 gene expression was dependent on prostaglandin E2 and its receptor pathway. Ovulation in both mouse models was reduced slightly, but cumulus expansion as well as fertilization was completely suppressed in these mutant mice. The fertilization defects of Ptgs2 or Ptger2 null mice were related to defective matrix stability/function because mature oocytes retrieved from these mutant mice could be fertilized in vitro by use of capacitated spermatozoa [3]. These reports suggest that the hyaluronan rich matrix produced by COCs is essential not only for ovulation but also for in vivo fertilization, and perhaps more specifically for sperm capacitation. Recently, we reported that cumulus cells express TLR2 and TLR4 that are well known to directly and selectively bind to bacteria released endotoxins, lipopolysaccharides and peptidoglycan.

Both types of TLRs also recognize small hyaluronan fragments, less than 10 kDa, but not the high molecular hyaluronan polymer. During fertilization, the high molecular weight HA polymers are broken-down by sperm-head associated hyaluronidase to small fragments that then stimulate chemokine secretion from cumulus cells by TLR-dependent mechanisms [4]. The secreted chemokines, in turn, act on specific receptors present on the mid piece of sperm to enhance successful fertilization at least in vitro. Therefore, the immune-related genes expressed in cumulus cells play important roles in oocyte maturation, COC expansion and fertilization.

References

1. Ochsner SA, Day AJ, Rugg MS, Breyer RM, Gomer RH, et al. Disrupted function of tumor necrosis factor-alpha-stimulated gene 6 blocks cumulus cell oocyte complex expansion. Endocrinol 2003; 144: 4376-4384.
2. Ochsner SA, Russell DL, Day AJ, Breyer RM, Richards JS. Decreased expression of tumor necrosis factor-alpha-stimulated gene 6 in cumulus cells of the cyclooxygenase-2 and EP2 null mice. Endocrinology 2003; 144: 1008-1019.
3. Matsumoto H, Ma W, Smalley W, Trzaskos J, Breyer RM, et al. Diversification of cyclooxygenase-2-derived prostaglandins in ovulation and implantation. Biol Reprod 2001; 64: 1557-1565.
4. Shimada M, Yanai Y, Okazaki T, Noma N, Kawashima I, et al. Hyaluronan fragments generated by sperm-secreted hyaluronidase stimulate cytokine/chemokine production via the TLR2 and TLR4 pathway in cumulus cells of ovulated COCs, which may enhance fertilization. Development 2008; 135: 2001-2011.