The secretion and metabolism of cumulus cells support fertilization in the bovine model

The cumulus oophorus is a structure that surrounds the mammalian oocyte [1]. Cumulus cells have been shown to secrete vital factors for oocyte growth, maturation, fertilization, and early embryo development. These factors provide many nutrients and cell signaling molecules including hyaluronate [2], cAMP [3], progesterone [4], glutathione [5], pentraxin 3 [6], chemokines [7], and noncoding RNAs [8].

Cumulus cells surrounding the egg release steroid hormone progesterone [9]. It is known to stimulate several functional properties in sperm, including hyper-activation and the acrosome reaction (AR) [9]. A recent study showed that nanomolar concentrations of progesterone are fundamentally able to stimulate calcium ion channels in the flagellum of human sperm [9]. In another study, a patch-clamping methodology was used to demonstrate how progesterone accelerates the completion of tyrosine phosphorylation, as a hallmark of sperm capacitation in sperm from Rhesus Macaque [10].

Hyaluronate is an anionic, non-sulfated glycosaminoglycan, which is distributed widely throughout connective, epithelial, and neural tissues [6]. The cumulus oophorus expands due to the deposition of a proteoglycan matrix after ovulation. Hyaluronate containing pentraxin 3 and heavy chains of the inter-α-trypsin inhibitor is critical for in vivo fertilization and fertility [6]. A glycosylphosphatidylinositol-anchored sperm hyaluronidase catalyze hyaluronan degradation, thus enabling acrosome-intact sperm to penetrate the cumulus mass [6]. Large amounts of Hyal5 are known to be released during the AR, thus implying that the function of Hyal5 is to assist hyaluronan hydrolysis in the cumulus cells [11]. Hyaluronidase treatment of the mouse sperm head was shown to dehydrate hyaluronate and produce fragments that activated a variety of cytokines or chemokine secretions through the toll-like receptor pathway present on cumulus cells, thus resulting in the induction of tyrosine phosphorylation [12].

Another report suggests that the presence of the cumulus mass matrix during in vitro fertilization (IVF) might protect the bovine oocyte against oxidative stress and improve the efficacy of first cleavage [13]. Upon fertilization, reactive oxygen species (ROS) was shown to affect oocytes and impair embryo development following IVF [14]. Oxygen in the fallopian tube was the low concentration at the fertilization in the oviduct in vivo [15]. The study shows that the cumulus cells increased the fertilizing ability of sperm penetration by generating a complex microenvironment of cumulus secretions and metabolic products around the oocyte [16]. However, it was obvious that progesterone and hyaluronate unsupported sperm fertility and fertilization [16]. It is assumed that bovine serum albumin, which is a highly complex material, mimics the effect of progesterone and hyaluronate to support fertilization.

Therefore, very little is known with regards to how cumulus cell plays a direct and critical role at fertilization, or whether the components and secretions from cumulus cells can promote fertilization. We hypothesized that the secretion and metabolism of cumulus cells support fertilization using a chemically defined, protein-free capacitation and fertilization medium supplemented with methyl-β-cyclodextrins. To accomplish this, we demonstrated that the cumulus cells from cumulus-oocyte-complexes (COCs) and secretions via cumulus cells enhance sperm fertilization, and that hyaluronate, progesterone, and a low oxygen stress environment all supported sperm function at fertilization.

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