Redox Biology of Human Cumulus Cells: Basic Concepts, Impact on Oocyte Quality, and Potential Clinical Use

Abstract

Significance: Four decades have passed since the first successful human embryo conceived from a fertilization in vitro. Despite all advances, success rates in assisted reproduction techniques still remain unsatisfactory and it is well established that oxidative stress can be one of the major factors causing failure in in vitro fertilization (IVF) techniques. Recent Advances: In the past years, researchers have been shown details of the supportive role CCs play along oocyte maturation, development, and fertilization processes. Regarding redox metabolism, it is now evident that the synergism between gamete and somatic CCs is fundamental to further support a healthy embryo, since the oocyte lacks several defense mechanisms that are provided by the CCs. Critical Issues: There are many sources of reactive oxygen species (ROS) in the female reproductive tract in vivo that can be exacerbated (or aggravated) by pathological features. While an imbalance between ROS and antioxidants can result in oxidative damage, physiological levels of ROS are essential for oocyte maturation, ovulation, and early embryonic growth where they act as signaling molecules. At the event of an assisted reproduction procedure, the cumulus/oophorus complex is exposed to additional sources of oxidative stress in vitro. The cumulus cells (CCs) play essential roles in protecting the oocytes from oxidative damage. Future Directions: More studies are needed to elucidate redox biology in human CCs and oocyte. Also, randomized controlled trials will identify possible benefits of in vivo or in vitro administration of antioxidants for patients seeking IVF procedure.

Keywords: IVF; antioxidant; cumulus cells; infertility; oocyte; redox.

Figures

FIG. 1.

Anatomy of the ovary. In the mature antral follicle, the oocyte is surrounded by specialized granulosa cells, named the cumulus cells, which are in contact with the follicular fluid inside the antrum. Color images are available online.

FIG. 2.

O2 exposure in the female reproductive tract. The mammalian reproductive female tract is a hypoxic environment, with O2 pressure ranging between 2% and 8%. The ovaries receive around 5% O2 from the circulatory system, while the oocytes are limited to follicular fluid and cumulus cells for their supply. The COC and preimplantation embryo are adapted to this hypoxic environment. The oocyte, contained inside the antral follicle, and the embryo until day 3 stage are highly dependent on OXPHOS for energy production. From days 3 to 5, on its way across the fallopian tube to the uterus, the embryo experiences an O2 supply around 2%–5% O2 in mammals; it shifts its metabolism to aerobic glycolysis. COC, cumulus/oocyte complex; O2, oxygen; OXPHOS, oxidative phosphorylation. Color images are available online.

FIG. 3.

In vivo sources of oxidative stress. There are many potential sources of ROS generation and possible oxidative stress in vivo. COCs are directly impacted by lifestyle habits such as smoking, exercising routine, stress, and nutritional habits. Besides, pathologies such as endometriosis and polycystic ovaries significantly impact on cumulus and oocyte health and functioning. ROS, reactive oxygen species. Color images are available online.

FIG. 4.

In vitro sources of oxidative stress. During in vitro fertilization techniques, the COC is exposed to several potential sources of oxidative stress. O2 pressure, visible lights, culture media composition, pH changes, temperature variations, and sperm concentrations can generate ROS, provoking an imbalance in redox potential and causing oxidative damage. Color images are available online.

FIG. 5.

Cumulus cell defensive mechanisms against oxidative stress in the oocyte. The cumulus cells are connected between themselves and the oocyte through gap junctions present in the transzonal projections that permit the transfer of several molecules essential for oocyte survival. The cumulus cells capture glucose from the follicle microenvironment and process it through glycolysis, generating pyruvate that the oocyte will metabolize through the TAC+OXPHOS, producing biomolecules, energy (ATP), and ROS. ROS such as the anion superoxide (O2•−) can be detrimental. The cumulus also deviates glucose to the PPP, essential for amino acid production and NADPH recycling, a cofactor essential for antioxidant reactions. Essential defensive molecules such as GSH and NADPH are also supplied. Besides that, the cumulus is responsible for CAT production, an enzyme that metabolizes the reactive hydrogen peroxide and that is not expressed by the oocyte. The cumulus and oocyte also possess SOD, the enzyme responsible for metabolizing superoxide anion into peroxide, a less reactive form; GR promotes GSSG recycling back to the reduced form, GSH; and GPx metabolizes peroxide into water and O2, using GSH as an electron acceptor, and reduces lipid hydroperoxides. All these enzymes are involved in oxidative stress defense. SOD can be located at the cytoplasm as the copper and zinc variant (CuZnSOD), or in mitochondria as the manganese variant (MnSOD). Both cell types are capable of synthesizing melatonin, but the oocyte itself does not produce enough levels of antioxidant defenses, being dependent on the cumulus cells. CAT, catalase; CuZnSOD, copper/zinc superoxide dismutase; GPx, glutathione peroxidase; GR, glutathione reductase; GSH, reduced glutathione; GSSG, oxidized glutathione; MnSOD, manganese superoxide dismutase; NADPH, reduced nicotinamide adenine dinucleotide phosphate; PPP, pentose phosphate pathway; SOD, superoxide dismutase; TAC, tricarboxylic acid cycle. Color images are available online.

FIG. 6.

Antioxidant administration strategies for overcoming COC oxidative stress. Several approaches have been studied in humans. Different antioxidants have been administrated orally, in vivo, or after COC collection, in vitro. While different outcomes were evaluated, distinct time frames of administration, concentrations, patient groups, and in vitro conditions make it difficult to find comparable results. In parentheses are the referenced studies for the administration of each substance. Color images are available online.