Oviductal Extracellular Vesicles: History
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In this review, we have described characteristics of extracellular vesicles in the oviduct from different species and their role in supporting oocytes, sperm, and embryos.

  • egg
  • embryo
  • extracellular vesicle
  • exosome
  • fallopian tube
  • microvesicle
  • oocyte
  • oviductosome
  • oviduct
  • sperm

1. Introduction

Extracellular vesicles (EVs) participate in intercellular and interorganismal communications (reviewed by [1]). EVs is the collective term used for both exosomes and microvesicles. Exosomes are vesicles with an approximate size of 30–100 nm in diameter. Exosomes are derived from endocytotic origin and are released from cells through plasma membrane fusion of a multi-vesicular body [2]. However, microvesicles (100–1000 nm) readily bud from the cell membrane (reviewed by [3]). EVs communicate their signal to recipient cells by transferring their molecular cargos using endocytosis and cellular fusion [4]. These cargos usually contain DNA, RNA, proteins, and other metabolites [1]. In this review, we have described characteristics of EVs in the oviduct from different species and their role in supporting oocytes, sperm, and embryos.

2. Extracellular Vesicles

2.1. General Characteristics of EVs

Exosomes are formed as intraluminal vesicles (ILVs) within multivesicular bodies (MVBs). MVBs then either fuse with cellular lysosomes and degrade, or fuse with the plasma membrane. MVB-fused plasma membranes are released as exosomes into the extracellular space (reviewed by [5]). Specific markers for exosomes used in different studies of oviductal EVs (oEVs) have also been identified. These oviduct exosomal markers include tetraspanin transmembrane superfamily (i.e., CD9, CD63, and CD81), heat shock proteins (HSPs; i.e., HSPA1A, HSP70, and HSPA8), annexin A1 (ANXA1), actin-linking ezrin-radixin-moesin (ERM), and tumor susceptibility gene 101 (TSG101) [6].
In contrast to exosomes, microvesicles are formed by an outward budding from the plasma membrane [7]. Marker proteins for microvesicles include TSG101, arrestin domain containing 1 (ARRDC1), gelatinases, ADP ribosylation factor 6 (ARF6), major histocompatibility complex 1 (MHC-1), β1-integrin, vesicle-associated membrane protein 3 (VAMP3), and membrane type 1-matrix metalloproteinase (MT1MMP) [8]. Apoptotic bodies are also considered a subclass of EVs. These apoptotic bodies are released only during apoptotic cell death and have molecular signals that attract phagocytes and promote apoptotic cell clearance (reviewed by [9]). However, we will focus solely on exosomes and microvesicles in this review.

2.2. EV Biogenesis

Proteins involved in the biogenesis of exosomes include Ras-related proteins (RAB11/RAB35, RAB27A/B, RAB7), diacylglycerol kinase alpha (DGKα), and vesicle associated membrane protein 7 (VAMP7) [8]. Rab11a−/−, Rab35−/−, and Rab7−/− mice are embryonically lethal in mice [10,11,12]. Rab27a/b double knockout mice have shown deficiency in exosome secretion, leading to a low-grade inflammatory phenotype [13]. However, Dgkα−/− and Vamp7−/− mice are viable [14,15]. Proteins involved in the biogenesis of microvesicles include ARRDC1, TSG101, vesicle-fusing ATPase (VSP4), RAB22A, hypoxia-inducible factors (HIF), ARF6, phospholipase D (PLD), extracellular-signal-regulated kinase (ERK), and myosin light-chain kinase (MLCK) [8]. However, only TSG101 and ARF6 appear to have indispensable biological functions in mammals as Tsg101−/− mice die around the time of implantation [16] whereas Arf6−/− mice die during mid-late gestation [17]. These findings indicate that some of the proteins involved in EV biogenesis are crucial for cellular function in mammals.

3. Are oEVs the Missing Key in Assisted Reproductive Technologies?

3.1. Natural Conception vs. In Vitro Fertilization

Assisted reproductive technologies (ARTs) include in vitro fertilization (IVF), gamete intrafallopian transfer (GIFT), zygote intrafallopian transfer (ZIFT), intrauterine insemination (IUI), and embryo transfer (ET). In the United States, according to the Center for Disease Control and Prevention’s report for 2017, approximately 306,197 ART cycles were performed, resulting in 73,831 live births out of 3.79 million [90]. Approximately 1.9% of infants born in the United States are conceived using ARTs. IVF procedures include the development of the embryo to the blastocyst stage in culture media, or for 3–7 days, depending on the protocol, followed by the transfer of embryo(s) into the uterine cavity. With these procedures, the entire Fallopian tube is bypassed. In procedures like ZIFT and GIFT, the zygote or gametes are transferred directly into the Fallopian tube. While there are no differences between implantation rates using ZIFT compared to IVF in healthy women, pregnancy and implantation rates are significantly higher when ZIFT is performed in women with repeated implantation failure using IVF (35.1% success rate with ZIFT vs 11.1% for IVF) [91]. It is obvious that the Fallopian tube is superior for fertilization and embryo development than artificially modified conditions in vitro. However, it is virtually unknown how oEVs from the Fallopian tube provide an optimal microenvironment for gametes and embryos in humans.

3.2. oEVs Could Improve the Quality of ART-Derived Embryos

Within the Fallopian tube, embryos are bathed in fluid containing oEVs, which are missing in culture media. Although the majority of babies born using ARTs are healthy, culture conditions in ARTs have been associated with epigenetic changes in the embryo. Alteration of expression patterns in imprinted genes may indicate imprinting disorders. Out of 10,000 live births following ARTs procedures, 3.9 children are diagnosed with Angelman syndrome, 3.9 with Beckwith-Wiedemann syndrome, 2.2 with Prader–Willi syndrome, and 1.5 with Silver-Russel syndrome [92]. The frequency of these imprinting disorders in the normal population is approximately 2 children out of every 10,000 live births [92].

As mentioned above, co-culture of embryos with oviductal fluid collected at various stages of embryo development differentially altered methylation patterns in bovine embryos [85]. Blastocysts that were cultured in SOF with addition of fetal calf serum exhibited downregulation of the imprinted gene called small nuclear ribonucleoprotein polypeptide N (SNRPN) compared to blastocysts cultured in synthetic fluid containing oEVs [72]. Accordingly, decreased SNRPN expression has been associated with Prader–Willi syndrome [93]. Therefore, it is possible that in vivo-derived oEVs are directly involved in methylation control in embryos. However, to date, we still cannot pin-point as to which proteins or molecular cargos from oEVs are responsible for normal embryo development. It is likely that the cumulation of distinct proteins present chronologically in the oEVs is correspondingly responsible for proper functions of gametes and embryos at various developmental stages.

This entry is adapted from the peer-reviewed paper 10.3390/ijms21218280

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