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RESEARCH |
1 Department of Applied Animal Science, Graduate School of Biosphere Science, Hiroshima University, 1-4-4, Kagamiyama, Higashi-Hiroshima, Hiroshima 739-8528, Japan and2 Smaller Livestock and Environment Section, Livestock Research Institute, Oita Prefectural Agriculture, Forestry and Fisheries Research Center, Bungo-ono, Oita 879-7111, Japan
Correspondence should be addressed to M Shimada; Email: mashimad{at}hiroshima-u.ac.jp
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Abstract |
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Introduction |
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In the pig ovary, numerous early antral follicles are present at the pro-estrous stage of the estrous cycle (Ainsworth et al. 1980). In response to equine chorionic gonadotropin (eCG) injection, the small antral follicles (more than 3 mm in diameter) enlarge to more than 10 mm diameter reaching a preovulatory stage of follicle development by 72 h post hormone stimulation. Ainsworth et al. (1980) reported that not only estrogen production but also progesterone accumulation were increased after eCG injections alone. Moreover, the functional roles of progesterone in the ovulation process of mice and pigs are different. Whereas PGR null mice (PRKO) exhibit impaired ovulation, the matured oocytes recovered from these follicles were developmental competent after in vitro fertilization (Lydon et al. 1995). By contrast, in the pig, either a progesterone synthesis inhibitor or PGR antagonist potently suppressed the cumulus cell functions (Shimada et al. 2004a, 2004b), the meiotic resumption (Yamashita et al. 2003), and the developmental competence of oocytes (Shimada et al. 2004b). Moreover, in pig follicles, the PGR is expressed in both cumulus and granulosa cells when cultured with FSH alone (Shimada et al. 2004c) or recovered from eCG-primed gilts (Slomaczynska et al. 2000). These observations suggest that, in the pig, progesterone as well as estrogen impacts functional changes in cumulus and granulosa cells that are critical for the acquisition of responses to the ovulatory LH signal. Although PGE2 accumulates within follicular fluid and the level was significantly increased after gonadotropin surge (Hunter & Poyser 1985, Xie et al. 1990), little is known about what regulates the production of PGE in porcine follicles. Moreover, there is little information in the pig model about the time course changes in the expression genes encoding steroidogenic enzymes, the effects of steroid hormones on cumulus cell function, the regulated expression of the EGF-like growth factors or PTGS2 mRNA by LH, or the role of the factors in cumulus cell-mediated regulation of oocyte maturation in vivo and in vitro.
Characterizing the mechanisms by which hormones control follicular development to the preovulatory stage and ovulation in vivo provides basic information for applying and improving hormonal treatments to stimulate successful maturation of porcine oocytes in vitro. For in vitro maturation of pig oocytes, COCs are typically recovered from small antral follicles (3–5 mm in diameter; Funahashi et al. 1994, 1997, Shimada et al. 2002, 2003) because oocytes recovered from COCs of follicles greater than 3 mm in diameter and cultured with FSH and LH can resume meiosis and progress to the metaphase II stage (Sun et al. 2004). However, in vitro-matured oocytes exhibit limited developmental competence as revealed by their inability to develop beyond the blastocyst stage. Additionally, cumulus cells of COCs recovered from small antral follicles exhibit limited responsiveness to LH (Shimada et al. 2003) and EGF (Prochazka et al. 2003), indicating that treatment with FSH is required for cumulus cells to acquire responses to LH and thereby mimic conditions in vivo. Thus, we hypothesized that cumulus cells of COCs recovered from small antral follicles exhibit minimal responses to LH due to their early stage of development and limited exposure to FSH and/or steroid hormones.
To define the in vivo and in vitro conditions that permit optimal maturation of pig oocytes, we collected follicular fluid, granulosa, and cumulus cells from follicles beginning at the small antral stage (3–5 mm) to preovulatory stage (more than 10 mm) following the treatment of swine with exogenous eCG. Additionally, the cumulus cells of COCs were recovered from the ovaries of eCG-primed swine at selected times after treatment with human chorionic gonadotropin (hCG). Using these samples, we documented that the temporal changes of steroid hormone production and the expression patterns of specific genes including those encoding the EGF-like factors were distinct compared with those observed in mouse models. On the basis of the unique porcine mechanisms in vivo, we altered the in vitro culture conditions for oocyte maturation (Fig. 1) and showed that if COCs are cultured first with FSH and steroid hormone and then cultured with LH and EGF-like factors, oocyte maturation, and blastocyst development are improved.
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The gene expressions involved in cumulus cell differentiation in vivo
The expression of the cell-cycle regulators, cyclin D2 (CCND2) and p27kip1 (CDKN1B), was significantly higher in cumulus cells obtained from middle-sized follicles (5–10 mm in diameter) than in cells from small antral follicles (3–5 mm in diameter) and decreased in response to eCG (Fig. 5). Low levels were maintained until 48 h after post hCG. By contrast, expression of AREG mRNA increased following eCG at 72 h and a further significant increase at 12-h post hCG. However, the increase in cumulus cells was only 5-fold when compared with 40-fold in granulosa cells (Fig. 3). In addition to AREG mRNA, the expression of other genes (EGFR, hyaluronan synthase 2 (HAS2), tumor necrosis factor 
-induced protein 6 (TNFAIP6), PTGS2, and PGR) was increased dramatically in COCs obtained from eCG- (72 h) and hCG- (12 h) treated gilts (Fig. 5). Unlike these genes, significant increases in a disintegrin and metalloprotease with thrombospondin-like repeats 1(ADAMTS1) and ADAM17 mRNAs were only detected at 12 and 24 h in ADAM17 and 24 and 48 h in ADAMTS1; and the level of ADAMTS1 mRNA remained significantly higher in cumulus cells of ovulated COCs 48 h after hCG injection (Fig. 5).
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Discussion |
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These data in the pig model provide several similarities but also distinct differences from the patterns of regulation in rat and mouse models. Major similarities are observed in factors controlling proliferation. FSH and estradiol have been shown to act synergistically to enhance granulosa cell proliferation in a rat model (Rao et al. 1978, Robker & Richards 1998). The cell-cycle regulatory molecule cyclin D2 (CCND2) was expressed in granulosa cells during follicular development stage, and the CCND2 knockout mice showed limited granulosa cell and cumulus cell proliferation and anovulatory phenotypes (Sicinski et al. 1996). Moreover, in the in vitro culture system of human COCs, the number of cumulus cells in COCs before culture was positively correlated (P<0.05) with the developmental competence of oocytes after in vitro maturation (Sato et al. 2007), suggesting that a sufficient number of cumulus cells is required to support oocyte maturation.
The major differences reside in the temporal appearance, cell-specific expression, and functional roles of PGR and LHCGR. In pig follicles, PGR is expressed not only in granulosa cells (Slomaczynska et al. 2000) but also in cumulus cells (Fig. 5) and is observed in these cells of antral follicles prior to the ovulatory hormone surge. Moreover, data herein document that progesterone acts coordinately after FSH and estradiol to induce the expression of full-length LHCGR mRNA but not the short form in cumulus cells of cultured COCs. It has been reported that LH receptor protein translated from the full-length LHCGR mRNA had biological activity (Loosfelt et al. 1989). In our previous study (Shimada et al. 2003), the full-length form of LHCGR mRNA in cumulus cells of porcine COCs was significantly increased by 20 h of culture with FSH. The addition of FSH also significantly increased the binding level of biotinylated hCG to the COCs (Shimada et al. 2003). Three other splicing variants that lack the putative transmembrane domain negatively regulate the function of the receptor (Nakamura et al. 2004), suggesting that porcine cumulus cells have functional LH receptor. Meanwhile, a low level of LHCGR mRNA expression was detected in cumulus cells of mouse COCs, since oocyte-secreted factors strongly suppressed the expression (Elvin et al. 1999). Thus, it is a possibility that porcine cumulus cells would have a unique role of progesterone–PGR pathway in the induction of functional LH receptor expression.
The addition of progesterone to these same COC cultures (i.e., 10 h after the combined FSH and estradiol treatment) reduced cumulus cell proliferation. These observations extend our previous study, which documented that the cumulus cell proliferation was down-regulated by the culturing COCs in the plain one-step culture system, i.e., with FSH and LH combined, and the reduction reversed by the PGR antagonist, RU486 (Okazaki et al. 2003, Shimada et al. 2004b). Moreover, eCG-induced increases in follicular levels of progesterone in vivo were associated with reduced levels of CCND2 mRNA indicating that eCG and progesterone impact cell proliferation in large antral porcine follicles. Similarly, anti-proliferative effects of progesterone have been observed in other tissue models (Lydon et al. 1995, Wang et al. 2007). These results indicate that the increase of progesterone and the expression of PGR before LH surge are essential for the reduction of proliferative activity and induction of LHCGR and the ability of pig cumulus cells to respond directly to LH.
In addition to the expression and critical role of the PGR pathway in eCG-primed porcine follicles and COCs, mRNAs encoding the EGF-like factors AREG and EREG, were increased by eCG in granulosa cells and to a lesser extent in cumulus cells of follicles prior to the LH/hCG surge. Moreover, the EGF receptor is increased in eCG- and hCG-primed COCs. This eCG-response pattern also differs from that in mouse models where AREG and EREG mRNAs are expressed highly only after hCG stimulation (Park et al. 2004, Shimada et al. 2006). Additionally, Hsieh et al. (2007) showed that in Areg or Ereg null mice, or in mice null for Areg and hypomorphic for EGF receptor, follicular development and LHCGR expression after eCG priming were not altered markedly. However, in mice null for Areg and hypomorphic for EGF receptor, the ovulation process was dramatically impaired with notable defects observed in oocyte maturation, cumulus cell expansion, granulosa cell luteinization, and follicle wall rupture. Because AREG and EREG are synthesized as transmembrane precursors, they are activated when cleaved at one or more sites in the extracellular domain by proteases such as TACE/ADAM17, thereby releasing the EGF peptide (Lee et al. 2003, Sahin et al. 2004). Our previous studies have shown the expression of TACE/ADAM17 in cumulus cells of porcine COCs cultured with FSH and LH, and that the protease activity was required for the activation of EGF receptor downstream pathway (Yamashita et al. 2007). Herein we document that TACE/ADAM17 mRNA is expressed in granulosa cells recovered from the middle-sized and large antral follicles but the level was increased further by hCG. Additionally, the expression of EGF receptor (EGFR) mRNA was also up-regulated by hCG injection. These results suggest that the release of active EGF peptides from granulosa cells would reach maximal levels and stimulate the receptors localized on cumulus cells only after hCG stimulation.
The induction and activation of the EGF-like factors combined with prostaglandin production have been shown to be essential for cumulus cell oocyte complex expansion and oocyte maturation in mouse models (Ochsner et al. 2003, Shimada et al. 2006). Expansion is mediated by the production of an extracellular matrix comprised a hyaluronan backbone, stabilized by various hyaluronan-binding proteins, including the serum-derived factor, inter--trypsin inhibitor as well as TNFAIP6 and PTX3 expressed by cumulus cells (Chen et al. 1992, Camaioni et al. 1993, Fülöp et al. 1997, Salustri et al. 2004). Mice null for Ambp, Tnfaip6, and Ptx3 exhibit impaired expansion and ovulation (Sato et al. 2001, Zhuo et al. 2001, Varani et al. 2002, Fülöp et al. 2003, Salustri et al. 2004). Adamts1, a target of progesterone and PGR action in mouse models (Robker et al. 2000) also impacts matrix formation and stability, presumably due to its ability to cleave the hyaluronan-binding proteoglycan, versican (Csg2) (Russell et al. 2003). In the porcine model, we reported previously that ADAMTS1 mRNA expression required the expression and activation of cumulus cell PGR, and was critical for expansion of porcine COCs (Shimada et al. 2004a). Herein, we document that ADAMTS1 and PTGS2 mRNAs are induced only after hCG stimulation in vivo whereas HAS2, TNFAIP6, and PGR are increased in eCG-primed follicles in which COCs are not expanded. In summary, changes in follicular (granulosa and cumulus) cell function in the porcine system show many similarities but also important specific differences to the mouse models. These differences are functionally important for appropriate COC expansion and oocyte maturation. Thus, COC culture conditions for the pig differ from the mouse, indicating that culture conditions for other species may also need to be carefully adjusted to changes that occur in vivo.
The in vivo data revealed that COCs recovered from small antral follicles are not fully differentiated and do not contain a sufficient number of cumulus cells to support oocyte maturation. However, when the COCs recovered from early antral follicles primed with FSH and estradiol, followed by progesterone in culture, they exhibited enhanced responsiveness to LH and EGF-like factors. Thus, an improved COC culture system for in vitro maturation of porcine oocytes is proposed.
Using this modified culture system based on in vivo changes in hormones and growth factor production, the matured porcine COCs exhibited full expansion, the cumulus cells remained healthy (low number of apoptotic cells) and when oocytes obtained from these COCs were used for in vitro fertilization, the developmental competence to blastocyst stage was significantly improved when compared with that using the plain one-step FSH+LH culture system, our two-step culture system as described in Shimada et al. (2002, 2003), or other two-step culture systems (Funahashi et al. 1997, Kikuchi et al. 1999). In conclusion, we have documented that the study of functional changes of porcine cumulus cells before and after LH stimulation in vivo permitted us to establish a better in vitro maturation system. We propose that because each species has a unique pattern of gene expression in cumulus cells, it is important to establish that there is disparity in molecular profiles among the species and they need to be assessed in developing optimal culture condition of COCs.
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Materials and Methods |
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General procedure
Isolation of porcine COCs from small antral follicles was performed as described previously (Shimada & Terada 2001). The COCs were cultured for a total of 44 h as described below. After culture, COCs were visualized using phase-contrast microscope (Olympus IMT2, Olympus, Tokyo, Japan) and x10 objective. The oocytes were fixed with acetic acid/ethanol (1:3) for 48 h and stained with aceto-lacmoid before examination under a phase-contrast microscope (400x) for evaluation of their chromatin configuration. Some oocytes were used for in vitro fertilization according to our previous study (Shimada et al. 2003). Visualization of apoptotic cells (cleaved caspase-3 positive cells) in COCs was detected by immunofluorescence using anti-cleaved caspase-3 antibody (Cell Signaling Technologies, Danvers, MA, USA) under a fluorescence microscope (Nicon DS-Fi1; Nicon, Tokyo, Japan) (Shimada et al. 2001). The proliferative activity of cumulus cells was measured with a BrdU proliferation kit (Roche Molecular Biochemicals) as described in Okazaki et al. (2003). The follicular fluid was used for the analyses of testosterone, E2 and progesterone levels according to our previous study (Shimada & Terada 2002, Shimada et al. 2002).
In vivo maturing COCs
Landrace sows (12–14 months old, about 150 kg) used for breeding were weaned at 28 days after farrowing. Estrus was induced by the injection of 1000 IU eCG at 24 h after weaning, followed 72 h later with 500 IU hCG. Estrus detection was performed twice a day (0900 and 1600 h), beginning 2 days after eCG administration, by allowing females to nose-to-nose contact with a mature boar and by applying back pressure. The treated gilts were slaughtered at 0, 6, 12, 24, or 48 h post-hCG injection and preovulatory follicles of more than 10 mm in diameter were aspirated with syringe for the collection of follicular fluid, granulosa cells, and COCs. Animals were treated according to the Animal Care and Use Committee at Hiroshima University.
Culture of COCs
Oocytes having evenly granulated cytoplasm with at least four layers of unexpanded cumulus oophorus cells were selected and washed thrice with maturation medium. The maturation medium was modified using NCSU37 (Petters & Reed 1991) containing 10% (v/v) FCS and 7 mM taurine (Sigma). Twenty COCs were cultured in 500 µl culture medium per well at 39 °C in a humidified atmosphere of 5% CO2 in air using Nunc 4-well multi-dishes (Nunc, Roskilde, Denmark). Some COCs were cultured with 20 ng/ml FSH and/or 1 µg/ml LH (plain one-step culture system, Okazaki et al. 2003). In other experiments, we used a two-step culture system as described by Shimada et al. (2003). Briefly, during the first step, COCs were cultured with or without 2.0 ng/ml FSH in the presence of 0.5 mM IBMX for 20 h. The cultured COCs were further cultured with 1 µg/ml LH. To investigate the additional effects of estrogen, COCs were cultured with IBMX, FSH, and 100 ng/ml E2 during the first step culture. Other COCs were cultured using a novel culture system. The COCs were cultured with IBMX, FSH, and E2, and 10 ng/ml of progesterone added to the medium at the 10-h point. The 20-h cultured COCs were washed twice by maturation medium and then were further cultured with 1 µg/ml LH, 1 ng/ml EGF, and 100 ng/ml progesterone for 24 h (novel culture system). The culture systems are shown in Fig. 1.
RT-PCR analysis
Total RNA was obtained from COCs or granulosa cells using the RNeasy mini kit (Qiagen sciences) according to the manufacturer's instructions, and semiquantitative RT-PCR analyses were performed as previously described (Shimada et al. 2004a). Briefly, total RNA was reverse transcribed using 500 ng poly-dT and 0.25 U avian myeloblastosis virus reverse transcriptase at 42 °C for 75 min and 95 °C for 5 min. LH receptor protein translated from the full-length LHCGR mRNA has physiological functions (Loosfelt et al. 1989). The other three splicing variants lack the putative transmembrane domain; however, they negatively regulate function of the receptor (Nakamura et al. 2004). Additionally, we detected the four types of LHCGR mRNA in cumulus cells of porcine COCs (Shimada et al. 2003). From these reports, we adopted a regular PCR method to detect LHCGR mRNA because the four splicing variant could not be detected by real-time PCR. Oligonucleotide primers used for the amplification of LHCGR were designed from known cDNA sequences of four porcine LHCGR isoforms (Loosfelt et al. 1989). The upstream primer (5'-CCAATCTCCTAGATGCCACATTGAC-3') is identical to nucleotides 861–885 of the porcine cDNA, while the downstream primer (5'-GCTCAGCAACAGAAAGAAATCCC-3') represents the reverse complement of nucleotides 1959–1981. This primer pair predicts 185, 411, 855, and 1121 bp fragments. β-Actin was used as a control for reaction efficiency and variations in concentrations of mRNA in the original RT reaction. Using the specific primer pairs, the cDNA products were amplified for 24 cycles (β-actin) or 32 cycles (LHCGR). The RT-PCRs were run with linear range. The amplified products were analyzed by 2% agarose gel electrophoresis. The intensity of the objective bands was quantified by densitometric scanning using a Gel-Pro Analyzer (Media Cybernetics, Bethesda, MD, USA).
Real-time RT-PCR analyses
cDNA and primers were added to 15 µl total reaction volume provided in the Power SYBR Green PCR Master Mix (Applied Biosystems, Foster City, CA, USA). The PCRs were then performed using the iCycler thermocycler (Bio-Rad Laboratories, Inc). Conditions were set to the following parameters: 10 min at 95 °C followed by 45 cycles of 15 s at 95 °C and 1 min at the annealing temperature. Each annealing temperature and specific primer pairs were selected and analyzed as indicated in Table 2.
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Statistical analysis
Data were tested for homogeneity of error variance by Bartlett's test before statistical analysis. Since heterogeneity of variance was not detected in this study, statistical analyses of all data from three or four replicates for comparison were carried out by analysis of one-way ANOVA followed by Duncan's multiple ranges test using STATVIEW (Abacus Concepts, Inc., Berkeley, CA, USA). All percentage data were subjected to arcsine transformation before statistical analysis. Values were determined to be significant when P<0.05.
Experimental designs
Experiment 1 was conducted to examine the time-dependent changes of follicular cell function during hormonally stimulated follicular development from the early antral stage to the preovulatory stage and during the ovulation process. Follicular fluid was used for analyses of the level of testosterone, E2 and progesterone. Total RNA was extracted from granulosa cells to analyze the expression of the genes encoding steroidogenic enzymes (aromatase (CYP19), P450scc (CYP11A1), and 3βHSD (HSD3B1)) and prostaglandin E biosynthesis (PTGS2), the EGF-like factors (AREG and EREG), a specific protease (TACE/ADAM17), and the gonadotropin receptors (FSHR and LHCGR). COCs were also collected from each follicle and used to analyze expression of selected genes involved in gonadotropin and progesterone reception (FSHR, LHCGR, and PGR), cumulus cell proliferation (cyclin D2; CCND2 and p21kip1, CDKN1B) and differentiation (ADAMTS1, HAS2, TNFAIP6, and PTGS2).
In experiment 2, we examined the effects of E2 and/or progesterone when added to the FSH-containing medium on cumulus cell proliferation and responses to LH in vitro. The gene expression pattern in cumulus cells of COCs cultured with FSH and LH as described in our previous study (Yamashita et al. 2007) was markedly different from that observed in vivo. Because we observed in the results of experiment 1, that testosterone was dominantly accumulated in small antral follicles whereas E2 was increased rapidly during follicular development, and that increased production of progesterone occurred later within preovulatory follicles, steroids were added to the culture medium to mimic these changes. Specifically, COCs recovered from small antral follicles were cultured with FSH and E2, and progesterone was added to the medium at 10 h of culture point. Total RNA was recovered from the COCs at 10 or 20 h of culture, and then used for RT-PCR analysis. The proliferative activity of cumulus cells were examined using BrdU proliferation kit. All the media contained 0.5 mM of IBMX to block spontaneous resumption of meiosis in the oocytes.
Experiment 3 was performed to investigate the functional activities of COCs cultured using the novel culture system as described in Fig. 1. Total RNA was recovered from the COCs at each culture point, and then used for RT-PCR analysis. Protein samples were used for Western blotting to detect the accumulation of ADAMTS1 within COC. Expansion of the COC and apoptosis of cumulus cells within the COCs were analyzed after 44 h. Some COCs cultured for 44 h were used for in vitro fertilization, and the gametes were cultured in vitro to develop to blastocyst stage.
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Footnotes |
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Received 16 February 2008
First decision 15 April 2008
Revised manuscript received 14 March 2008
Accepted 23 April 2008
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References |
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