白细胞介素6及其受体在绵羊早期胚胎中的表达和作用研究
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摘要
细胞因子及其受体在哺乳动物胚胎和同一时期母体中的转录和表达模式近年来得到了广泛的研究,对其在胚胎发生过程中功能的发挥以及调节有了深入的了解。白细胞介素-6(Interleukin-6, IL-6)是一种多功能的细胞因子,有研究表明在生理状况下IL-6参与调节排卵、着床、胚胎发育等生殖过程。本研究通过免疫荧光化学、实时定量PCR及蛋白印迹检测等分子生物学技术,结合体外受精技术,观察了白细胞介素6及其受体在绵羊卵母细胞和早期胚胎发育过程中的表达情况；在发育培养液中添加不同剂量的IL-6,观察了其对卵母细胞和胚胎发育的影响；并采用RNAi技术,对绵羊体外受精卵进行siRNA注射,进一步探讨IL-6及其受体在绵羊早期胚胎发育中的作用,为研究绵羊胚胎早期发育机理提供一定的试验依据。
一IL-6和IL-6R在绵羊卵母细胞和体外受精早期胚胎中的表达
实时定量PCR结果表明,IL-6和IL-6R mRNA在绵羊卵母细胞和体外受精胚胎发育的各个时期中均有表达。在卵母细胞成熟过程中,IL-6在成熟培养4h呈现显著升高,随后则降低,而在16-20h时重新升高；IL-6R在成熟培养早期(0h-8h)表达量较高,4h最高,之后降低。在体外受精胚胎发育过程中,IL-6在2-细胞期胚胎中表达量低,到桑椹胚和囊胚期时达到最高,分别是2-细胞期含量的3.51倍、5.16倍、26.10倍和43.16倍。IL-6R与IL-6表达模式相似,在2-细胞期的表达量较低,在桑椹胚和囊胚中的表达量较高且差异显著。
免疫荧光检测结果显示,在绵羊卵母细胞和体外受精的各个发育时期的胚胎中,IL-6和IL-6R蛋白均有表达,在体外成熟过程中IL-6和IL-6R表达部位基本一致,并主要分布在细胞膜区域及膜下区域,在细胞质中分布很少,而在细胞核中未检测到；在早期胚胎发育过程中,IL-6中主要在细胞质中表达,而IL-6R则集中在细胞膜附近。通过蛋白印迹检测发现IL-6和IL-6R蛋白在绵羊卵母细胞和体外受精胚胎发育的各个时期中均有表达且表达规律与其转录水平相似。在绵羊卵母细胞成熟过程中,IL-6和IL-6R蛋白的相对表达量在成熟培养4h左右呈现显著升高,随后则降低；而在20-24h时卵母细胞中IL-6的表达重新升高；在早期胚胎中其表达量较低,在桑椹胚和囊胚中的表达量较高,且差异显著。
二IL-6对绵羊早期胚胎发育的影响
在成熟培养液中分别添加10、50、100ng/mL的重组人IL-6,不添加IL-6组为对照组,另一个对照组用10%发情羊血清(OES)代替BSA。结果表明添加10ng/mL IL-6与BSA对照组相比可显著提高核成熟率(P<0.05),与OES组成熟率相近,但不影响后续体外受精胚胎的发育率。添加50ng/mL IL-6成熟率与BSA对照组相比变化不大。而添加100ng/mL IL-6使核成熟率,囊胚率和孵化囊胚显著降低(P<0.05)。结果表明低浓度的IL-6可能促进了卵母细胞的核成熟,而高浓度对卵母细胞成熟和之后胚胎发育有一定的抑制作用。
发育培养液中分别添加10、50、100ng/mL的重组人IL-6,不添加IL-6组为对照组。结果表明添加10ng/mL IL-6组卵裂率显著升高(P<0.05),而添加100ng/mL IL-6组卵裂率、囊胚率和孵化囊胚显著降低(P<0.05)。推测低浓度的IL-6可能对于胚胎发育有一定的促进作用。而添加100ng/mL IL-6严重影响了绵羊早期胚胎的发育,可能高浓度的IL-6对于胚胎发育有一定毒性。
三发育培养液中添加IL-6对IL-6和IL-6R相对表达量的影响
在发育培养液中分别添加10、50、100ng/mL的IL-6,添加组与对照组相比发现胚胎中IL-6mRNA含量明显增加(P<0.05),而IL-6R mRNA表达量到桑椹胚和囊胚期才有明显的增加(P<0.05)。蛋白印迹实验表明,与对照组相比,胚胎中IL-6和IL-6R蛋白表达量均有增加,50ng/mL添加组蛋白含量增加明显。
四显微注射IL-6dsRNA对IL-6和IL-6R相对表达量的影响
将IL-6siRNA和Non-Targeting siRNA分别注入绵羊体外受精卵,以未注射组为对照组。IL-6siRNA注射组、Non-Targeting siRNA注射组和未注射对照组的卵裂率分别为77.07%、76.81%、78.05%,siRNA处理组与Non-Targeting siRNA注射组和未注射组之间囊胚发育率无显著差异(P<0.05),表明IL-6的降低对于绵羊早期胚胎的发育没有明显影响。
通过Real-time PCR方法检测,与对照组相比,当胚胎发育到桑椹胚期时IL-6mRNA含量下降了69.63%,而到囊胚期时IL-6及IL-6RmRNA含量分别下降了87.45%和71.77%；而Non-Targeting siRNA的IL-6和IL-6RmRNA含量与未注射的对照组基本一致。同时检测到作为对照的β-actin基因的mRNA水平则在各组中基本保持一致,表明体外合成的siRNA并未对其它对照基因mRNA的表达产生影响,能够特异而有效的降低目的基因的水平。
蛋白免疫印迹检测实验结果表明,注射siRNA的方法有效消减了IL-6的蛋白水平,从8-cell到囊胚期干扰效果明显,IL-6R蛋白也随着IL-6下降而下降。因此,向绵羊体外受精卵中注射IL-6siRNA能够使IL-6和IL-6R的mRNA及蛋白含量下降并持续到囊胚期。
综上所述,IL-6和IL-6R在绵羊体外受精胚胎发育的各个时期均有表达,其分布有规律性。在成熟培养液中添加10ng/mL IL-6能够促进绵羊卵母细胞核成熟,但不影响后续的胚胎发育；在发育培养液中添加10ng/mL IL-6能够促进绵羊早期胚胎的卵裂。显微注射IL-6siRNA能够有效消减胚胎中IL-6及其受体的mRNA及蛋白的表达,但不影响绵羊体外受精胚的发育率。IL-6可能在绵羊卵母细胞成熟和早期胚胎发育过程中起着重要的作用。
In recent years, the transcription and expression patterns of cytokines and their receptors in mammalian embryos and the dams during embryonic development, have been extensively studied. Significant progress has then also been made toward understanding the functions and regulation during embryogenesis. Interleukin-6(IL-6) is a multifunctional cytokine, being involved in the regulation of ovulation, implantation, embryonic development, and other reproductive processes under normal physiological conditions. In this study, the expression of IL-6and IL-6R was evaluated during early ovine embryonic development, using immunohistochemistry, real-time quantitative PCR and protein blotting. The impacts of IL-6on embryonic development were evaluated via the supplementation with IL-6, using different concentrations in the embryo culture medium. The roles of IL-6and IL-6R in early ovine embryonic development were further investigated through RNAi-mediated inhibition. The present study could thus provide an experimental basis for the study of the mechanisms underlying early ovine embryonic development.
1. The expression patterns of IL-6and IL-6R during the development of the ovine oocytes and IVF embryos
The real-time quantitative PCR results illustrate the expression patterns of the IL-6and IL-6R mRNAs at different developmental stages of the ovine oocytes and IVF embryos. IL-6and IL-6R were expressed significantly at higher levels in the maturation around4h, and then decreased dramatically. However the level slightly elevated at16h-20h. IL-6R was expressed at a high level in the early maturation oocytes from Oh to8h and significantly higher levels at4h oocytes, and then showed lower expression levels. IL-6was expressed at a low level in the2-cell embryos-which level was set at1, and reached its peak expression at the morula and blastocyst stages. IL-6R showed a similar expression pattern to IL-6, with a lower expression level at the2-cell stage and significantly higher levels at the morula and blastocyst stages.
The immunohistochemistry results demonstrate the expression of IL-6and IL-6R at different developmental stages of the ovine oocytes and IVF embryos. The cellular distribution of IL-6and IL-6R expression was similar in the ovine oocytes at each maturation stages. Their expression was mainly localized on the cell membrane, with little expression in the cytoplasm and none in the nucleus. However in the IVF-derived ovine embryos, the expression of IL-6was mainly localized on the cytoplasm, IL-6R was concentrated much more on the cell membrane. Protein blotting showed that IL-6and IL-6R were expressed in the IVF-derived ovine embryos at each developmental stage. The expression patterns were consistent with the levels of transcription. IL-6protein showed higher expression levels at4h-8h and then decreased at12-16h. However the level slightly elevated at20h-24h of the immature stage. The level of IL-6R protein is significantly higher at4h, and then showed lower expression. Both proteins showed lower expression levels at the early embryonic stages, and significantly higher levels at the morula and blastocyst stages. The levels of IL-6and IL-6R were higher at the blastocyst than at the morula stage. In conclusion, IL-6may influence the initiation of oocytes meiotic and the subsequent meiotic process, thereby act on the ovine oocytes maturation.
2. Effects of IL-6on embryonic development
IL-6was added to the oocyte maturation medium at a concentration of10,50and100ng/mL respectively, the samples without exogenous IL-6were used as a control, and in another control10%ovine estrus serum (OES) was instead of BSA The results showed that the maturation rates significantly increased in the10ng/mL IL-6group compared with the BSA control group (P<0.05), and were similar to the OES control group, but did not affect the rates of development of the subsequence IVF ovine embryos. No significant difference was observed in the50ng/mL IL-6groups. While the maturation rates, cleavage rates, blastocyst rates, and hatching blastocyst rates significantly decreased in the100ng/mL IL-6group.
Recombinant IL-6was added to the development culture medium at a concentration of10,50, or100ng/mL, while samples without exogenous IL-6served as the control. The cleavage rate significantly increased in the10ng/mL IL-6group (p<0.05), while the cleavage rate, blastocyst rate, and hatching blastocyst rate significantly decreased in the100ng/mL IL-6group (p<0.05). This finding suggests that low concentrations of IL-6may promote embryonic development._However, indicating the toxicity of high concentrations bf IL-6on embryonic development. After the micro-injection of IL-6dsRNA, no significant differences in the cleavage rate or blastocyst rate were recorded between the siRNA-injected group, the Non-Targeting siRNA-injected group, and the uninjected group.
3. Effects of supplementation IL-6to the development culture medium on the relative expression levels of IL-6and IL-6R.
IL-6was added to the development culture medium at a concentration of10,50, or100ng/mL. The IL-6mRNA level was significantly higher in the embryos of the IL-6groups, compared to the control group (p<0.05). The IL-6R mRNA level did not increase significantly, until the morula and blastocyst stages (p<0.05) were reached. Protein blotting experiments showed that compared to the control group, IL-6and IL-6R protein levels were increased in the embryos of the IL-6groups, with the most significant increase being in the50ng/mL IL-6group.
4. Effects of micro-injected IL-6siRNA on the relative expression levels of IL-6and IL-6R
The IVF ovine oocytes were micro-injected with IL-6siRNA or Non-Targeting siRNA and cultured along with the uninjected control oocytes. Real-time PCR showed that compared to the control group, the IL-6mRNA level decreased by69.6%in the IL-6siRNA-injected morula embryos. The levels of IL-6and IL-6R mRNA decreased by87.5%and71.8%in the IL-6siRNA-injected blastocyst embryos, respectively. The IL-6and IL-6R mRNA levels of Non-Targeting siRNA-injected group were similar to those of the control (uninjected) group. Meanwhile, the mRNA levels in the β-actin internal reference gene were similar between groups. These results suggest that the in vitro-synthesized siRNA can effectively and specifically decrease the expression of the target gene, without affecting the mRNA expression of other reference genes.
Protein blotting results illustrate that the micro-injection of siRNA effect was especially evident in the8-cell and blastocyst stages. IL-6R protein levels decreased as the IL-6level decreased. Therefore, the injection of IL-6siRNA into IVF ovine oocytes can decrease the mRNA and protein levels of IL-6and IL-6R, until the blastocyst stage.Therefore, the mRNA and protein expression of IL-6and IL-6R was effectively decreased.
In summary, IL-6and IL-6R were present at all the developmental stages of IVF-derived ovine embryos and exhibited distinct expression patterns. The addition of IL-6in the oocyte culture medium at10ng/mL promoted oocytes nuclear maturation, but did not affect the subsequence development of the IVF ovine embryos. The supplementation of the embryonic culture medium with10ng/mL IL-6promoted the cleavage of early stage ovine embryos. The micro-injection of IL-6siRNA also effectively reduced the embryonic mRNA and protein expression of IL-6and IL-6R, without affecting the development rate of the IVF-derived ovine embryos. IL-6as such likely plays an important role in the ovine oocytes maturation and early embryos development..
一IL-6和IL-6R在绵羊卵母细胞和体外受精早期胚胎中的表达
实时定量PCR结果表明,IL-6和IL-6R mRNA在绵羊卵母细胞和体外受精胚胎发育的各个时期中均有表达。在卵母细胞成熟过程中,IL-6在成熟培养4h呈现显著升高,随后则降低,而在16-20h时重新升高；IL-6R在成熟培养早期(0h-8h)表达量较高,4h最高,之后降低。在体外受精胚胎发育过程中,IL-6在2-细胞期胚胎中表达量低,到桑椹胚和囊胚期时达到最高,分别是2-细胞期含量的3.51倍、5.16倍、26.10倍和43.16倍。IL-6R与IL-6表达模式相似,在2-细胞期的表达量较低,在桑椹胚和囊胚中的表达量较高且差异显著。
免疫荧光检测结果显示,在绵羊卵母细胞和体外受精的各个发育时期的胚胎中,IL-6和IL-6R蛋白均有表达,在体外成熟过程中IL-6和IL-6R表达部位基本一致,并主要分布在细胞膜区域及膜下区域,在细胞质中分布很少,而在细胞核中未检测到；在早期胚胎发育过程中,IL-6中主要在细胞质中表达,而IL-6R则集中在细胞膜附近。通过蛋白印迹检测发现IL-6和IL-6R蛋白在绵羊卵母细胞和体外受精胚胎发育的各个时期中均有表达且表达规律与其转录水平相似。在绵羊卵母细胞成熟过程中,IL-6和IL-6R蛋白的相对表达量在成熟培养4h左右呈现显著升高,随后则降低；而在20-24h时卵母细胞中IL-6的表达重新升高；在早期胚胎中其表达量较低,在桑椹胚和囊胚中的表达量较高,且差异显著。
二IL-6对绵羊早期胚胎发育的影响
在成熟培养液中分别添加10、50、100ng/mL的重组人IL-6,不添加IL-6组为对照组,另一个对照组用10%发情羊血清(OES)代替BSA。结果表明添加10ng/mL IL-6与BSA对照组相比可显著提高核成熟率(P<0.05),与OES组成熟率相近,但不影响后续体外受精胚胎的发育率。添加50ng/mL IL-6成熟率与BSA对照组相比变化不大。而添加100ng/mL IL-6使核成熟率,囊胚率和孵化囊胚显著降低(P<0.05)。结果表明低浓度的IL-6可能促进了卵母细胞的核成熟,而高浓度对卵母细胞成熟和之后胚胎发育有一定的抑制作用。
发育培养液中分别添加10、50、100ng/mL的重组人IL-6,不添加IL-6组为对照组。结果表明添加10ng/mL IL-6组卵裂率显著升高(P<0.05),而添加100ng/mL IL-6组卵裂率、囊胚率和孵化囊胚显著降低(P<0.05)。推测低浓度的IL-6可能对于胚胎发育有一定的促进作用。而添加100ng/mL IL-6严重影响了绵羊早期胚胎的发育,可能高浓度的IL-6对于胚胎发育有一定毒性。
三发育培养液中添加IL-6对IL-6和IL-6R相对表达量的影响
在发育培养液中分别添加10、50、100ng/mL的IL-6,添加组与对照组相比发现胚胎中IL-6mRNA含量明显增加(P<0.05),而IL-6R mRNA表达量到桑椹胚和囊胚期才有明显的增加(P<0.05)。蛋白印迹实验表明,与对照组相比,胚胎中IL-6和IL-6R蛋白表达量均有增加,50ng/mL添加组蛋白含量增加明显。
四显微注射IL-6dsRNA对IL-6和IL-6R相对表达量的影响
将IL-6siRNA和Non-Targeting siRNA分别注入绵羊体外受精卵,以未注射组为对照组。IL-6siRNA注射组、Non-Targeting siRNA注射组和未注射对照组的卵裂率分别为77.07%、76.81%、78.05%,siRNA处理组与Non-Targeting siRNA注射组和未注射组之间囊胚发育率无显著差异(P<0.05),表明IL-6的降低对于绵羊早期胚胎的发育没有明显影响。
通过Real-time PCR方法检测,与对照组相比,当胚胎发育到桑椹胚期时IL-6mRNA含量下降了69.63%,而到囊胚期时IL-6及IL-6RmRNA含量分别下降了87.45%和71.77%；而Non-Targeting siRNA的IL-6和IL-6RmRNA含量与未注射的对照组基本一致。同时检测到作为对照的β-actin基因的mRNA水平则在各组中基本保持一致,表明体外合成的siRNA并未对其它对照基因mRNA的表达产生影响,能够特异而有效的降低目的基因的水平。
蛋白免疫印迹检测实验结果表明,注射siRNA的方法有效消减了IL-6的蛋白水平,从8-cell到囊胚期干扰效果明显,IL-6R蛋白也随着IL-6下降而下降。因此,向绵羊体外受精卵中注射IL-6siRNA能够使IL-6和IL-6R的mRNA及蛋白含量下降并持续到囊胚期。
综上所述,IL-6和IL-6R在绵羊体外受精胚胎发育的各个时期均有表达,其分布有规律性。在成熟培养液中添加10ng/mL IL-6能够促进绵羊卵母细胞核成熟,但不影响后续的胚胎发育；在发育培养液中添加10ng/mL IL-6能够促进绵羊早期胚胎的卵裂。显微注射IL-6siRNA能够有效消减胚胎中IL-6及其受体的mRNA及蛋白的表达,但不影响绵羊体外受精胚的发育率。IL-6可能在绵羊卵母细胞成熟和早期胚胎发育过程中起着重要的作用。
In recent years, the transcription and expression patterns of cytokines and their receptors in mammalian embryos and the dams during embryonic development, have been extensively studied. Significant progress has then also been made toward understanding the functions and regulation during embryogenesis. Interleukin-6(IL-6) is a multifunctional cytokine, being involved in the regulation of ovulation, implantation, embryonic development, and other reproductive processes under normal physiological conditions. In this study, the expression of IL-6and IL-6R was evaluated during early ovine embryonic development, using immunohistochemistry, real-time quantitative PCR and protein blotting. The impacts of IL-6on embryonic development were evaluated via the supplementation with IL-6, using different concentrations in the embryo culture medium. The roles of IL-6and IL-6R in early ovine embryonic development were further investigated through RNAi-mediated inhibition. The present study could thus provide an experimental basis for the study of the mechanisms underlying early ovine embryonic development.
1. The expression patterns of IL-6and IL-6R during the development of the ovine oocytes and IVF embryos
The real-time quantitative PCR results illustrate the expression patterns of the IL-6and IL-6R mRNAs at different developmental stages of the ovine oocytes and IVF embryos. IL-6and IL-6R were expressed significantly at higher levels in the maturation around4h, and then decreased dramatically. However the level slightly elevated at16h-20h. IL-6R was expressed at a high level in the early maturation oocytes from Oh to8h and significantly higher levels at4h oocytes, and then showed lower expression levels. IL-6was expressed at a low level in the2-cell embryos-which level was set at1, and reached its peak expression at the morula and blastocyst stages. IL-6R showed a similar expression pattern to IL-6, with a lower expression level at the2-cell stage and significantly higher levels at the morula and blastocyst stages.
The immunohistochemistry results demonstrate the expression of IL-6and IL-6R at different developmental stages of the ovine oocytes and IVF embryos. The cellular distribution of IL-6and IL-6R expression was similar in the ovine oocytes at each maturation stages. Their expression was mainly localized on the cell membrane, with little expression in the cytoplasm and none in the nucleus. However in the IVF-derived ovine embryos, the expression of IL-6was mainly localized on the cytoplasm, IL-6R was concentrated much more on the cell membrane. Protein blotting showed that IL-6and IL-6R were expressed in the IVF-derived ovine embryos at each developmental stage. The expression patterns were consistent with the levels of transcription. IL-6protein showed higher expression levels at4h-8h and then decreased at12-16h. However the level slightly elevated at20h-24h of the immature stage. The level of IL-6R protein is significantly higher at4h, and then showed lower expression. Both proteins showed lower expression levels at the early embryonic stages, and significantly higher levels at the morula and blastocyst stages. The levels of IL-6and IL-6R were higher at the blastocyst than at the morula stage. In conclusion, IL-6may influence the initiation of oocytes meiotic and the subsequent meiotic process, thereby act on the ovine oocytes maturation.
2. Effects of IL-6on embryonic development
IL-6was added to the oocyte maturation medium at a concentration of10,50and100ng/mL respectively, the samples without exogenous IL-6were used as a control, and in another control10%ovine estrus serum (OES) was instead of BSA The results showed that the maturation rates significantly increased in the10ng/mL IL-6group compared with the BSA control group (P<0.05), and were similar to the OES control group, but did not affect the rates of development of the subsequence IVF ovine embryos. No significant difference was observed in the50ng/mL IL-6groups. While the maturation rates, cleavage rates, blastocyst rates, and hatching blastocyst rates significantly decreased in the100ng/mL IL-6group.
Recombinant IL-6was added to the development culture medium at a concentration of10,50, or100ng/mL, while samples without exogenous IL-6served as the control. The cleavage rate significantly increased in the10ng/mL IL-6group (p<0.05), while the cleavage rate, blastocyst rate, and hatching blastocyst rate significantly decreased in the100ng/mL IL-6group (p<0.05). This finding suggests that low concentrations of IL-6may promote embryonic development._However, indicating the toxicity of high concentrations bf IL-6on embryonic development. After the micro-injection of IL-6dsRNA, no significant differences in the cleavage rate or blastocyst rate were recorded between the siRNA-injected group, the Non-Targeting siRNA-injected group, and the uninjected group.
3. Effects of supplementation IL-6to the development culture medium on the relative expression levels of IL-6and IL-6R.
IL-6was added to the development culture medium at a concentration of10,50, or100ng/mL. The IL-6mRNA level was significantly higher in the embryos of the IL-6groups, compared to the control group (p<0.05). The IL-6R mRNA level did not increase significantly, until the morula and blastocyst stages (p<0.05) were reached. Protein blotting experiments showed that compared to the control group, IL-6and IL-6R protein levels were increased in the embryos of the IL-6groups, with the most significant increase being in the50ng/mL IL-6group.
4. Effects of micro-injected IL-6siRNA on the relative expression levels of IL-6and IL-6R
The IVF ovine oocytes were micro-injected with IL-6siRNA or Non-Targeting siRNA and cultured along with the uninjected control oocytes. Real-time PCR showed that compared to the control group, the IL-6mRNA level decreased by69.6%in the IL-6siRNA-injected morula embryos. The levels of IL-6and IL-6R mRNA decreased by87.5%and71.8%in the IL-6siRNA-injected blastocyst embryos, respectively. The IL-6and IL-6R mRNA levels of Non-Targeting siRNA-injected group were similar to those of the control (uninjected) group. Meanwhile, the mRNA levels in the β-actin internal reference gene were similar between groups. These results suggest that the in vitro-synthesized siRNA can effectively and specifically decrease the expression of the target gene, without affecting the mRNA expression of other reference genes.
Protein blotting results illustrate that the micro-injection of siRNA effect was especially evident in the8-cell and blastocyst stages. IL-6R protein levels decreased as the IL-6level decreased. Therefore, the injection of IL-6siRNA into IVF ovine oocytes can decrease the mRNA and protein levels of IL-6and IL-6R, until the blastocyst stage.Therefore, the mRNA and protein expression of IL-6and IL-6R was effectively decreased.
In summary, IL-6and IL-6R were present at all the developmental stages of IVF-derived ovine embryos and exhibited distinct expression patterns. The addition of IL-6in the oocyte culture medium at10ng/mL promoted oocytes nuclear maturation, but did not affect the subsequence development of the IVF ovine embryos. The supplementation of the embryonic culture medium with10ng/mL IL-6promoted the cleavage of early stage ovine embryos. The micro-injection of IL-6siRNA also effectively reduced the embryonic mRNA and protein expression of IL-6and IL-6R, without affecting the development rate of the IVF-derived ovine embryos. IL-6as such likely plays an important role in the ovine oocytes maturation and early embryos development..
引文
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