2. 北京市农林科学院-美国俄克拉荷马州立大学动物科学联合实验室, 北京 100097;
3. 甘肃农业大学动物科学技术学院, 兰州 730070
2. Joint Laboratory of Animal Science between IAHVM of BAAFS and Division of Agricultural Science and Natural Resource of Oklahoma State University, Beijing 100097, China;
3. College of Animal Science and Technology, Gansu Agricultural University, Lanzhou 730070, China
随着我国养猪业的快速发展和产业结构的不断升级，繁殖效率在生猪生产中具有越来越重要的意义[1]。批次化生产因其可以提高母猪繁殖效率，在养猪业中的运用也越来越广泛[2-3]，尤其是非洲猪瘟流行以来，越来越多的场户选择批次化生产模式。该生产模式的核心是定时输精技术，即用孕马血清促性腺激素(pregnant horse serum gonadotropin，PMSG)增加母猪排卵数，利用促性腺激素释放激素(gonadotrophin releasing hormone，GnRH)同期排卵，但PMSG的应用在增加排卵数的同时导致子宫内膜容受性下降，使得排卵数增多的优势未能转化为产仔数[4-5]。产仔数损失的主要原因是由于胚胎未成功附植以及异常发育造成的妊娠期胚胎死亡[6]，有学者认为在自然状态下75%妊娠失败的主要原因之一是子宫内膜容受性不足导致的胚胎着床失败[7-8]。胚胎着床的基础是胎儿与母体之间持续不断的交流即母胎对话(maternal-fetal dialogue)[9-11]，而异常的母胎对话通常会造成附植失败[12]。母胎对话是母体子宫为适应妊娠过程和为胚胎附植提供理想环境，以及胚胎为了同步子宫环境的变化保证附植成功双方互相交流实时建立的一种对话关系。而猪的胚胎附植是一种在整个妊娠过程中胚胎都不侵入子宫内膜特殊的附植方式，即猪胚胎滋养层细胞不会与母体供应的血液接触[13-15]。这种特殊的附植方式使得猪妊娠期依赖于信号分子(黏附因子和细胞因子等)通过旁分泌、自分泌和邻分泌3种主要信号通路进行母胎对话[16]。
本文主要以猪为模式动物通过对胚胎附植前后母体与胎儿间相关激素、黏附因子、细胞因子等方面综述猪母胎对话的内容及其调控途径，以期为猪母胎对话的研究和产仔数的提高提供参考依据。
1 胚胎附植前的母胎对话胚胎附植的前提条件是妊娠识别，在这一期间母体与胚胎间的对话主要通过生殖激素信号实现[17]。妊娠识别的激素信号主要包括子宫以及囊胚滋养层合成的雌激素(estrogen)与孕激素(progestogen)，其是母体与胚胎交流和正常妊娠的必要条件[18]。从猪妊娠的第11天开始，囊胚合成并分泌雌二醇(estradiol，E2)以刺激子宫内膜腺体细胞合成前列腺素F2α(prostaglandin F2α，PGF2α)并释放在子宫腔中[19]。另外母体子宫在第11~13天也会合成释放雌激素从而调节营养和PGF2α进入子宫腔，延长黄体周期，促进妊娠识别[20]。也有研究证明，E2对于附植前胚胎的发育和早期黄体维持是非必要的，因子宫内膜及子宫肌层也能合成E2，当子宫环境E2不足时，机体会以这种合成方式进行补偿[21-22]。
胚胎的数量对于母猪维持妊娠也具有重要作用，Polge等[23]研究发现需要4个以上的胚胎才能达到与母体激素相对平衡的状态并继续妊娠，当胚胎数量不足时无法对抗黄体的溶解作用，导致妊娠识别失败和妊娠终止。并且每个子宫角中必须存在至少两个胚胎，才能建立和维持妊娠[15]。所以在胚胎附植前，胚胎已经通过激素等信号与母体进行对话，保证母体成功进行妊娠识别，为其后续附植提供相应的条件。此外，部分基因在猪母胎识别中也具有重要作用，例如整合素(ITG)、连接蛋白(CXs)和白细胞介素1B(IL1B)等基因可通过调控识别过程中的重要激素保证识别的正常进行[17]。
2 胚胎附植期间及附植后的母胎对话由于猪胎盘的特殊性在胚胎黏附后并不会侵入子宫且不形成蜕膜，而是子宫腔上皮与胚胎滋养层细胞部分融合，开始建立母体与胎儿间的联系。猪胚胎附植在妊娠后第10~13天开始[24]，在此期间胚胎与母体间通过对话调整并满足胚胎附植的条件以此保证妊娠进行。胚胎附植期的母胎对话涉及很多附植因子，如激素及其受体、生长因子、细胞外囊泡等，这些因子共同发挥作用促进胚胎着床(图 1)。
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图 1 猪胚胎附植期母胎对话图 Fig. 1 Maternal-fetal dialogue during porcine embryo implantation |
2.1.1 孕酮及雌二醇对胚胎附植期间母胎对话的影响 胚胎的成功附植离不开胚胎发育与子宫内膜的增殖分化，这两个过程都受到母体激素的调控，主要以E2和孕酮(progesterone，P4)为主。附植期P4可以刺激子宫内膜分泌各种物质促进胚胎发育和胎盘形成[9]。另外当猪胚胎植入时母体会产生免疫反应从而激活子宫内膜中的炎症途径，子宫内膜会进一步增加P4分泌诱导子宫内膜容受性增加以此响应胚胎信号[25]。在猪妊娠期E2在第11~12天附植前期以及第15~25天附植中期出现两个分泌高峰，说明子宫内附植的胚胎也可以分泌E2[26-27]。
在人上研究发现，子宫容受性的建立受到卵巢雌激素和孕激素的调控，雌激素促使子宫内膜发育，孕激素将子宫内膜的发育状态转变为容受状态使胚胎可以正常附植[28]。雌激素和孕激素的适当平衡是调节子宫容受性的微妙机制[29]。另外，雌激素和孕激素可以协同调节子宫内膜蛋白的表达调控子宫内膜容受性[30]。在小鼠上研究证明，过量的P4会造成子宫上皮的细胞因子水平异常导致胚胎植入失败[31]，例如下调子宫白血病抑制因子(leukemia inhibitory factor，LIF)的表达抑制胚胎附植[32]。但E2与P4的协同作用对子宫内膜的调控作用在猪上报道较少，有待进一步研究。
2.1.2 PGF2α、PGE2和PGI2对胚胎附植期间母胎对话的影响 前列腺素通过促进子宫内膜血管的重塑及发育在胚胎附植中发挥作用，主要包括前列腺素E2(prostaglandin E2，PGE2)、前列环素I2(prostacyclin I2，PGI2)以及PGF2α。PGE2被认为是子宫内膜中胚胎信号的传导介质[25]，通过介导子宫内膜中血管内皮生长因子(vascular endothelial growth factor，VEGF)的合成促进子宫内膜血管的发育[33]，在附植前后其增加可以刺激PGE2受体(PTGER2)表达从而增加猪胚胎信号E2的合成和分泌，并通过整合素促进滋养层细胞黏附[24]。PGI2也是胚胎附植期母胎对话的一个重要内容[24]。一方面其在猪妊娠过程中的合成量增加，通过血管扩张和抑制血小板聚集促进子宫血流增加[34-36]，另一方面在附植期PGI2的合成及其受体PTGIR的表达可以促进猪胎盘滋养层细胞增殖和黏附[37]。同时由于PGI2对猪黄体组织中的P4合成分泌具有刺激作用，推测其可能有类似于PGE2和PGF2α维持黄体的作用[38]。
PGF2α由于其有促进黄体退化的作用在早期被认为是一种不利于妊娠的因素，但在胚胎附植期PGF2α在子宫内膜的合成量会增加[39]。有研究发现，PGF2α通过其在猪妊娠过程中子宫内膜上的受体作为胚胎信号促进血管生成和调节子宫内膜重塑及胚胎母体对话相关基因的表达，参与妊娠的建立[40]。另外有学者研究发现，PGF2α也会通过诱导猪胚胎滋养细胞中的基因转录发生改变进而影响植入过程[41]。
2.1.3 细胞因子对胚胎附植期间母胎对话的影响 细胞因子包括白细胞介素(interleukins，IL)、干扰素(interferons，IFN)、趋化因子(chemokines)、集落刺激因子和肿瘤坏死因子等，最初认为细胞因子只会影响免疫细胞[42]，随后被证明在胚胎附植过程中也发挥重要作用[43]。
在胚胎附植期间子宫的结构会发生变化，这些变化受到生长因子(表皮生长因子、转化生长因子α、胰岛素生长因子、血管内皮生长因子等)的调节[24]。通常子宫内膜组织产生的生长因子会通过自分泌和旁分泌的形式参与妊娠，促进胚胎的发育及子宫上皮组织结构的变化[44-45]。有研究表明，表皮生长因子受体在猪妊娠期间表达，促进子宫内膜间质细胞与腺细胞生成前列腺素，转化生长因子α也参与这一过程[46-47]。血管内皮生长因子及其受体存在于子宫内膜中，在着床期间表达升高并参与猪子宫内膜血管系统发育进而调节血管通透性[33, 48]。也有研究发现，PGF2α通过与其配体结合促进VEGFA表达诱导猪子宫内膜血管生成与组织重塑[40]。肝素结合生长因子(heparin-binding epidermal growth factor，HB-EGF)是表皮生长因子家族成员之一，在猪黄体发育第4天和妊娠第15~22天子宫内膜高表达，其可以协同激活PI3K-AKT1和ERK1/2MAPK-P90RSK细胞信号通路刺激猪原代胚胎滋养层细胞的增殖与迁移，在胚胎附植过程中发挥作用[44, 49-50]。
妊娠的成功建立需要母胎免疫耐受达到平衡状态，这种平衡状态是指母体的免疫系统对于胚胎产生免疫耐受，而胚胎附植过程中胚胎与母体间的免疫因子交流有利于达到这种平衡状态并促进胚胎正常附植，参与这一对话的促炎因子包括IL、IFN等[51-52]。白细胞介素-1(interleukin-1，IL-1)及其信号系统在胚胎附植期表达[53-54]，除IL-1外猪还存在有IL1β1和IL1β2两种亚型，具有增加子宫内膜容受性和促进附植的作用，并且IL1β1可以增加PGE2的合成[55-56]。有研究证明，LIF在猪的胚胎附植启动阶段在子宫内膜中表达上调，IL-6和LIF可以通过刺激猪胎盘滋养层细胞增殖和黏附在胚胎附植过程中发挥作用，但其对子宫内膜发挥作用的机制目前尚不清楚[57-58, 22]。IFN分为I型和II型，已有研究证明在猪胎盘滋养层中的IFN-γ能够调控参与子宫内膜与滋养层细胞交流的趋化因子(CCL2、CCL5、CCL11和CXCL12)的表达[59-60]。
2.1.4 细胞外囊泡对胚胎附植期间母胎对话的影响 细胞外囊泡(extracellular vesicle，EVs)是细胞间交流的有效载体，包括外泌体、凋亡小体及微囊泡等，在人、猪、鼠、牛、羊中均发现其与早期妊娠相关，主要通过来源于胚胎、胎盘、子宫内膜等的EVs介导母胎对话[15, 61]。miRNAs在胚胎附植期间发挥重要作用，研究发现猪在妊娠与未妊娠、胚胎着床、胎盘植入和妊娠中期的miRNAs表达模式都有所不同[62-63]。目前报道对猪胚胎附植有调控作用的miRNAs有miR-204、miR-199a-5p、miR-451、miR-199b-5p、miR-181a、miR-181c和miR-125b[64]，而外泌体可以携带miRNA和蛋白质介导胚胎与母体间的信息交流[62]，Bidarimath等[65-66]研究证明miRNA与蛋白质会被子宫内膜细胞包裹经外泌体运输至子宫腔液最终到达滋养层细胞发挥调控胚胎附植作用。但EVs携带蛋白质在猪胚胎附植过程中介导对话的报道较少[67]，EVs以何种机制将特定miRNAs运输至母胎界面的特定细胞还不清楚[68]。
2.1.5 相关基因和蛋白质对胚胎附植期间母胎对话的影响 与猪胚胎附植过程相关的基因有HB-EGF、瘦素受体基因(OB-R)等，另外曹永芝[69]研究发现hmga2基因在胚胎附植期呈现规律性变化，表明其在这一过程中发挥一定作用。同时在胚胎附植过程中猪胚胎在形态上发生剧烈变化，成纤维细胞生长因子4(fgf4)、IL1β2和IFN能够通过对胚胎发育及形态变化的调控参与胚胎附植过程[70]。
目前已有研究证明, 酪氨酸激酶家族中的促红细胞生成素产生肝细胞激酶(erythropoietin producing hepatocyte kinase，Eph)受体与其结合配体Ephrin形成的Eph-ephrin系统参与猪的胚胎附植过程，并且控制这一系统的基因参与调节胚胎附植期间胚胎对子宫的黏附，Ephrin A1是这一系统中重要的配体基因，该基因的表达可能在猪胚胎附植后期参与基因调控[71-76]。综上所述，虽然这一系统及相关基因已被发现参与胚胎附植过程，但具体分子调控机制仍需进一步研究。
在胚胎附植过程中一些蛋白质如视黄醇结合蛋白(retinol binding protein 4，RBP 4)、转甲状腺素蛋白(transthyretin，TTR)、促动力素1(prokineticin 1，PROK1)等也会参与这一过程。视黄醇结合蛋白4通过参与子宫内膜上皮和间质细胞的增殖、迁移和凋亡进而参与母猪胚胎的附植过程[77]。转甲状腺素蛋白在猪妊娠第12天的子宫内膜上表达量最高，通过对甲状腺素与视黄醇的转运参与胚胎附植过程。促动力素1是一种11-kDa分泌蛋白，表达受到E2与PGE2的协同调节，有PROKR1和PROKR2两个受体，但在子宫内膜中PROKR1比PROKR2表达水平高[78]。PROK1及其受体PROKR1一方面通过增加猪滋养层细胞中细胞因子在胚胎粘附和早期胎盘形成期间的表达从而调节免疫反应和子宫中促炎环境参与植入过程，另一方面通过刺激猪原代内皮细胞增殖和毛细管样结构的形成影响子宫内膜血管生成参与附植过程。另外也会通过增加VEGFA及PGF2α的分泌间接参与附植过程[79-80]。说明PROK1在胚胎附植过程中会通过多途径促进胚胎附植[78]。另外，祁梦凡等[81]通过对妊娠第15天与未妊娠的母猪外周血液中蛋白表达研究筛选出端粒重复结合因子2、结合珠蛋白、脂联素和细丝蛋白C四种差异蛋白，推测其可作为胚胎附植的潜在标志物。
2.1.6 其他 除上述因素外，参与胚胎附植过程的还有黏附因子、醛糖还原酶(aldose reductase，ALDR)、透明质酸(HA)等。黏附因子在胚胎附植期间发挥主要作用的分子是整合素(integrins)，其是细胞表面受体家族成员之一。母猪子宫内膜局部分泌整合素β1不足可能会导致子宫内膜功能成熟延迟，内膜容受性下降从而导致着床失败[82]。ALDR会随着妊娠发生变化，与妊娠第9天相比，妊娠第12天其表达量增加9倍左右，ALDR除了抗氧化作用外还可以通过调控前列腺素参与调节子宫容受性和胚胎着床[83]。
HA是一种糖胺聚糖，其存在于胚胎与母体界面处导致子宫内膜接受度降低并抑制滋养层与子宫腔内上皮的相互作用，HA的清除有利于胚胎附着[84]。HA对于胚胎附着的不利影响在人和其他动物上都已有研究报道[84-85]，在猪上还需进一步研究。另外，有研究发现在猪的不同妊娠状态和时期子宫内膜中的聚糖类型有所不同，在妊娠第12、15天存在有大量中性和酸性聚糖，并且其中与酸性聚糖合成相关的糖基转移酶基因的表达存在显著差异，表明这种基因对于猪的胚胎附植也具有调控作用[86]。
2.2 胚胎附植后的母胎对话胎盘是母体和胎儿间交流的平台，胚胎附植后母体与胎儿之间形成胎盘，并通过胎盘进行气体、营养及代谢物交流[87]。胎儿对养分的需求信号主要通过胎盘营养感应和养分分配系统进行调控，包括mTOR、AMPK和IIS信号通路等[88]。胎盘通过这些信号通路调控氨基酸、脂肪和蛋白质等营养的运输，以保证胎儿的正常发育和母体健康[89]。
3 小结综上所述，母体与胎儿间的母胎对话通过不同的信号分子、信号通路发生在整个妊娠期以保证胎儿的正常发育。在胚胎附植前胚胎会释放一定量的雌激素使母体接受到妊娠信号防止黄体溶解造成妊娠失败；胚胎附植期间子宫容受性与胚胎需同步发育，母体与胚胎之间通过多种信号因子及信号通路相互调节促进胚胎成功附植；胚胎附植后母体与胎儿之间通过胎盘开展对话协调母体与胎儿间以及各胎儿间的养分分配，保证胎儿的正常发育。母体与胎儿的对话贯穿整个妊娠期对于胎儿发育和母体健康十分重要，母胎对话的内容和调控网络十分复杂，近期发现的细胞外囊泡及其运输miRNAs也介导了妊娠期的母胎对话，这些均需进一步研究。猪妊娠期的母胎对话十分重要，如果在妊娠前期出现对话异常会造成胚胎附植失败，后期则会造成胎儿发育不良等，从而引起产仔数下降和经济效益降低。所以在已有研究的基础上，如何保证猪妊娠期正常的母胎对话、母胎对话过程的调控以及相关机制是未来研究的方向。
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(编辑 郭云雁)