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通讯作者:

邵璇(1983-),男,河北保定人,副研究员,主要从事胎盘发育和妊娠适应性调节机制的研究。E-mail:shaoxuan@ioz.ac.cn。朱玥霖,李倩倩为共同第一作者

中图分类号:R321.4

文献标识码:A

文章编号:2096-8965(2022)04-0022-08

DOI:10.12287/j.issn.2096-8965.20220403

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目录contents

    摘要

    胎盘是妊娠期间胎儿和母体之间的桥梁,具有血流灌注、物质交换、免疫耐受和妊娠适应性调节等功能,对保障胎儿发育和母体健康发挥关键作用。胎盘发育不良与子痫前期等妊娠疾病密切相关。在本文中,我们总结了人类滋养层细胞分化和胎盘功能单元构建的最新研究进展,并讨论了可能导致子痫前期发病的因素。

    Abstract

    Serving as the interface between the fetal and maternal environment during gestation, the placenta plays critical roles in the protection of the developing fetus and the maintenance of pregnancy. The placenta is responsible for blood perfusion and maternal-fetal material exchange, immune tolerance, and the regulation of pregnancy adaptation. Defects in placental development and functional maintenance are in tight association with adverse pregnancy outcomes such as preeclampsia. In this article, we reviewed recent advances on human trophoblast cell differentiation and the construction of placental functional units and discuss the pathogenic factors that may contribute to the occurrence of preeclampsia.

  • 0 前言

  • 胎盘是妊娠期特有的临时性、多功能器官,对母体健康和胎儿发育具有重要意义。胎盘的形成依赖于胎盘滋养层细胞的有序分化,及其与母胎界面众多母体细胞的相互作用,从而形成胎盘的多个功能单元。胎盘是母胎营养交换的场所,负责母胎间的气体、营养物质和代谢废物的交换;同时它是一个内分泌器官,分泌多种对妊娠维持有重要作用的激素、生长因子、细胞因子等;此外,胎盘还具有免疫屏障功能,保护胎儿免受母体的免疫攻击[1]。然而,滋养层细胞的发育分化和/或功能损伤与子痫前期等多种妊娠疾病直接相关,因而阐明胎盘发育的调控机制是预测或干预妊娠疾病的重要途径。本文将对人类胎盘发育、滋养层细胞分化以及胎盘功能单元进行简要介绍,并探讨胎盘发育失调导致子痫前期发生发展的机制。

  • 1 胎盘发育

  • 胎盘发育起始于囊胚期的滋养外胚层 (Trophectoderm,TE)。在受精后第6-7天,靠近内细胞团 (Inner Cell Mass,ICM) 的 TE 形成初级合胞体,并迅速侵入子宫内膜;受精后第14天左右,囊胚完全植入子宫内膜,滋养层细胞也开始了复杂的分化。人类滋养层主要有两种分化途径:绒毛滋养层细胞 (Villous Trophoblasts,VTs) 和绒毛外滋养层细胞 (Extravillous Trophoblasts,EVTs)。VTs 主要包括单核的细胞滋养层细胞 (Cytotrophoblast, CTB) 和多核的合体滋养层细胞 (Syncytiotro-phoblast,STB)。EVTs 主要包括间质绒毛外滋养层细胞 (interstitial EVTs,iEVTs) 和血管内绒毛外滋养层细胞 (endovascular EVTs,enEVTs)。

  • 1.1 绒毛滋养层细胞分化途径

  • 在绒毛滋养层细胞分化途径中,单核CTB融合形成多核 STB,覆盖在胎盘绒毛表面,浸泡在绒毛间隙 (Intervillous Space,IVS) 的母血中[23],构成绒毛的初级结构。CTB 表达特异性转录因子 Yes 相关蛋白 1(Yes1 Associated Protein,YAP1)、TEA 结构域转录因子 4(TEA Domain Transcription Factor 4, TEAD4)、尾型同源异型盒基因 2(Caudal Type Homeobox 2,CDX2)、肿瘤蛋白 p63(Tumor Protein p63,TP63)、E74 样 ETS 转录因子 5(E74 like ETS Transcription Factor 5,ELF5)、GATA 结合蛋白 3 (GATA Binding Protein 3,GATA3)、T细胞转录因子1 (Transcription Factor T Cell Factor 1,TCF1)、转录因子 AP-2γ (Transcription Factor AP-2 gamma, TFAP2)、WW 结构域的转录调节子 1(WW-Domain Containing Transcription Regulator 1,WWTR1)和 Myc 原癌基因(Myc Proto-Oncogene,MYC),维持自身增殖的同时抑制合体化[4-8]。STB 与母血直接接触,分泌大量妊娠相关的激素,包括孕酮(Progesterone,P4)、人绒毛膜促性腺激素(human Chorionic Gonadotropin, hCG)和人催乳素(human Prolactin,hPL)。

  • 滋养层细胞合体化是一个复杂的过程,一般认为起始于蛋白激酶 A (Protein Kinase A,PKA) 的激活,随后 cAMP 水平增加,激活转录因子 (如 GCM1) 及其下游靶基因,从而诱导 CTB 合体化形成STB[9]。STB以自分泌或旁分泌方式分泌hCG,促进细胞融合。hCG与促黄体激素/绒毛膜促性腺激素受体结合诱导细胞内 cAMP 产生以激活 PKA 信号,作用于下游的 GCM1,诱导融合关键基因表达,包括hCG、连接蛋白43和合胞素,维持合体化[10-13]

  • 1.2 绒毛外滋养层细胞分化途径

  • 从受精后第 3 周开始,快速增殖的 CTB 突破 STB 并聚集形成滋养层细胞柱 (Cell Column Trophoblast,CCT),CCT 中的一些细胞迁移至蜕膜形成 EVT,随后它们与蜕膜细胞外基质 (Extracel⁃ lular Matrix,ECM) 接触,分化为iEVTs和 enEVTs,从而将绒毛锚定在子宫壁上[2314]

  • 侵入蜕膜的滋养层细胞称为 iEVTs,它具有粘附分子、蛋白酶和组织相容性抗原的独特表达特征,如 E-cadherin 和整合素 α6β4 下调,而整合素 α5β1和整合素α1β1上调[15];表达非典型的I类主要组织相容性复合体 (Class I Major Histocompatibility Complex,MHC I) 抗原,包括人类白细胞抗原-E (Human Leukocyte Antigen-E,HLA-E)、HLA-G 和 HLA-C[1]。在母胎界面上,iEVTs与多种母体细胞相互作用,包括蜕膜基质细胞、子宫血管内皮细胞、血管平滑肌细胞、蜕膜杀伤 (decidual NK,dNK) 细胞、巨噬细胞和 T细胞。这些细胞之间复杂的相互作用对于胎盘血流灌注和母胎免疫耐受至关重要[101617]

  • enEVTs 是一类可侵入蜕膜和子宫内膜的母体血管的细胞,使子宫螺旋动脉从高阻力、低容量的血管改建为低阻力、高容量的血管。血管改建导致螺旋动脉血流的剧烈变化,以确保母血最大限度地灌注到胎盘中,满足胎儿的生长发育需要[10]

  • enEVTs 的起源备受争议,有观点认为,在蜕膜浅层的螺旋动脉区域是从 iEVT到 enEVT的转换,而动脉的较深区域则是由滋养层细胞栓 (Trophoblast Plugs) 来源的 enEVT 来改建[10]。此外,我们发现 enEVTs 在某种程度上有类似于内皮细胞的特性。enEVTs下调上皮细胞标志物E-cadherin和整合素α6β4,并上调粘附分子VE-Cadherin、血小板内皮细胞粘附分子1 (Platelet-Endothelial Cell Adhe⁃ sion Molecule1,PCAM1)、神经细胞粘附分子又称 CD56 (Neural Cell Adhesion Molecule,NCAM)、整合素 α5β1、α1β1 以及 αVβ3 等[151819],由上皮细胞表型转变为内皮细胞表型,随后整合到血管内皮层,促进螺旋动脉血管内皮细胞凋亡,最终完全替代血管内皮细胞[2021]

  • 2 胎盘功能单元

  • 2.1 胎盘内分泌功能单元

  • 胎盘是孕期特有的内分泌器官,可以产生多种激素、神经肽、神经递质和生长因子,如hCG、hPL、促性腺激素释放激素(Gonadotropin-Releasing Hormone, GnRH) 和多种类固醇激素如孕酮 (Progesterone, P4)、雌激素、雄激素等,形成下丘脑-垂体-性腺内分泌轴。胎盘分泌的激素在胚胎着床、胎盘细胞分化、免疫适应、胎儿发育和分娩启动中发挥着至关重要的作用[122]

  • hCG是胎盘产生的最重要的激素之一,能够促进滋养层细胞融合,刺激P4的产生、以及促进胎盘血管内皮细胞增殖和血管形成[123-25];胎盘产生Ⅰ型 GnRH(GnRH I)和人类特异的Ⅱ型GnRH(GnRH Ⅱ),它们作为下丘脑-垂体-性腺轴的上游激素可以合成促性腺激素,包括卵泡刺激素和黄体生成素,对卵巢、子宫、胎盘和免疫系统具有重要的调节作用[26-28]。妊娠第 6-8 周,胎盘代替卵巢黄体细胞合成类固醇激素 P4,P4是抑制母体对胎儿抗原免疫排斥、维持母胎界面免疫耐受的关键激素[29-32]。除此之外,胎盘还会产生雌激素和雄激素等其他激素,在胚胎着床、胎盘细胞分化、免疫适应、胎儿发育和分娩启动中起着至关重要的作用[33-37]

  • 2.2 胎盘物质交换功能单元

  • 母-胎间营养物质交换主要发生在胎盘绒毛表面的 STB。STB 表面的微绒毛显著增加了胎盘与母血接触的表面积,有效地保证了母-胎间多种分子和代谢物质的双向运输[38]。胎儿所需的葡萄糖、氨基酸和脂肪酸等代谢物主要由母体提供。作为主要营养物质的葡萄糖通过葡萄糖转运蛋白 (Glucose Transporter Protein,GLUT) 运至胎儿;氨基酸主要通过氨基酸转运蛋白 SLC1、SLC6 和 SLC38 逆浓度梯度由母血转运至胎儿[38-41];胎盘通过脂肪酸结合蛋白和脂肪酸转运蛋白 (FAT/CD36) 促进脂肪酸从母血的高浓度向胎盘的低浓度方向转运[42]。这些转运体蛋白分布在绒毛的滋养层细胞上,因此胎盘绒毛构成母胎物质交换的功能单元。

  • 在哺乳动物中,母体和胎儿之间的营养分配影响着胎儿生长和妊娠进程,尤其是在营养缺乏的情况下,更能体现营养适当分配的重要性。胎盘是母体和胎儿之间的桥梁,平衡营养分配,维持正常的妊娠进程。我们最近的研究发现,滋养层细胞的合体化触发了巨胞饮这一内吞机制,摄取细胞外大分子作为营养来源;这种独特的营养摄取机制在氨基酸缺乏的条件下,通过抑制哺乳动物雷帕霉素靶蛋白 (mammalian Target Of Rapamycin,mTOR) 信号而进一步激活,使胎盘能够活跃摄取大分子营养物质,为胎盘/胎儿提供新的营养来源[43]。mTOR 通路如何协调营养微环境、滋养层分化和细胞代谢以维持胎盘功能,仍有待进一步研究。

  • 2.3 母胎界面血流灌注功能单位

  • 母胎界面充足的血流灌注对妊娠进程至关重要,这主要通过 EVT 对子宫螺旋动脉 (Spiral Arteries, SPA) 改建来实现。未改建的 SPA 由完整的内皮细胞和散布的血管平滑肌细胞组成[1]。而妊娠期间 SPA改建的生理过程仍不清楚,有假设认为该过程可分为五个阶段:(1) 蜕膜相关的早期血管改建; (2) iEVT 相关的血管改建;(3) enEVT 迁移;(4) enEVT与血管壁的结合;(5) 再内皮化和内膜下增厚[23]。子宫螺旋动脉的改建主要包括内皮细胞空泡化、平滑肌肿胀和血管平滑肌细胞去分化等细胞事件[44]。在这一阶段,蜕膜基质细胞和淋巴细胞,特别是dNK和巨噬细胞,以不依赖滋养层细胞的方式参与母体血管改建;螺旋动脉周围 iEVT 的侵润导致血管平滑肌细胞显著去分化,从而破坏血管平滑肌层[44];enEVTs侵入动脉管腔,以假血管生成的方式取代母体血管的内皮细胞[15]。这一改建过程使得母胎界面处的螺旋动脉变为低阻高容的血管。然而迄今有关SPA改建过程中多种细胞事件 (主要包括 SPA的血管平滑肌细胞消失、enEVTs替代子宫SPA 内皮细胞、血管周围 ECM 的分解代谢等[45-48)] 的调节机制如何,参与其中的多种细胞类型之间如何进行复杂而协调的相互作用,仍是悬而未知的。

  • 2.4 母胎界面的免疫适应性调节

  • 哺乳动物的正常妊娠很大程度上取决于母体对同种半异体胎儿的免疫耐受,这意味着母体在妊娠期间对胎儿抗原的免疫反应是受到抑制的;与此同时,为防止胎盘感染,母体对外源微生物抗原需保持完备的免疫反应能力。最近的研究显示,母体产前的不良免疫应激将会降低小胶质细胞的免疫反应性,尤其在子代接触内源性及外源性应激时表现出来[49]。临床分析和动物模型研究表明,母体免疫适应失调与各种不良妊娠结局密切相关,例如复发流产和子痫前期[5051]

  • 母胎界面有两个免疫耐受部位。一个是蜕膜免疫微环境,主要由EVT和各种母体免疫细胞之间的相互作用形成免疫适应微环境;另一个是绒毛免疫微环境,与母血直接接触的STB和母血中的多种免疫细胞相互作用形成免疫屏障[1]

  • 妊娠早期,蜕膜中积累了大量的母体免疫细胞,约占蜕膜细胞的 40%~50%。子宫内膜中聚集的免疫细胞包括 dNK细胞 (约 50%~70%)、巨噬细胞 (约 20%)、T细胞 (约 10%~20%),以及少量的树突状细胞 (Dendritic Cell,DC)、肥大细胞和B细胞。这些免疫细胞参与了多种免疫事件,包括局部免疫反应、滋养层细胞的分化和侵袭、血管改建等[5253]。滋养层细胞与多种免疫细胞相互作用,训导免疫细胞的表型和功能,建成免疫耐受微环境。这种相互作用主要涉及两种方式:直接的配体-受体识别[54-57],以及由生长因子、细胞因子或趋化因子介导的间接相互作用[58-64]。因此,滋养层细胞是局部免疫耐受微环境的主要构建者[52]

  • 3 胎盘功能障碍和子痫前期

  • 胎盘发育障碍和功能受损与不良妊娠结局甚至胎儿死亡密切相关。多种妊娠相关疾病,例如子痫前期、复发性流产、胎儿生长受限和胎盘植入等,已被认为是胎盘起源的疾病[65]。以下重点介绍子痫前期发病因素的近期研究进展。

  • 3.1 子痫前期概述

  • 子痫前期是妊娠20周后新发高血压并伴有蛋白尿或多个母体器官功能障碍的妊娠期并发症,威胁约 5%~7% 的孕产妇,是产期、围产期母儿发病和死亡的主要原因。临床指征发生于孕34周前的子痫前期定义为早发型子痫前期;相应地,孕34周之后发病者定义为晚发型子痫前期[66]。目前认为早发型子痫前期多与妊娠早期胎盘发育受损和随后胎儿生长受限相关,而晚发型子痫前期通常与母体内皮功能障碍有关。

  • 关于子痫前期胎盘的病理变化已有较多报道。子痫前期胎盘的 iEVT 细胞数量和侵润性不足,这可能是持续缺氧情况下滋养层分化障碍和/或细胞凋亡增加所致。

  • 3.2 子痫前期发病因素

  • 3.2.1 血管生成和抗血管生成因子异常

  • 胎盘来源的血管生成因子可作为预测子痫前期的生物分子,包括 VEGF、 PlGF、可溶性 Flt-1 (sFLT1) 以及可溶性内皮素 (soluble Endoglin, sENG)。妊娠早中期母体血清中 VEGF 或 PlGF水平的降低和/或 sFLT1、sENG 或 sFLT/PlGF 水平的升高,预示着更高的子痫前期 (尤其是早发型子痫前期) 发病风险[1]。在妊娠小鼠或大鼠中,全身性或胎盘特异性过表达 sFLT1可导致胎盘发育缺陷和子痫前期样表型,并损害子宫 SPA 重塑[67];妊娠大鼠中同时注射 sENG 和 sFLT1 过表达腺病毒可导致 HELLP 综合征 (一种极其严重的子痫前期并发症) 样表型[66];通过结扎单侧子宫动脉诱导子宫胎盘缺血构建的子痫前期样狒狒模型中,sFLT1 的特异性 siRNA可抑制sFLT1过表达并改善子痫前期症状[68]

  • 3.2.2 类固醇激素合成失衡

  • 胎盘是妊娠期类固醇激素的主要来源。我们发现,子痫前期患者的类固醇激素合成失衡,表现为外周血中睾酮 (Testosterone,T) 升高,雌二醇 (17β-estradiol,E2) 降低;子痫前期胎盘的 T 合成限速酶 17β-HSD3表达和活性异常升高,而雌激素合成酶芳香酶 (Aromatase) 的表达及活性异常降低[6970];这种失衡可能与miR-22/ERα/aromatase途径有关,但T异常升高的具体原因仍需进一步探究。

  • 胎盘中存在抵御这种过量雄激素危害滋养层细胞分化的机制。蛋白质 O-乙酰氨基葡萄糖(O-linked-beta-D-N-Acetylglucosamine,O-GlcNAc)修饰是真核细胞胞内一种普遍存在的蛋白质翻译后修饰[71]。PKA 信号可诱导胱硫醚-γ-裂解酶 (CSE) O-GlcNAc修饰显著上调,并由此促进其合成H2S的酶活性,而 H2S 可通过阻碍雄激素受体 (Androgen Receptor,AR) 的二聚化来抑制 T 的促滋养层细胞合体化的作用; 子痫前期胎盘中 CSE 蛋白 O-GlcNAc修饰异常增高,可能参与防止过量T引起的过度合体化[37]。这种胎盘细胞分化的复杂调控,也提示我们不能简单地将子痫前期胎盘中所发现的差异分子认定为病理诱因。

  • 3.2.3 代谢紊乱

  • 子痫前期胎盘中存在线粒体功能失调,包括三羧酸循环、电子传递链、脂肪酸氧化等相关蛋白的表达异常[7273]。此外,子痫前期胎盘中表现出蛋白质降解异常和有害蛋白质积累[7475],如细胞外囊泡增加,血小板激活等[76]。进一步研究子痫前期独特的代谢表型,有望挖掘新的分型依据,探索更多病因学机制,为子痫前期提供新的干预策略。

  • 4 总结和展望

  • 近年来,在滋养层细胞谱系分化调控、胎盘发育和功能建立机制、妊娠疾病生物标志物及潜在治疗靶点等方面,均取得了越来越多令人兴奋的进展。妊娠成功取决于“种子”(胚胎/胎儿和胎盘) 和“土壤”(子宫微环境以及母体免疫和代谢状态) 之间复杂的动态平衡,这一生理进程涉及胚胎着床、蜕膜发育、免疫豁免、胎盘形成等多个环节、多种细胞事件的精细级联。生理过程的精妙和妊娠疾病的复杂性决定了这一领域的研究必须将发育过程的复杂事件系统地联系起来,既要强调由神经-内分泌所调节的机体大环境的稳态,又要深入局部,从细胞与分子水平上精细地研究细胞之间相互作用的程序性调控机理。

  • 目前,我们对人类胎盘的了解非常有限。由于医学伦理和技术手段的限制,很难获取连续和准确妊娠时间节点的母胎界面加以分析。此外,胎盘的物种差异较大,因而在模拟人类胎盘的生理或病理动物模型的选择上也面临挑战。新型研究模型例如 hTSCs、胎盘类器官、重构胚胎等,加之包括单细胞组学、高分辨率成像等前沿技术的发展,以及日益紧密的学科间的交叉协作,有望为揭示胚外细胞的精确调控、母胎界面细胞间的相互作用提供崭新的研究平台,极大地促进对人类妊娠奥秘的探究,并加快基础研究成果转化为妊娠并发症的临床预测和治疗方案。

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