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通讯作者:

王海滨(1974-),男,浙江义乌人,教授,主要从事早期胚胎发育、着床和胎盘发生的生理机制研究。E-mail:haibin.wang@vip.163.com

中图分类号:R321.3

文献标识码:A

文章编号:2096-8965(2022)04-0037-08

DOI:10.12287/j.issn.2096-8965.20220405

参考文献 1
WASSARMAN P M.Fertilization in animals[J].Dev Genet,1999,25(2):83-86.
参考文献 2
DEY S K.How we are born[J].J Clin Invest,2010,120(4):952-955.
参考文献 3
CHA J,SUN X,DEY S K.Mechanisms of implantation:strategies for successful pregnancy[J].Nat Med,2012,18(12):1754-1767.
参考文献 4
WANG H,DEY S K.Roadmap to embryo implantation:clues from mouse models[J].Nat Rev Genet,2006,7(3):185-199.
参考文献 5
NORWITZ E R,SCHUST D J,FISHER S J.Implantation and the survival of early pregnancy[J].N Engl J Med,2001,345(19):1400-1408.
参考文献 6
CRACIUNAS L,GALLOS I,CHU J,et al.Conventional and modern markers of endometrial receptivity:a systematic review and meta-analysis[J].Hum Reprod Update,2019,25(2):202-223.
参考文献 7
CARSON D D,BAGCHI I,DEY S K,et al.Embryo implantation[J].Dev Biol,2000,223(2):217-237.
参考文献 8
MATSUMOTO H.Molecular and cellular events during blastocyst implantation in the receptive uterus:clues from mouse models[J].J Reprod Dev,2017,63(5):445-454.
参考文献 9
DEY S K,LIM H,DAS S K,et al.Molecular cues to implantation[J].Endocr Rev,2004,25(3):341-373.
参考文献 10
TRANGUCH S,DAIKOKU T,GUO Y,et al.Molecular complexity in establishing uterine receptivity and implantation[J].Cell Mol Life Sci,2005,62(17):1964-1973.
参考文献 11
PARIA B C,HUET-HUDSON Y M,DEY S K.Blastocyst's state of activity determines the "window" of implantation in the receptive mouse uterus[J].Proc Natl Acad Sci U S A,1993,90(21):10159-10162.
参考文献 12
QUINN C E,CASPER R F.Pinopodes:a questionable role in endometrial receptivity[J].Hum Reprod Update,2009,15(2):229-236.
参考文献 13
MURPHY C R.Uterine receptivity and the plasma membrane transformation[J].Cell Res,2004,14(4):259-267.
参考文献 14
SEHRING J,BELTSOS A,JEELANI R.Human implantation:the complex interplay between endometrial receptivity,inflammation,and the microbiome[J].Placenta,2022,117:179-186.
参考文献 15
LIM H J,WANG H.Uterine disorders and pregnancy complications:insights from mouse models[J].J Clin Invest,2010,120(4):1004-1015.
参考文献 16
CONNEELY O M,MULAC-JERICEVIC B,DEMAYO F,et al.Reproductive functions of progesterone receptors [J].Recent Prog Horm Res,2002,57:339-355.
参考文献 17
CURTIS HEWITT S,GOULDING E H,EDDY E M,et al.Studies using the estrogen receptor alpha knockout uterus demonstrate that implantation but not decidualization-associated signaling is estrogen dependent [J].Biol Reprod,2002,67(4):1268-1277.
参考文献 18
MARQUARDT R M,KIM T H,SHIN J H,et al.Progesterone and estrogen signaling in the endometrium:what goes wrong in endometriosis?[J].Int J Mol Sci,2019,20(15):3822.
参考文献 19
LUBAHN D B,MOYER J S,GOLDING T S,et al.Alteration of reproductive function but not prenatal sexual development after insertional disruption of the mouse estrogen receptor gene[J].Proc Natl Acad Sci U S A,1993,90(23):11162-11166.
参考文献 20
YU K,HUANG Z Y,XU X L,et al.Estrogen receptor function:impact on the human endometrium[J].Front Endocrinol(Lausanne),2022,13:827724.
参考文献 21
KURITA T,LEE K J,COOKE P S,et al.Paracrine regulation of epithelial progesterone receptor and lactoferrin by progesterone in the mouse uterus[J].Biol Reprod,2000,62(4):831-838.
参考文献 22
DEMAYO F J,LYDON J P.90 years of progesterone:New insights into progesterone receptor signaling in the endometrium required for embryo implantation[J].J Mol Endocrinol,2020,65(1):T1-T14.
参考文献 23
COOKE P S,BUCHANAN D L,YOUNG P,et al.Stromal estrogen receptors mediate mitogenic effects of estradiol on uterine epithelium[J].Proc Natl Acad Sci U S A,1997,94(12):6535-6540.
参考文献 24
WINUTHAYANON W,HEWITT S C,ORVIS G D,et al.Uterine epithelial estrogen receptor alpha is dispensable for proliferation but essential for complete biological and biochemical responses[J].Proc Natl Acad Sci U S A,2010,107(45):19272-19277.
参考文献 25
BUCHANAN D L,SETIAWAN T,LUBAHN D B,et al.Tissue compartment-specific estrogen receptor-alpha participation in the mouse uterine epithelial secretory response[J].Endocrinology,1999,140(1):484-491.
参考文献 26
KURITA T,YOUNG P,BRODY J R,et al.Stromal progesterone receptors mediate the inhibitory effects of progesterone on estrogen-induced uterine epithelial cell deoxyribonucleic acid synthesis[J].Endocrinology,1998,139(11):4708-4713.
参考文献 27
FRANCO H L,RUBEL C A,LARGE M J,et al.Epithelial progesterone receptor exhibits pleiotropic roles in uterine development and function[J].FASEB J,2012,26(3):1218-1227.
参考文献 28
TAN J,PARIA B C,DEY S K,et al.Differential uterine expression of estrogen and progesterone receptors correlates with uterine preparation for implantation and decidualization in the mouse[J].Endocrinology,1999,140(11):5310-5321.
参考文献 29
WETENDORF M,WU S P,WANG X,et al.Decreased epithelial progesterone receptor A at the window of receptivity is required for preparation of the endometrium for embryo attachment[J].Biol Reprod,2017,96(2):313-326.
参考文献 30
LI R,WANG X Q,HUANG Z Y,et al.The role of epithelial progesterone receptor isoforms in embryo implantation[J].iScience,2021,24(12):103487.
参考文献 31
SONG H,LIM H,DAS S K,et al.Dysregulation of EGF family of growth factors and COX-2 in the uterus during the preattachment and attachment reactions of the blastocyst with the luminal epithelium correlates with implantation failure in LIF-deficient mice[J].Mol Endocrinol,2000,14(8):1147-1161.
参考文献 32
CHENG J G,CHEN J R,HERNANDEZ L,et al.Dual control of LIF expression and LIF receptor function regulate Stat3 activation at the onset of uterine receptivity and embryo implantation[J].Proc Natl Acad Sci U S A,2001,98(15):8680-8685.
参考文献 33
SUN X,BARTOS A,WHITSETT J A,et al.Uterine deletion of Gp130 or Stat3 shows implantation failure with increased estrogenic responses[J].Mol Endocrinol,2013,27(9):1492-1501.
参考文献 34
CHEN J R,CHENG J G,SHATZER T,et al.Leukemia inhibitory factor can substitute for nidatory estrogen and is essential to inducing a receptive uterus for implantation but is not essential for subsequent embryogenesis[J].Endocrinology,2000,141(12):4365-4372.
参考文献 35
DAIKOKU T,CHA J,SUN X,et al.Conditional deletion of Msx homeobox genes in the uterus inhibits blastocyst implantation by altering uterine receptivity[J].Dev Cell,2011,21(6):1014-1025.
参考文献 36
AGHAJANOVA L.Leukemia inhibitory factor and human embryo implantation[J].Ann N YAcad Sci,2004,1034(1):176-183.
参考文献 37
LEE K,JEONG J,KWAK I,et al.Indian hedgehog is a major mediator of progesterone signaling in the mouse uterus[J].Nat Genet,2006,38(10):1204-1209.
参考文献 38
KURIHARA I,LEE D K,PETIT F G,et al.COUP-TFII mediates progesterone regulation of uterine implantation by controlling ER activity[J].PLoS Genet,2007,3(6):e102.
参考文献 39
WEI Q,LEVENS E D,STEFANSSON L,et al.Indian Hedgehog and its targets in human endometrium:menstrual cycle expression and response to CDB-2914 [J].J Clin Endocrinol Metab,2010,95(12):5330-5337.
参考文献 40
LI Q,KANNAN A,DEMAYO F J,et al.The antiproliferative action of progesterone in uterine epithelium is mediated by Hand2[J].Science,2011,331(6019):912-916.
参考文献 41
MURATA H,TANAKA S,TSUZUKI-NAKAO T,et al.The transcription factor HAND2 up-regulates transcription of the IL15 gene in human endometrial stromal cells[J].J Biol Chem,2020,295(28):9596-9605.
参考文献 42
TRANGUCH S,CHEUNG-FLYNN J,DAIKOKU T,et al.Cochaperone immunophilin FKBP52 is critical to uterine receptivity for embryo implantation[J].Proc Natl Acad Sci U S A,2005,102(40):14326-14331.
参考文献 43
YANG Z,WOLF I M,CHEN H,et al.FK506-binding protein 52 is essential to uterine reproductive physiology controlled by the progesterone receptor A isoform[J].Mol Endocrinol,2006,20(11):2682-2694.
参考文献 44
TRANGUCH S,WANG H,DAIKOKU T,et al.FKBP52 deficiency-conferred uterine progesterone resistance is genetic background and pregnancy stage specific[J].J Clin Invest,2007,117(7):1824-1834.
参考文献 45
MUKHERJEE A,SOYAL S M,FERNANDEZVALDIVIA R,et al.Steroid receptor coactivator 2 is critical for progesterone-dependent uterine function and mammary morphogenesis in the mouse[J].Mol Cell Biol,2006,26(17):6571-6583.
参考文献 46
MUKHERJEE A,AMATO P,ALLRED D C,et al.Steroid receptor coactivator 2 is required for female fertility and mammary morphogenesis:insights from the mouse,relevance to the human[J].Nucl Recept Signal,2007,5:e011.
参考文献 47
GREGORY C W,WILSON E M,APPARAO K B,et al.Steroid receptor coactivator expression throughout the menstrual cycle in normal and abnormal endometrium [J].J Clin Endocrinol Metab,2002,87(6):2960-2966.
参考文献 48
KOMMAGANI R,SZWARC M M,KOVANCI E,et al.Acceleration of the glycolytic flux by steroid receptor coactivator-2 is essential for endometrial decidualization [J].PLoS Genet,2013,9(10):e1003900.
参考文献 49
ZHANG X L,ZHANG D,MICHEL F J,et al.Selective interactions of Kruppel-like factor 9/basic transcription element-binding protein with progesterone receptor isoforms A and B determine transcriptional activity of progesterone-responsive genes in endometrial epithelial cells[J].J Biol Chem,2003,278(24):21474-21482.
参考文献 50
PABONA J M,ZENG Z,SIMMEN F A,et al.Functional differentiation of uterine stromal cells involves crossregulation between bone morphogenetic protein 2 and Kruppel-like factor(KLF)family members KLF9 and KLF13[J].Endocrinology,2010,151(7):3396-3406.
参考文献 51
XIN Q L,KONG S B,YAN J H,et al.Polycomb subunit BMI1 determines uterine progesterone responsiveness essential for normal embryo implantation[J].J Clin Invest,2018,128(1):175-189.
参考文献 52
TANG Y D,QIU J T,TANG Z Z,et al.P38alpha MAPK is a gatekeeper of uterine progesterone responsiveness at peri-implantation via Ube3c-mediated PGR degradation [J].Proc Natl Acad Sci U S A,2022,119(32):e2206000119.
参考文献 53
HUANG P X,DENG W B,BAO H L,et al.SOX4 facilitates PGR protein stability and FOXO1 expression conducive for human endometrial decidualization[J].Elife,2022,11:e72073.
参考文献 54
YI P,WANG Z,FENG Q,et al.Structure of a biologically active estrogen receptor-coactivator complex on DNA[J].Mol Cell,2015,57(6):1047-1058.
参考文献 55
KAWAGOE J,LI Q,MUSSI P,et al.Nuclear receptor coactivator-6 attenuates uterine estrogen sensitivity to permit embryo implantation[J].Dev Cell,2012,23(4):858-865.
参考文献 56
RAN H,KONG S B,ZHANG S,et al.Nuclear Shp2 directs normal embryo implantation via facilitating the ERalpha tyrosine phosphorylation by the Src kinase[J].Proc Natl Acad Sci U S A,2017,114(18):4816-4821.
参考文献 57
CHENG J H,LIANG J,LI Y Z,et al.Shp2 in uterine stromal cells critically regulates on time embryo implantation and stromal decidualization by multiple pathways during early pregnancy[J].PLoS Genet,2022,18(1):e1010018.
参考文献 58
MACLEAN J A,HAYASHI K.Progesterone actions and resistance in gynecological disorders[J].Cells,2022,11(4):647.
参考文献 59
TURCO M Y,GARDNER L,HUGHES J,et al.Longterm,hormone-responsive organoid cultures of human endometrium in a chemically defined medium[J].Nat Cell Biol,2017,19(5):568-577.
参考文献 60
KAGAWA H,JAVALI A,KHOEI H H,et al.Human blastoids model blastocyst development and implantation [J].Nature,2022,601(7894):600-605.
参考文献 61
YU L Q,WEI Y L,DUAN J L,et al.Blastocyst-like structures generated from human pluripotent stem cells [J].Nature,2021,591(7851):620-626.
目录contents

    摘要

    妊娠过程包含胚胎植入、蜕膜分化、胎盘发育到最终分娩等多个不可逆环节,其中胚胎植入的发生需要囊胚获得植入能力与子宫内膜进入容受态的同步化进行。内膜容受态的建立过程是子宫在卵巢分泌雌孕激素的动态调控下,通过雌孕激素受体协同各种转录因子、细胞因子和生长因子,诱导子宫上皮和基质细胞有序的增殖和分化来完成。

    Abstract

    The process of pregnancy includes several irreversible steps from embryo implantation, decidualization, placenta development to final delivery. The successful occurrence of embryo implantation requires the synchronization between implantation-competent blastocysts and receptive uterus. The establishment of uterine receptivity is under the dynamic regulation of ovarian progesterone and oestrogen through their respective nuclear receptors, which cooperate with various transcription factors, cytokines and growth factors to induce the orderly proliferation and differentiation of uterine epithelial and stromal cells.

  • 新生命的诞生起始于受精过程,即精卵结合形成受精卵或称合子[1],合子经历数次有丝分裂和形态发生之后形成囊胚,囊胚必须着床到处于容受态的子宫内膜中,才能进一步在体内发育。着床后胚胎刺激基质细胞走向蜕膜分化,为发育中的胚胎提供营养,待功能性胎盘形成之后,胎儿主要通过胎盘摄取母体营养,供其进一步分化发育直至胎儿娩出。从胚胎植入、蜕膜分化、胎盘发育到最终分娩等多个妊娠过程的重要环节是连续且不可逆的生理过程[2-4]。作为整个妊娠的关键环节,只有在囊胚激活与子宫内膜进入容受态同步化时,胚胎植入才能正常发生。临床研究数据显示,在育龄妇女中,不采取避孕措施情况下最大生殖力 (一个月经周期内受孕的概率) 仅约为 30%,其中在妊娠失败患者中,约有 75% 是因为胚胎植入异常导致的[56],而子宫容受态异常常被认为是一个非常关键的限制因素。不论在小鼠还是人类中,容受态的建立都受到源于卵巢雌孕激素的严格调控,卵巢分泌的雌孕激素主要通过相应核受体发挥转录调控作用,同时还需要其他细胞因子、转录因子和生长因子等的调控作用,促使子宫内膜容受态正常建立。

  • 1 胚胎植入

  • 胚胎植入作为妊娠过程的重要步骤之一,该动态过程涉及多种细胞类型之间的互作,主要包括囊胚滋养外胚层、子宫内膜中的上皮细胞 (腔上皮和腺上皮) 和基质细胞,其大致可分为三个时期:定位期,粘附期和侵入期[7]。在哺乳动物尤其是啮齿类动物中,定位期开始之前子宫腔会闭合,从而导致定位期胚胎滋养外胚层的微绒毛和腔上皮细胞的接触交错并逐渐紧密;紧接着是粘附期,滋养外胚层和腔上皮细胞之间的联系变得更加紧密,在这个阶段,囊胚植入位点处的子宫间质血管通透性增加,通过静脉注射大分子蓝色染料溶液后,沿着子宫角的植入位点处会有蓝色反应,可以标记囊胚植入位点[8];侵入阶段胚胎的滋养外胚层穿过子宫腔上皮及紧邻的基底膜进入基质,同时建立与母体血供之间的联系,为之后功能性胎盘形成之前的胚胎生长发育提供营养物质与生长环境。以上三个阶段是一个连续发生的动态事件,最终实现胚胎在子宫内膜中的成功植入[9]

  • 2 子宫容受态的建立

  • 囊胚获得植入能力的同时子宫内膜进入容受态,植入才能成功发生[410]。在胎生类哺乳动物中,子宫细胞响应内分泌雌孕激素的波动发生分化促进其进入植入的准备阶段,子宫的这一状态称之为子宫容受态,这一状态仅维持在一个短暂的时期,将这一时期称为“植入窗口期”[11]

  • 子宫进入容受态时会发生明显的形态学改变,子宫腔发生闭合,腔上皮细胞由圆柱状形态转变为立方形,细胞极性逐渐降低,囊胚定位处的子宫上皮细胞微绒毛消失,质膜变得光滑平整,细胞表面出现胞饮突结构[12]。人类子宫内膜中微绒毛结构还有待进一步确认,而胞饮突存在于人类胚胎着床阶段处于容受态的子宫内膜上皮中,许多研究已证明胞饮突能够作为子宫内膜容受性的指标[13]

  • 根据子宫对植入的敏感性分为容受前期 (Prereceptive)、容受期 (Receptive) 和不应期 (Nonreceptive or Refractory) 三个主要阶段[3-5]。在小鼠中,子宫妊娠第1-3天 (小鼠交配见栓当天定义为妊娠第 1天) 为容受前期;第 4天早上开始进入容受期,此时少量的雌激素分泌是子宫进入容受态的关键[10],且能够决定植入窗口期持续的时间; 第5天下午子宫开始过渡到不应期。在人类中,子宫内膜在整个月经周期中都在重塑,根据组织学形态及功能的变化,月经周期以 28 天为例,可分为增殖期、分泌期和月经期。在分泌期内,容受前期为排卵 (记为 0天) 后的约前 7天;在分泌期的中期进入容受期,持续时间为排卵后的 7-10 天,对应人月经周期的第 20-24 天,之后子宫进入不应期,包括分泌期的剩余时间[14]。处于容受前期时,子宫内所处环境利于胚胎存活,但此时胚胎不能起始植入;容受期时,囊胚能够与子宫内膜发生互作,起始植入反应;进入不应期后,此时子宫内所处环境不利于胚胎存活。

  • 处于容受态的子宫可促进囊胚的生长、黏附以及精确调控随后植入过程中涉及的分子和细胞事件。子宫容受态的建立主要是通过卵巢所分泌的雌孕激素结合其同源受体调控下游靶基因,同时协同转录因子、生长因子和细胞因子等众多分子,共同对子宫基质和上皮细胞有序的增殖和/或分化进行调控,使得子宫能够容受接纳胚胎。

  • 3 卵巢雌孕激素分泌的动态变化

  • 卵巢雌激素和孕激素在时空上协同调节子宫中不同类型细胞特异性作用来调节妊娠的不同阶段[3]

  • 在人类整个月经周期中,随着上个周期的结束,新的卵泡开始发育,伴随着卵泡发育卵巢开始合成并分泌雌激素,子宫内膜中的上皮、基质和血管内皮细胞在雌激素的影响下增殖,子宫内膜逐渐完成修复,此时内膜处于增殖期。雌激素的水平在排卵前达到峰值,排卵后开始下降,排卵后卵泡颗粒细胞和卵泡膜细胞形成黄体,开始合成孕激素并迅速达到一个峰值,子宫内膜中增殖的基质细胞在孕激素的作用下逐渐停止增殖并走向分化,腺体分泌,伴随子宫水肿,内膜进入分泌期,此时孕激素一直处于较高水平到月经周期结束,孕激素作用 5-7天后叠加再次出现的一个较小雌激素峰,子宫内膜进入分化较好的状态,此时子宫处于容受态或着床窗口[3415]

  • 在小鼠整个动情周期中,动情前期孕激素水平很低,而雌激素分泌水平较高,妊娠第1天 (排卵后的第一天),子宫上皮细胞在排卵前雌激素作用下增殖并能持续到妊娠第 2天,妊娠第 3天时黄体形成并开始分泌孕激素,其分泌水平快速上升且保持在较高水平,启动基质细胞增殖,同时上皮细胞的增殖受到抑制,走向分化[34],妊娠第4天早上有少量雌激素分泌,进一步协同孕激素抑制上皮细胞增殖促进分化和腺体分泌,诱导基质细胞增殖,该雌激素是子宫获得容受态的关键[10]

  • 4 雌孕激素调节子宫容受态

  • 在体内子宫容受态建立的这一事件受到母体来源激素的严格调控,特别是源于卵巢的雌激素和孕激素[1617]。卵巢雌孕激素在小鼠、大鼠胚胎植入过程中都是不可或缺的,而对猪、豚鼠、兔子和仓鼠来说,卵巢雌激素是可有可无的,而是源于胚胎的雌激素被认为对这四个物种胚胎的植入很重要[4]。在人类中,子宫内膜中孕激素和雌激素信号以一种严格调节的、动态的相互作用协调,以驱动正常的月经周期,促进内膜处于胚胎容受状态,以实现容受态窗口期的正常植入[18]。与人类月经周期 (28-30天) 的时长相比,小鼠的发情周期 (4-5天) 较短,但两种物种的着床窗口均由雌孕激素以类似的方式调节。因此,在小鼠中的研究对理解人类早期妊娠中雌孕激素的功能十分重要。

  • 4.1 雌孕激素受体对子宫内膜容受态的调节

  • 在人和小鼠中,雌孕激素响应信号通路调控容受态建立主要通过其同源核受体。雌孕激素的各自经典核受体都包括两类,分别是雌激素受体 α/β (Ostrogen Receptor alpha/beta) 和孕激素受体 A/B (Progesterone Receptor A/B)。目前对子宫中雌孕激素受体的了解大部分是通过各种基因工程小鼠和体外细胞培养实验了解的。ERα 和 ERβ 敲除小鼠研究发现,ERα敲除小鼠子宫发育不良,不能发生胚胎植入[19],而ERβ基因缺失后子宫无明显异常,胚胎正常植入,且雌激素响应正常[9],表明在小鼠子宫中雌激素发挥作用主要依赖ERα;同样在人类中 ERα 也是子宫中表达的主要亚型[20]。小鼠子宫中 PRA 和 PRB 同时表达,研究显示,对 PRA 和 PRB 在小鼠中同时敲除后卵巢排卵异常,植入异常,雌性小鼠不育,特异性缺失 PRA 或 PRB 显示 PRA 是子宫中PR发挥功能的主要亚型[1621],而在人中PRA 和 PRB 对妊娠成功都很重要的,但在体外人子宫内膜基质细胞 (Human Endometrial Stromal Cell, HESC) 中证明 PRB 是蜕膜化中发挥作用的主要亚型[22]

  • 4.2 雌孕激素对于子宫容受态的时空特异性调节

  • 雌孕激素调控子宫进入容受态的本质是内膜中不同类型细胞响应激素后彼此之间的互作。子宫功能层的细胞类型主要包括基质细胞、腔上皮细胞和腺上皮细胞,子宫不同或相同类型细胞之间的信息交流对于子宫功能的改变是很重要的,细胞与细胞间的自分泌或者旁分泌作用,导致不同类型细胞对雌孕激素产生时空特异性的反应。雌孕激素受体广泛表达于子宫不同类型细胞中,同时可以调控不同类型细胞的增殖和分化。雌激素通过基质细胞表达的ERα,以生长因子介导的旁分泌作用方式诱导上皮增殖[23]。虽然子宫上皮表达的ERα对雌激素诱导的上皮增殖不是必需的,但是在上皮特异性敲除 ERα后会导致雌激素响应的子宫增生以及上皮增殖后细胞凋亡异常[24]。而基质和上皮细胞中表达的 ERα对于子宫上皮的分化都是不可或缺的,需要它们共同作用[2125]。利用组织重构实验发现,基质中表达的PR能够抵抗雌激素诱导的子宫上皮增殖[26],上皮 PR 的表达对子宫-基质交流对话具有重要作用,上皮中 PR 的缺失会导致胚胎黏附失败,蜕膜化受损,雌激素诱导的上皮增殖失调,最终妊娠失败[27]。PR 在妊娠过程中是动态表达的,在容受态建立时,PR在子宫中表达广泛,而在胚胎植入前, PR 在上皮中的表达消失,仅表达于基质细胞中[28],这是子宫容受态和胚胎黏附的一个标志,分别在上皮和子宫中持续表达 PRA 的小鼠模型都表现为胚胎黏附失败,蜕膜化异常,最终雌性小鼠不育。进一步发现 PRA 在容受态窗口期上皮中的表达消失对 IHH 的下调,LIF 信号的激活是必要的,上皮 PRA的消失有利于诱导子宫产生胚胎黏附的容受态环境[29]。同时有研究也证明在上皮中PRA和PRB在胚胎植入前子宫中的功能相似[30]。总之,孕激素通过上皮和基质 PR 共同参与发挥调控作用,诱导基质细胞增殖,同时拮抗雌激素诱导的上皮增殖,以时空特异性方式调节子宫容受态。

  • 雌孕激素在激活受体后主要通过在子宫不同类型细胞中诱导产生一些时空特异性的自分泌、旁分泌或邻分泌因子来调控子宫容受态的建立。在小鼠子宫中,IL-6家族成员之一白血病抑制因子LIF是雌激素效应的一个靶基因,在妊娠第4天早上分泌的雌激素作用下,LIF 在子宫腺上皮细胞中特异性表达,雌性小鼠中 LIF缺失后表现为容受态建立异常,不能发生胚胎植入[31]。研究发现,LIF 通过结合腔上皮中表达的 LIFR 受体进而促进下游 STAT3 磷酸化激活,导致腔上皮细胞的极性发生变化,最终调控子宫容受态的建立[32-34]。转录因子 Msx1 是 LIF 信号通路下游的一个关键靶基因,妊娠第 4 天表达于子宫上皮,LIF信号激活后能够诱导Msx1的表达下调;在子宫中 Msx1 特异性缺失小鼠表现为上皮极性的变化异常,在敲除小鼠中子宫上皮细胞极性仍然很强,导致子宫上皮细胞与滋养层细胞间的互作出现异常,胚胎植入失败[35]。在健康女性的子宫内膜中,发现 LIF在整个月经周期中表达,在分泌中期显著增加,与着床窗口相一致,受体 LIFR和gp130同样在整个周期的子宫内膜上皮中表达,在分泌中期强烈增加。而 LIF及其受体在不孕妇女子宫内膜容受态期表达明显减少[36]

  • 在孕激素作用下,Hedgehog 家族成员 IHH 特异表达于子宫上皮细胞,而相应受体 Patched-1 (PTCH1) 和下游靶基因 Nr2f2 (Coup-TFⅡ) 表达于子宫基质细胞中,孕激素激活受体后通过IHH信号通路介导上皮与基质细胞之间的互作。子宫中 Ihh特异性缺失小鼠表现为孕激素诱导的基质增殖、血管生成和蜕膜化异常,孕激素效应减弱,相应上皮雌激素响应过度,造成两种激素活性的失衡,影响子宫容受态的建立,最终导致植入失败,这与 PR缺失小鼠的表型相似[3738],表明IHH信号通路是孕激素在子宫中介导上皮与基质间互作,参与胚胎植入所必需的。在人子宫内膜中同样有IHH及其受体的表达,调控子宫内膜容受态,且发现在子宫内膜异位症和腺肌症病人的子宫内膜中,IHH信号表达异常[39]。HAND2 是受孕激素诱导的特异性表达于子宫基质细胞中的一个分子,主要在孕激素对上皮细胞增殖抑制中是必须的,子宫中Hand2特异性缺失引起妊娠第4天雌激素诱导的上皮细胞持续增殖,导致子宫内膜容受态建立异常,胚胎植入失败[40]。在人分泌期子宫内膜和体外培养的蜕膜化 HESC 中, HAND2 受雌孕激素诱导表达,沉默 HAND2 后 HESC 蜕膜化异常[41]。同源框基因 (Homeobox Genes,HOX) HOXA10 对子宫内膜容受态十分重要,在人月经周期的分泌中期的子宫内膜中高表达,在整个过程受到雌孕激素的调控[14]

  • 4.3 孕激素受体活性与容受态

  • 雌孕激素受体作为甾体类激素受体,它们发挥转录调控功能时依赖于同分子伴侣、共激活因子等辅助因子相互作用,从而能够与激素结合以及发挥随后的转录激活功能。研究发现,伴侣分子 FKBP52可以通过调节PR的转录活性从而调节子宫对孕激素的敏感性。小鼠缺失 FKBP52后,血清中雌孕激素水平正常,雌激素响应正常,但孕激素效应减弱,子宫容受态异常,导致胚胎植入失败,而这种缺陷可以通过高剂量孕激素的外源补充得以挽救,说明了 FKBP52在孕激素信号调控子宫容受态建立中的关键作用[42-44]。SRC 是一类经典的激素核受体辅助因子,有 SRC1、SRC2、SRC3 等多个成员,其中 SRC2 与孕激素受体可以发生互作,在小鼠中条件性敲除SRC2 (也称TIF-2或GRIP-1) 后,具有与激素受体缺失相似的表型,即孕激素响应缺陷,导致容受态建立异常,最终植入失败[4546],同时人类中也发现 SRC2 高表达于子宫内膜中[47], HESC 体外蜕膜化实验证明 SRC2 对于蜕膜化是必须的[48]。KLF 家族成员 KLF9 也可以作为孕激素受体转录活性的调节因子,小鼠缺失 KLF9 后表现为生育能力低下,孕激素敏感性下降[49]。在人类中,在蜕膜化发生前 KLF9与 PRA和 PRB的表达呈现正相关,但是在蜕膜化 HESC 中无正相关,提示 KLF9与PR调节网络与子宫容受态建立有关[50]

  • PR 作为孕激素发挥下游调控作用的核受体,也受到蛋白水平存在的修饰影响,进而调控子宫容受态的建立。研究发现多梳复合体成员之一 BMI1 能够通过泛素连接酶 E6AP 调节 PR 的泛素化修饰,进而影响子宫细胞对孕激素的响应,Bmi1 条件性缺失小鼠表现出孕激素效应减弱,容受态异常,最终导致植入失败,进一步研究表明,BMI1与PR和 E6AP互作,调节PR泛素化修饰,进而影响孕激素响应性,而且BMI1对PR的影响在人和小鼠中是保守的,在临床复发性流产患者的子宫内膜样本中检测 BMI1 和 E6AP 表达,与对照相比,部分样本中 BMI1 的表达水平较低,对应孕激素的响应基因表达也异常。研究者发现,异常低的 BMI1 表达与流产妇女子宫内膜PR反应性的降低密切相关[51]。P38 MAPK 丝氨酸/苏氨酸蛋白激酶家族成员 p38α 的条件性缺失会导致子宫基质中 PR 蛋白水平的急剧下调和孕激素响应紊乱,从而导致子宫容受态异常,最终植入失败,雌性不孕。进一步研究表明, p38α 缺失之后,HECT 家族 E3 泛素连接酶 UBE3C 能够异常增加 PR 的泛素化,并通过蛋白酶体降解 PR,揭示p38α通过调控子宫内膜PR蛋白稳定性调节子宫容受态[52]。有研究发现,高度保守的转录因子 SOX4 在人子宫内膜分泌期的基质细胞中高表达,体外培养的人子宫内膜基质细胞中缺失 SOX4 后,表现为 PR 表达降低,蜕膜化异常,机制研究发现,SOX4缺失后,E3泛素连接酶HERC4能够靶向PR泛素化,使其发生泛素化降解,从而调控PR 蛋白稳定性,蜕膜化异常,同时在人反复种植失败的内膜样本中也检测到 SOX4-HERC4-PR 信号轴异常[53]

  • 4.4 雌激素受体活性与容受态

  • 相比于孕激素来说,对雌激素受体发挥转录调控作用时所需伴侣分子或者共激活因子的研究较少,其中在固醇类受体的共激活因子家族中,发现 P300 以及 SRC1、SRC2、SRC3 几个成员都可与 ER 互作,影响 ER转录活性[54]。研究发现,SRC6作为一个负调节因子调节 ER 的转录活性,调节雌激素敏感性,从而决定子宫容受态的建立。在子宫上皮和基质细胞对Ncoa6条件敲除后,雌激素的敏感性不降低反而显著增加,抑制孕激素调控基因的表达和蜕膜反应,最终胚胎植入失败。机制上,SRC6 能够加强 ERα 的泛素化,加速 ERα 降解,同时促使 ERα共激活分子 SRC3表达下调,从而平衡雌孕激素受体活性,促进子宫容受态的建立[55]。酪氨酸磷酸酶SHP2,研究发现,其可通过增强Src激酶介导的 ERα 酪氨酸磷酸化,增加 ERα 转录活性,参与调节子宫容受态的建立。在 Shp2 特异性敲除的小鼠子宫中,子宫基质中 ERα 活性降低,PR 表达水平下调,子宫基质与上皮间对话受损,容受态发生异常,胚胎植入不能发生[56]。在 HESC中,SHP2 随着蜕膜化进程表达逐渐升高,敲除和过表达实验证明 SHP2 在 HESC 蜕膜化中通过多个信号途径影响蜕膜化,调节胚胎植入[57]

  • 5 总结与展望

  • 本文综述了卵巢来源的雌孕激素在子宫内膜容受性建立过程中的重要调节作用。雌孕激素通过子宫中表达的雌孕激素受体,严格动态调控内膜容受性建立。雌孕激素受体活性受到伴侣分子、共激活因子和泛素化等修饰的调节,最终影响容受态建立。

  • 雌孕激素及其信号传导受到严格调控,雌孕激素信号活性的失衡会破坏它们精密的调节机制,导致雌激素优势和孕激素抵抗,影响容受态建立以及子宫内膜相关疾病的发生。已有的研究显示,表观标记、炎症信号、癌症相关基因以及其他与 PR 直接或间接相关的基因都会导致孕激素抵抗[58]。目前对调节雌孕激素受体活性的分子网络,以及雌孕激素受体在子宫内膜容受态建立过程中发挥的具体功能和分子机制的研究都在持续更新,这是深入了解子宫容受态的关键,有助于解决容受态相关疾病造成的不孕不育。

  • 子宫容受态的研究大多以遗传修饰小鼠和体外培养的 HESC为模型,对人类子宫内膜容受态研究缺乏体外模型,其分子调控的机制研究难以实现。近几年已经有研究者在体外建立三维类器官培养体系,成功培养出能够响应激素的人子宫内膜类器官[59],甚至已经培养出类似植入前胚胎的类囊胚,并能够体外模拟胚胎植入中囊胚黏附反应[6061],这样的培养体系有利于我们在体外对人类内膜容受态建立的调控机制以及反复植入失败等相关疾病发病机制进行研究。雌孕激素对子宫容受态的调控精密且复杂,虽然目前在小鼠和体外细胞培养模型中已经揭示了雌孕激素相关的部分信号传递网络,仍有众多生理和疾病相关的问题需要思考和研究,例如在人类月经周期中,雌孕激素协同调节基质和上皮的增殖分化以进入容受态的分子机制?分泌期存在的小雌激素峰是否类似在小鼠中的发现、可协同孕激素调控内膜更好地分化以进入容受态?雌孕激素受体在转录和翻译水平上存在的各种修饰、结合的共调节分子如何调控以实现其时空表达?孕激素抵抗如何发生又如何造成子宫内膜相关疾病,导致女性不孕不育?目前遗传修饰小鼠结合人类生理病理的临床材料已经证实很多卵巢雌孕激素调节子宫内膜容受态建立的关键分子;有研究者对子宫内膜的动态变化进行转录组测序分析,获得两百多个基因在胚胎植入过程中的不同时间段表达[14],可用于临床中对容受态状态的判断,利用上述三维类器官模型,有望实现对这些分子动态表达的调控机理和功能机制开展深入研究,揭示人类中内膜容受态调控的关键网络,为女性不孕不育等生殖疾病的预防治疗提供理论指导。

  • 参考文献

    • [1] WASSARMAN P M.Fertilization in animals[J].Dev Genet,1999,25(2):83-86.

    • [2] DEY S K.How we are born[J].J Clin Invest,2010,120(4):952-955.

    • [3] CHA J,SUN X,DEY S K.Mechanisms of implantation:strategies for successful pregnancy[J].Nat Med,2012,18(12):1754-1767.

    • [4] WANG H,DEY S K.Roadmap to embryo implantation:clues from mouse models[J].Nat Rev Genet,2006,7(3):185-199.

    • [5] NORWITZ E R,SCHUST D J,FISHER S J.Implantation and the survival of early pregnancy[J].N Engl J Med,2001,345(19):1400-1408.

    • [6] CRACIUNAS L,GALLOS I,CHU J,et al.Conventional and modern markers of endometrial receptivity:a systematic review and meta-analysis[J].Hum Reprod Update,2019,25(2):202-223.

    • [7] CARSON D D,BAGCHI I,DEY S K,et al.Embryo implantation[J].Dev Biol,2000,223(2):217-237.

    • [8] MATSUMOTO H.Molecular and cellular events during blastocyst implantation in the receptive uterus:clues from mouse models[J].J Reprod Dev,2017,63(5):445-454.

    • [9] DEY S K,LIM H,DAS S K,et al.Molecular cues to implantation[J].Endocr Rev,2004,25(3):341-373.

    • [10] TRANGUCH S,DAIKOKU T,GUO Y,et al.Molecular complexity in establishing uterine receptivity and implantation[J].Cell Mol Life Sci,2005,62(17):1964-1973.

    • [11] PARIA B C,HUET-HUDSON Y M,DEY S K.Blastocyst's state of activity determines the "window" of implantation in the receptive mouse uterus[J].Proc Natl Acad Sci U S A,1993,90(21):10159-10162.

    • [12] QUINN C E,CASPER R F.Pinopodes:a questionable role in endometrial receptivity[J].Hum Reprod Update,2009,15(2):229-236.

    • [13] MURPHY C R.Uterine receptivity and the plasma membrane transformation[J].Cell Res,2004,14(4):259-267.

    • [14] SEHRING J,BELTSOS A,JEELANI R.Human implantation:the complex interplay between endometrial receptivity,inflammation,and the microbiome[J].Placenta,2022,117:179-186.

    • [15] LIM H J,WANG H.Uterine disorders and pregnancy complications:insights from mouse models[J].J Clin Invest,2010,120(4):1004-1015.

    • [16] CONNEELY O M,MULAC-JERICEVIC B,DEMAYO F,et al.Reproductive functions of progesterone receptors [J].Recent Prog Horm Res,2002,57:339-355.

    • [17] CURTIS HEWITT S,GOULDING E H,EDDY E M,et al.Studies using the estrogen receptor alpha knockout uterus demonstrate that implantation but not decidualization-associated signaling is estrogen dependent [J].Biol Reprod,2002,67(4):1268-1277.

    • [18] MARQUARDT R M,KIM T H,SHIN J H,et al.Progesterone and estrogen signaling in the endometrium:what goes wrong in endometriosis?[J].Int J Mol Sci,2019,20(15):3822.

    • [19] LUBAHN D B,MOYER J S,GOLDING T S,et al.Alteration of reproductive function but not prenatal sexual development after insertional disruption of the mouse estrogen receptor gene[J].Proc Natl Acad Sci U S A,1993,90(23):11162-11166.

    • [20] YU K,HUANG Z Y,XU X L,et al.Estrogen receptor function:impact on the human endometrium[J].Front Endocrinol(Lausanne),2022,13:827724.

    • [21] KURITA T,LEE K J,COOKE P S,et al.Paracrine regulation of epithelial progesterone receptor and lactoferrin by progesterone in the mouse uterus[J].Biol Reprod,2000,62(4):831-838.

    • [22] DEMAYO F J,LYDON J P.90 years of progesterone:New insights into progesterone receptor signaling in the endometrium required for embryo implantation[J].J Mol Endocrinol,2020,65(1):T1-T14.

    • [23] COOKE P S,BUCHANAN D L,YOUNG P,et al.Stromal estrogen receptors mediate mitogenic effects of estradiol on uterine epithelium[J].Proc Natl Acad Sci U S A,1997,94(12):6535-6540.

    • [24] WINUTHAYANON W,HEWITT S C,ORVIS G D,et al.Uterine epithelial estrogen receptor alpha is dispensable for proliferation but essential for complete biological and biochemical responses[J].Proc Natl Acad Sci U S A,2010,107(45):19272-19277.

    • [25] BUCHANAN D L,SETIAWAN T,LUBAHN D B,et al.Tissue compartment-specific estrogen receptor-alpha participation in the mouse uterine epithelial secretory response[J].Endocrinology,1999,140(1):484-491.

    • [26] KURITA T,YOUNG P,BRODY J R,et al.Stromal progesterone receptors mediate the inhibitory effects of progesterone on estrogen-induced uterine epithelial cell deoxyribonucleic acid synthesis[J].Endocrinology,1998,139(11):4708-4713.

    • [27] FRANCO H L,RUBEL C A,LARGE M J,et al.Epithelial progesterone receptor exhibits pleiotropic roles in uterine development and function[J].FASEB J,2012,26(3):1218-1227.

    • [28] TAN J,PARIA B C,DEY S K,et al.Differential uterine expression of estrogen and progesterone receptors correlates with uterine preparation for implantation and decidualization in the mouse[J].Endocrinology,1999,140(11):5310-5321.

    • [29] WETENDORF M,WU S P,WANG X,et al.Decreased epithelial progesterone receptor A at the window of receptivity is required for preparation of the endometrium for embryo attachment[J].Biol Reprod,2017,96(2):313-326.

    • [30] LI R,WANG X Q,HUANG Z Y,et al.The role of epithelial progesterone receptor isoforms in embryo implantation[J].iScience,2021,24(12):103487.

    • [31] SONG H,LIM H,DAS S K,et al.Dysregulation of EGF family of growth factors and COX-2 in the uterus during the preattachment and attachment reactions of the blastocyst with the luminal epithelium correlates with implantation failure in LIF-deficient mice[J].Mol Endocrinol,2000,14(8):1147-1161.

    • [32] CHENG J G,CHEN J R,HERNANDEZ L,et al.Dual control of LIF expression and LIF receptor function regulate Stat3 activation at the onset of uterine receptivity and embryo implantation[J].Proc Natl Acad Sci U S A,2001,98(15):8680-8685.

    • [33] SUN X,BARTOS A,WHITSETT J A,et al.Uterine deletion of Gp130 or Stat3 shows implantation failure with increased estrogenic responses[J].Mol Endocrinol,2013,27(9):1492-1501.

    • [34] CHEN J R,CHENG J G,SHATZER T,et al.Leukemia inhibitory factor can substitute for nidatory estrogen and is essential to inducing a receptive uterus for implantation but is not essential for subsequent embryogenesis[J].Endocrinology,2000,141(12):4365-4372.

    • [35] DAIKOKU T,CHA J,SUN X,et al.Conditional deletion of Msx homeobox genes in the uterus inhibits blastocyst implantation by altering uterine receptivity[J].Dev Cell,2011,21(6):1014-1025.

    • [36] AGHAJANOVA L.Leukemia inhibitory factor and human embryo implantation[J].Ann N YAcad Sci,2004,1034(1):176-183.

    • [37] LEE K,JEONG J,KWAK I,et al.Indian hedgehog is a major mediator of progesterone signaling in the mouse uterus[J].Nat Genet,2006,38(10):1204-1209.

    • [38] KURIHARA I,LEE D K,PETIT F G,et al.COUP-TFII mediates progesterone regulation of uterine implantation by controlling ER activity[J].PLoS Genet,2007,3(6):e102.

    • [39] WEI Q,LEVENS E D,STEFANSSON L,et al.Indian Hedgehog and its targets in human endometrium:menstrual cycle expression and response to CDB-2914 [J].J Clin Endocrinol Metab,2010,95(12):5330-5337.

    • [40] LI Q,KANNAN A,DEMAYO F J,et al.The antiproliferative action of progesterone in uterine epithelium is mediated by Hand2[J].Science,2011,331(6019):912-916.

    • [41] MURATA H,TANAKA S,TSUZUKI-NAKAO T,et al.The transcription factor HAND2 up-regulates transcription of the IL15 gene in human endometrial stromal cells[J].J Biol Chem,2020,295(28):9596-9605.

    • [42] TRANGUCH S,CHEUNG-FLYNN J,DAIKOKU T,et al.Cochaperone immunophilin FKBP52 is critical to uterine receptivity for embryo implantation[J].Proc Natl Acad Sci U S A,2005,102(40):14326-14331.

    • [43] YANG Z,WOLF I M,CHEN H,et al.FK506-binding protein 52 is essential to uterine reproductive physiology controlled by the progesterone receptor A isoform[J].Mol Endocrinol,2006,20(11):2682-2694.

    • [44] TRANGUCH S,WANG H,DAIKOKU T,et al.FKBP52 deficiency-conferred uterine progesterone resistance is genetic background and pregnancy stage specific[J].J Clin Invest,2007,117(7):1824-1834.

    • [45] MUKHERJEE A,SOYAL S M,FERNANDEZVALDIVIA R,et al.Steroid receptor coactivator 2 is critical for progesterone-dependent uterine function and mammary morphogenesis in the mouse[J].Mol Cell Biol,2006,26(17):6571-6583.

    • [46] MUKHERJEE A,AMATO P,ALLRED D C,et al.Steroid receptor coactivator 2 is required for female fertility and mammary morphogenesis:insights from the mouse,relevance to the human[J].Nucl Recept Signal,2007,5:e011.

    • [47] GREGORY C W,WILSON E M,APPARAO K B,et al.Steroid receptor coactivator expression throughout the menstrual cycle in normal and abnormal endometrium [J].J Clin Endocrinol Metab,2002,87(6):2960-2966.

    • [48] KOMMAGANI R,SZWARC M M,KOVANCI E,et al.Acceleration of the glycolytic flux by steroid receptor coactivator-2 is essential for endometrial decidualization [J].PLoS Genet,2013,9(10):e1003900.

    • [49] ZHANG X L,ZHANG D,MICHEL F J,et al.Selective interactions of Kruppel-like factor 9/basic transcription element-binding protein with progesterone receptor isoforms A and B determine transcriptional activity of progesterone-responsive genes in endometrial epithelial cells[J].J Biol Chem,2003,278(24):21474-21482.

    • [50] PABONA J M,ZENG Z,SIMMEN F A,et al.Functional differentiation of uterine stromal cells involves crossregulation between bone morphogenetic protein 2 and Kruppel-like factor(KLF)family members KLF9 and KLF13[J].Endocrinology,2010,151(7):3396-3406.

    • [51] XIN Q L,KONG S B,YAN J H,et al.Polycomb subunit BMI1 determines uterine progesterone responsiveness essential for normal embryo implantation[J].J Clin Invest,2018,128(1):175-189.

    • [52] TANG Y D,QIU J T,TANG Z Z,et al.P38alpha MAPK is a gatekeeper of uterine progesterone responsiveness at peri-implantation via Ube3c-mediated PGR degradation [J].Proc Natl Acad Sci U S A,2022,119(32):e2206000119.

    • [53] HUANG P X,DENG W B,BAO H L,et al.SOX4 facilitates PGR protein stability and FOXO1 expression conducive for human endometrial decidualization[J].Elife,2022,11:e72073.

    • [54] YI P,WANG Z,FENG Q,et al.Structure of a biologically active estrogen receptor-coactivator complex on DNA[J].Mol Cell,2015,57(6):1047-1058.

    • [55] KAWAGOE J,LI Q,MUSSI P,et al.Nuclear receptor coactivator-6 attenuates uterine estrogen sensitivity to permit embryo implantation[J].Dev Cell,2012,23(4):858-865.

    • [56] RAN H,KONG S B,ZHANG S,et al.Nuclear Shp2 directs normal embryo implantation via facilitating the ERalpha tyrosine phosphorylation by the Src kinase[J].Proc Natl Acad Sci U S A,2017,114(18):4816-4821.

    • [57] CHENG J H,LIANG J,LI Y Z,et al.Shp2 in uterine stromal cells critically regulates on time embryo implantation and stromal decidualization by multiple pathways during early pregnancy[J].PLoS Genet,2022,18(1):e1010018.

    • [58] MACLEAN J A,HAYASHI K.Progesterone actions and resistance in gynecological disorders[J].Cells,2022,11(4):647.

    • [59] TURCO M Y,GARDNER L,HUGHES J,et al.Longterm,hormone-responsive organoid cultures of human endometrium in a chemically defined medium[J].Nat Cell Biol,2017,19(5):568-577.

    • [60] KAGAWA H,JAVALI A,KHOEI H H,et al.Human blastoids model blastocyst development and implantation [J].Nature,2022,601(7894):600-605.

    • [61] YU L Q,WEI Y L,DUAN J L,et al.Blastocyst-like structures generated from human pluripotent stem cells [J].Nature,2021,591(7851):620-626.

  • 参考文献

    • [1] WASSARMAN P M.Fertilization in animals[J].Dev Genet,1999,25(2):83-86.

    • [2] DEY S K.How we are born[J].J Clin Invest,2010,120(4):952-955.

    • [3] CHA J,SUN X,DEY S K.Mechanisms of implantation:strategies for successful pregnancy[J].Nat Med,2012,18(12):1754-1767.

    • [4] WANG H,DEY S K.Roadmap to embryo implantation:clues from mouse models[J].Nat Rev Genet,2006,7(3):185-199.

    • [5] NORWITZ E R,SCHUST D J,FISHER S J.Implantation and the survival of early pregnancy[J].N Engl J Med,2001,345(19):1400-1408.

    • [6] CRACIUNAS L,GALLOS I,CHU J,et al.Conventional and modern markers of endometrial receptivity:a systematic review and meta-analysis[J].Hum Reprod Update,2019,25(2):202-223.

    • [7] CARSON D D,BAGCHI I,DEY S K,et al.Embryo implantation[J].Dev Biol,2000,223(2):217-237.

    • [8] MATSUMOTO H.Molecular and cellular events during blastocyst implantation in the receptive uterus:clues from mouse models[J].J Reprod Dev,2017,63(5):445-454.

    • [9] DEY S K,LIM H,DAS S K,et al.Molecular cues to implantation[J].Endocr Rev,2004,25(3):341-373.

    • [10] TRANGUCH S,DAIKOKU T,GUO Y,et al.Molecular complexity in establishing uterine receptivity and implantation[J].Cell Mol Life Sci,2005,62(17):1964-1973.

    • [11] PARIA B C,HUET-HUDSON Y M,DEY S K.Blastocyst's state of activity determines the "window" of implantation in the receptive mouse uterus[J].Proc Natl Acad Sci U S A,1993,90(21):10159-10162.

    • [12] QUINN C E,CASPER R F.Pinopodes:a questionable role in endometrial receptivity[J].Hum Reprod Update,2009,15(2):229-236.

    • [13] MURPHY C R.Uterine receptivity and the plasma membrane transformation[J].Cell Res,2004,14(4):259-267.

    • [14] SEHRING J,BELTSOS A,JEELANI R.Human implantation:the complex interplay between endometrial receptivity,inflammation,and the microbiome[J].Placenta,2022,117:179-186.

    • [15] LIM H J,WANG H.Uterine disorders and pregnancy complications:insights from mouse models[J].J Clin Invest,2010,120(4):1004-1015.

    • [16] CONNEELY O M,MULAC-JERICEVIC B,DEMAYO F,et al.Reproductive functions of progesterone receptors [J].Recent Prog Horm Res,2002,57:339-355.

    • [17] CURTIS HEWITT S,GOULDING E H,EDDY E M,et al.Studies using the estrogen receptor alpha knockout uterus demonstrate that implantation but not decidualization-associated signaling is estrogen dependent [J].Biol Reprod,2002,67(4):1268-1277.

    • [18] MARQUARDT R M,KIM T H,SHIN J H,et al.Progesterone and estrogen signaling in the endometrium:what goes wrong in endometriosis?[J].Int J Mol Sci,2019,20(15):3822.

    • [19] LUBAHN D B,MOYER J S,GOLDING T S,et al.Alteration of reproductive function but not prenatal sexual development after insertional disruption of the mouse estrogen receptor gene[J].Proc Natl Acad Sci U S A,1993,90(23):11162-11166.

    • [20] YU K,HUANG Z Y,XU X L,et al.Estrogen receptor function:impact on the human endometrium[J].Front Endocrinol(Lausanne),2022,13:827724.

    • [21] KURITA T,LEE K J,COOKE P S,et al.Paracrine regulation of epithelial progesterone receptor and lactoferrin by progesterone in the mouse uterus[J].Biol Reprod,2000,62(4):831-838.

    • [22] DEMAYO F J,LYDON J P.90 years of progesterone:New insights into progesterone receptor signaling in the endometrium required for embryo implantation[J].J Mol Endocrinol,2020,65(1):T1-T14.

    • [23] COOKE P S,BUCHANAN D L,YOUNG P,et al.Stromal estrogen receptors mediate mitogenic effects of estradiol on uterine epithelium[J].Proc Natl Acad Sci U S A,1997,94(12):6535-6540.

    • [24] WINUTHAYANON W,HEWITT S C,ORVIS G D,et al.Uterine epithelial estrogen receptor alpha is dispensable for proliferation but essential for complete biological and biochemical responses[J].Proc Natl Acad Sci U S A,2010,107(45):19272-19277.

    • [25] BUCHANAN D L,SETIAWAN T,LUBAHN D B,et al.Tissue compartment-specific estrogen receptor-alpha participation in the mouse uterine epithelial secretory response[J].Endocrinology,1999,140(1):484-491.

    • [26] KURITA T,YOUNG P,BRODY J R,et al.Stromal progesterone receptors mediate the inhibitory effects of progesterone on estrogen-induced uterine epithelial cell deoxyribonucleic acid synthesis[J].Endocrinology,1998,139(11):4708-4713.

    • [27] FRANCO H L,RUBEL C A,LARGE M J,et al.Epithelial progesterone receptor exhibits pleiotropic roles in uterine development and function[J].FASEB J,2012,26(3):1218-1227.

    • [28] TAN J,PARIA B C,DEY S K,et al.Differential uterine expression of estrogen and progesterone receptors correlates with uterine preparation for implantation and decidualization in the mouse[J].Endocrinology,1999,140(11):5310-5321.

    • [29] WETENDORF M,WU S P,WANG X,et al.Decreased epithelial progesterone receptor A at the window of receptivity is required for preparation of the endometrium for embryo attachment[J].Biol Reprod,2017,96(2):313-326.

    • [30] LI R,WANG X Q,HUANG Z Y,et al.The role of epithelial progesterone receptor isoforms in embryo implantation[J].iScience,2021,24(12):103487.

    • [31] SONG H,LIM H,DAS S K,et al.Dysregulation of EGF family of growth factors and COX-2 in the uterus during the preattachment and attachment reactions of the blastocyst with the luminal epithelium correlates with implantation failure in LIF-deficient mice[J].Mol Endocrinol,2000,14(8):1147-1161.

    • [32] CHENG J G,CHEN J R,HERNANDEZ L,et al.Dual control of LIF expression and LIF receptor function regulate Stat3 activation at the onset of uterine receptivity and embryo implantation[J].Proc Natl Acad Sci U S A,2001,98(15):8680-8685.

    • [33] SUN X,BARTOS A,WHITSETT J A,et al.Uterine deletion of Gp130 or Stat3 shows implantation failure with increased estrogenic responses[J].Mol Endocrinol,2013,27(9):1492-1501.

    • [34] CHEN J R,CHENG J G,SHATZER T,et al.Leukemia inhibitory factor can substitute for nidatory estrogen and is essential to inducing a receptive uterus for implantation but is not essential for subsequent embryogenesis[J].Endocrinology,2000,141(12):4365-4372.

    • [35] DAIKOKU T,CHA J,SUN X,et al.Conditional deletion of Msx homeobox genes in the uterus inhibits blastocyst implantation by altering uterine receptivity[J].Dev Cell,2011,21(6):1014-1025.

    • [36] AGHAJANOVA L.Leukemia inhibitory factor and human embryo implantation[J].Ann N YAcad Sci,2004,1034(1):176-183.

    • [37] LEE K,JEONG J,KWAK I,et al.Indian hedgehog is a major mediator of progesterone signaling in the mouse uterus[J].Nat Genet,2006,38(10):1204-1209.

    • [38] KURIHARA I,LEE D K,PETIT F G,et al.COUP-TFII mediates progesterone regulation of uterine implantation by controlling ER activity[J].PLoS Genet,2007,3(6):e102.

    • [39] WEI Q,LEVENS E D,STEFANSSON L,et al.Indian Hedgehog and its targets in human endometrium:menstrual cycle expression and response to CDB-2914 [J].J Clin Endocrinol Metab,2010,95(12):5330-5337.

    • [40] LI Q,KANNAN A,DEMAYO F J,et al.The antiproliferative action of progesterone in uterine epithelium is mediated by Hand2[J].Science,2011,331(6019):912-916.

    • [41] MURATA H,TANAKA S,TSUZUKI-NAKAO T,et al.The transcription factor HAND2 up-regulates transcription of the IL15 gene in human endometrial stromal cells[J].J Biol Chem,2020,295(28):9596-9605.

    • [42] TRANGUCH S,CHEUNG-FLYNN J,DAIKOKU T,et al.Cochaperone immunophilin FKBP52 is critical to uterine receptivity for embryo implantation[J].Proc Natl Acad Sci U S A,2005,102(40):14326-14331.

    • [43] YANG Z,WOLF I M,CHEN H,et al.FK506-binding protein 52 is essential to uterine reproductive physiology controlled by the progesterone receptor A isoform[J].Mol Endocrinol,2006,20(11):2682-2694.

    • [44] TRANGUCH S,WANG H,DAIKOKU T,et al.FKBP52 deficiency-conferred uterine progesterone resistance is genetic background and pregnancy stage specific[J].J Clin Invest,2007,117(7):1824-1834.

    • [45] MUKHERJEE A,SOYAL S M,FERNANDEZVALDIVIA R,et al.Steroid receptor coactivator 2 is critical for progesterone-dependent uterine function and mammary morphogenesis in the mouse[J].Mol Cell Biol,2006,26(17):6571-6583.

    • [46] MUKHERJEE A,AMATO P,ALLRED D C,et al.Steroid receptor coactivator 2 is required for female fertility and mammary morphogenesis:insights from the mouse,relevance to the human[J].Nucl Recept Signal,2007,5:e011.

    • [47] GREGORY C W,WILSON E M,APPARAO K B,et al.Steroid receptor coactivator expression throughout the menstrual cycle in normal and abnormal endometrium [J].J Clin Endocrinol Metab,2002,87(6):2960-2966.

    • [48] KOMMAGANI R,SZWARC M M,KOVANCI E,et al.Acceleration of the glycolytic flux by steroid receptor coactivator-2 is essential for endometrial decidualization [J].PLoS Genet,2013,9(10):e1003900.

    • [49] ZHANG X L,ZHANG D,MICHEL F J,et al.Selective interactions of Kruppel-like factor 9/basic transcription element-binding protein with progesterone receptor isoforms A and B determine transcriptional activity of progesterone-responsive genes in endometrial epithelial cells[J].J Biol Chem,2003,278(24):21474-21482.

    • [50] PABONA J M,ZENG Z,SIMMEN F A,et al.Functional differentiation of uterine stromal cells involves crossregulation between bone morphogenetic protein 2 and Kruppel-like factor(KLF)family members KLF9 and KLF13[J].Endocrinology,2010,151(7):3396-3406.

    • [51] XIN Q L,KONG S B,YAN J H,et al.Polycomb subunit BMI1 determines uterine progesterone responsiveness essential for normal embryo implantation[J].J Clin Invest,2018,128(1):175-189.

    • [52] TANG Y D,QIU J T,TANG Z Z,et al.P38alpha MAPK is a gatekeeper of uterine progesterone responsiveness at peri-implantation via Ube3c-mediated PGR degradation [J].Proc Natl Acad Sci U S A,2022,119(32):e2206000119.

    • [53] HUANG P X,DENG W B,BAO H L,et al.SOX4 facilitates PGR protein stability and FOXO1 expression conducive for human endometrial decidualization[J].Elife,2022,11:e72073.

    • [54] YI P,WANG Z,FENG Q,et al.Structure of a biologically active estrogen receptor-coactivator complex on DNA[J].Mol Cell,2015,57(6):1047-1058.

    • [55] KAWAGOE J,LI Q,MUSSI P,et al.Nuclear receptor coactivator-6 attenuates uterine estrogen sensitivity to permit embryo implantation[J].Dev Cell,2012,23(4):858-865.

    • [56] RAN H,KONG S B,ZHANG S,et al.Nuclear Shp2 directs normal embryo implantation via facilitating the ERalpha tyrosine phosphorylation by the Src kinase[J].Proc Natl Acad Sci U S A,2017,114(18):4816-4821.

    • [57] CHENG J H,LIANG J,LI Y Z,et al.Shp2 in uterine stromal cells critically regulates on time embryo implantation and stromal decidualization by multiple pathways during early pregnancy[J].PLoS Genet,2022,18(1):e1010018.

    • [58] MACLEAN J A,HAYASHI K.Progesterone actions and resistance in gynecological disorders[J].Cells,2022,11(4):647.

    • [59] TURCO M Y,GARDNER L,HUGHES J,et al.Longterm,hormone-responsive organoid cultures of human endometrium in a chemically defined medium[J].Nat Cell Biol,2017,19(5):568-577.

    • [60] KAGAWA H,JAVALI A,KHOEI H H,et al.Human blastoids model blastocyst development and implantation [J].Nature,2022,601(7894):600-605.

    • [61] YU L Q,WEI Y L,DUAN J L,et al.Blastocyst-like structures generated from human pluripotent stem cells [J].Nature,2021,591(7851):620-626.

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