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1 종 설 대한생식의학회지 : 제 37 권제 3 호 2010 착상및태반발달과정에따른영양막세포의역할 차의과학대학교의생명과학과 김기진 * Role of Trophobolast in Implantation and Placenta Development Gi Jin Kim * Department of Biomedical Science, CHA University School of Medicine, Seoul, Korea The placenta, which is a temporary organ derived from the fetus during pregnancy, is critical to support fetus development via optimal regulation between mother and fetus. Trophoblast as a major cell population of the placenta is one of the earliest to differentiate and shows an extensive proliferation or/and differentiation up to the formation of the placenta. The role of the trophoblast show dynamic changes from early embryo implantation to placentation during pregnancy. Implantation of the blastocyst into the endometrium of the maternal uterus is mediated by invasion of the differentiated trophoblast (e.g. syncytiotrophoblast) from the trophectoderm. During pregnancy, the unique role of the trophoblast is to invasion, eroding, and metastasizing in the placenta as well as to ensure appropriate bidirectional nutrient or waste flow required for growth and maturation of the embryo. The dysfunction of the trophoblast during pregnancy can result in several gynecological diseases including preeclampsia and congenital malformation in neonatal medicine. Therefore, trophoblasts act as a conclusive factor in placental and fetal development. This brief review outlines the classification of trophoblast and its function in the placenta during pregnancy. Also, we introduce the latest research in trophoblast for implantation and the placenta development, and the application potential of trophoblast for infertility and obstetrical diseases. [Korean. J. Reprod. Med. 2010; 37(3): ] Key Words: Placenta, Trophoblast, Implantation, Invasion, Infertility 태반은정자와난자가수정된후발생된포배 (blastocyst) 의바깥부분에존재하는영양외배엽 (trophectoderm) 으로부터유래한영양막세포 (trophoblast) 의증식과분화에의해발생되는태아기원의장기이다. 1 임신기간동안일시적으로생성된태반은태아의발생및발달에필요한영양성분, 노폐물, 그리고산소등이탯줄을통하여산모와태아 접수일 : 2010 년 9 월 7 일, 수정일 : 2010 년 9 월 13 일게재확정일 : 2010 년 9 월 20 일주관책임자 : 김기진, 우 ) 서울특별시강남구역삼동 , 차의과학대학교의생명과학부 Tel: (02) , Fax: (02) gjkim@cha.ac.kr * 본연구는보건복지가족부보건의료기술연구개발사업의지원에의하여이루어진것임 ( 과제번호 A084923). 에게전달될수있도록매개체역할을할뿐아니라태반내다양한세포들에서자체적으로다양한호르몬을포함한생리활성물질들을합성과분비를수행함으로써임신기간동안태아와자궁의성장에중요한역할을하며, 태반은정상적인분만시태아체중의약 25% 내외까지증식된다고알려져있다. 2 영양막세포는태반을형성하는대표적인세포로, 배아 (blastos: germinator) 에영양공급 (trephein: to feed) 을한다는그리스어원처럼, 발생초기부터포배의가장자리에위치하면서포배내태아로발달될수있는세포내괴 (inner cell mass) 에배아발생 (embryogenesis) 관련신호전달과영양물질을제

2 착상및태반발달과정에따른영양막세포의역할 대한생식의학회지 공하고, 착상초기모체의자궁내막에존재하는탈락막세포 (decidual cells) 와의상호작용을통하여자궁내막층으로침윤하여성공적인착상을유도함으로서임신유지와태아의발달에중요한역할을한다. 영양막세포는크게융모 (villi) 에존재하는융모성영양막세포 (villous trophoblast) 와태반의세포외기질내존재하는융모외성영양막세포 (extravillous trophoblast) 로구분될수있으며, 분화 (differentiation) 에따라, 세포영양막세포 (cytotrophoblast) 와합포영양막세포 (syncytiotrophoblast) 로구분될수있다. 3 특히, 포배시기에존재하는영양막세포는세포영양막세포로분열과증식력이왕성하고다른종류의영양막세포로분화할수있는가능성을갖고있어영양막줄기세포라고도명명된다. 4 이러한, 세포영양막세포는착상초기급격히세포영양막세포가세포간합체 (cell-to-cell fusion) 기전을통하여합포영양막세포로분화되면서모체의자궁내막세포와상호작용으로안정적인착상이이루어질수있도록기능을한다. 또한, 영양막세포는태아의발달뿐아니라태반발달시기에따라필요한여러물질들의발현정도를조절하고, 임신초기자궁내막층에존재하는모체의관상동맥 (spiral artery) 의혈관구조를변형시킴으로써복잡한그물망형태의혈관구조를갖는태반의혈관구조형성에결정적인역할을하는것으로알려져있다. 5 따라서, 태반발달단계별영양막세포의기능부전에따른태반의기형적인구조발생이태반의기능부전으로연결되고, 이에따른태반내혈관내피세포의기능저하, 그리고영양막세포의세포자멸사 (apoptosis) 와세포증식 (proliferation) 간의부조화등에의해직, 간접적으로태아의성장발달에영향을미쳐심각한성장장애를비롯한다양한태아의발달에손상을초래할수있고, 혈관확장을통한태반발달에중요할뿐아니라산과질환에도영향을주는중요한요소이다. 3,6 그렇지만, 최근까지출산후적출되는태반에대한연구가시작되는실정에서, 임신초기인착상단계와임신기간동안의태반발달에서의영 양막세포의역할에대한연구는미흡한실정으로, 최근들어영양막세포관련연구의필요성이대두되었다. 본고찰에서는다양한영양막세포들의기능을이해하기위해분류및그종류별특징등을살펴보고, 착상단계와태반발달에따른영양막세포의고유한역할에대해알아보고향후활용될수있는연구분야에대해알아보고자한다. 1. 영양막세포의분류및특징영양막세포는영양막줄기세포 (trophbolast stem cell) 라고명명될수있는세포영양막세포로부터분열, 세포융합, 분화, 그리고위치한주변의환경에따라다양한영양막세포들로구분된다 (Figure 1). 영양막세포는태아로부터기원한정상적인세포임에도불구하고분화 (differentiation) 에따른침윤성 (invasion) 과이수성 (aneuploidy) 등, 암세포와유사한특징을가지고있다. 3 특히, 태반내존재하는영양막세포의위치에따라융모성영양막세포와태반의세포외기질내존재하는융모외성영양막세포로구분될수있으며, 분화 (differentiation) 여부에따라세포영양막세포와합포영양막세포로구분될수있다. 융모 (villi) 의 basal lamina, 혹은 cell columns 등과같은 fetoplacental mesenchymae의 basal lamina에존재하는융모성세포영양막세포는분열능력이높은일종의줄기세포의기능을갖고있으면서, 세포영양막세포는 O 2 의분압이낮은저산소상태에서 hypoxia inducible factor-1α의발현이증가, human achaete/scute homologue (Hash)-2 유전자와 Id-2 유전자의발현증가로그분열능력이유지가되면서자연적인분화가억제된다. 7,8 이러한세포영양막세포는 Hash-2 유전자의발현이감소되고, syncytin 유전자의증가, activator protein-2 유전자등의증가, 그리고세포간융합을통하여합포영양막세포로분화가진행되는반면, transforming growth factor (TGF)-β와 endoglin의감소와 wingless-type MMTV integration site family (Wnt) signaling의활성화, 그리고주변환경에따라이동과침윤능력을

3 제 37 권제 3 호, 2010 김기진 Trophoblastic stem cells Resting on the basal laminas of villi, cell columns, cell islands, chorionic plate, and smooth chorion Contact to maternal blood Contact to Fibrin or other extracellular matrix Villous syncytiotrophoblast Extravillous trophoblast Contact to maternal blood or blood vessels Invasive extravillous trophoblast Unknowns Proliferative extravillous trophoblast Endovascular trophoblast Multinucleated trophoblast (interstitial trophoblast) Figure 1. Nomenclature of the various subtypes of trophoblast cells depends on differentiation of trophoblast (modified by Benirschke K, Kaufmann P. Pathology of the human placenta. 4th ed. New York: Springer; 2000). Gi Jin Kim. Role of Trophobolast in Implantation and Placenta Development. Korean J Reprod Med 갖는융모외성영양막세포로분화된다. 9,10 융모성영양막세포는융모의외벽을싸고있는융모성합포영양막세포로, 착상초기모체의자궁내막에침윤하면서임상에서도착상성공유무를확인할수있는진단마커로활용되는 human chorionic gonadotropin를분비할뿐아니라태아발달과태반발달에관여되는다양한물질들의합성과분비를하는실질적인세포라할수있다. 또한, 임신기간동안모체와태아간의물질이동시태아발달에유해한물질들의이동을조절하는태반장벽 (placental barrier) 역할을한다. 융모성합포영양막세포로써기능을다한합포영양막세포은 syncytial fusion에의해서다핵 (aggregated nuclei) 을갖는 syncytial knots을형성하면서세포의노화단계를거쳐세포사멸기전으로태반내혈액으로 apoptotic nuclei가배출되는과정을갖는다. 이렇게제거된부분의합포영양막세포손실은융모의기질내에존재하는세포영양막세포의빠른분열과 분화로다시보완된다. 한편, 태반조직내 fibrin 혹은다른 extracellular matrix (ECM) 과의접촉된영양막세포는융모외성영양막세포로구분되는데, 이세포의특징은침윤하는능력을갖고있고, 혈액및혈관과의접촉으로혈관내로침윤되어혈관확장을유도하는혈관내영양막세포 (endovascular trophoblast) 와전반적인태반내 ECM으로침윤되는간질성영양막세포 (interstitial trophoblast) 등으로침윤되는위치에따라구분된다. 이러한, 융모외성영양막세포는착상시모체자궁내막층에존재하는다양한면역세포들과의상호작용을통해서침윤능이조절되는데, 모체면역시스템에서태아유래영양막세포에대한과도한면역반응은 uterin NK cell들이분비하는 interferon-gamma (INF-γ), tumor necrosis factor-alpha (TNF-α), interleukin (IL) 등과같은다양한사이토카인들의분비를촉진시켜 cytotoxic T cell 의활성도를높임으로써침윤중인영양막세포를공격하여침윤

4 착상및태반발달과정에따른영양막세포의역할 대한생식의학회지 억제를유도한다. 이러한현상은부절절한태반형성 (placentation) 을유발하여, 태아의발달에영향을미칠수있는자간전증 (pre-eclampsia), 링성장제한 (intrauterine growth restriction, IUGR) 등과같은산과질환을유발한다. 11~13 2. 착상단계에서의영양막세포의역할 수정된배아는 7일전, 후모체의자궁내막층으로착상이이루어진다. 이때, 포배의바깥부위에 Table 1. Key factors regulating trophoblast cells functions (Referred to the reference Lunghi L, et al. Control of human trophoblast function. Reprod Biol Endocrinol 2007; 5: 6) Factors Sources Effects Proliferation Migration Invasiveness Adhesion molecules Trophoblast Angiopoietins Deciduas, trophoblast Colony stimulating factor-1 Placenta, decidua Decorin Decidua Epidermal growth factor Deciduas, trophoblast Endothelin Placental blood vessels, CT, ST, EVT Hepatocyte growth factor Decidua, trophoblast Insulin-like growth factor II Trophoblast Insulin-like growth factor binding protein I Decidua Melanoma cell adhesion molecule Uterin smooth muscle cells Metalloproteinases Trophoblast Nodal Placenta Hypoxia Urokinase-type plasminogen activator Trophbolast Prostaglandin E2 Deciduas, trophoblast 15-F2t-Isoprostanes Decidua Placenta growth factor Trophoblast Transforming growth factor-β Deciduas, trophoblast, unk cells Tumor necrosis factor-α Deciduas, unk cells, decidual macrophages Vascular endothelial growth factor Deciduas, trophoblast Gi Jin Kim. Role of Trophobolast in Implantation and Placenta Development. Korean J Reprod Med

5 제 37 권제 3 호, 2010 김기진 존재하는세포영양막세포가합포영양막세포로빠른분화가유도되면서, 모체의자궁내막층으로의침윤이일어나는데, 이를착상 (implantation) 이라한다. 14,15 영양막세포가자궁내막에착상하는위치는포배의위치를잡아주는자궁내막에 pinopode가존재하는부위로, 자궁내막세포에서분비되는인테그린 (integrin) 을포함한다양한사이토카인들이분비될뿐아니라포배의영양막세포에서도성공적인착상을위해인테그린등과같이다양한부착성분 (adhesion molecule) 들이발현되고, 16 자궁내막내로침윤하기위한 matrix metalloproteinases (MMPs) 등의발현이증가된다. 특히, 착상초기 (10~12주) 는배아가착상된자궁내막내의혈관구조가발달되지못한상태로, 배아의주변환경의산소분압은정상대기분압인 20% (po 2 =140 mm Hg) 보다훨씬낮은 6~8% 정도의분압 (40 mm Hg) 으로유지되는데, 17,18 낮은분압은영양막세포의세포영양막세포에서합포영양막세포로의분화를촉진하고, 침윤능력을향상시켜모체자궁내막내에존재하는관상동맥혈관으로이동을촉진하게된다. 따라서, angiogenic potential을갖는영양막세포요인들은저산소상태 (hypoxia) 에의해활성화된다. 19 착상단계에서영양막세포의기능은크게증식, 이동, 그리고침윤등으로구분될수있는데, 이러한영양막세포의기능을조절하는인자는대표적으로부착성분 (adhesion molecule), 성장요소 (growth factor), 혈관형성인자 (angiogenic factors), MMPs, 그리고저산소증 (hypoxia) 등으로구분될수있으며, 요약하면 Table 1과같다. 8,20 착상단계시영양막세포가갖는고유한특징중하나인침윤능력은암세포가아닌정상세포가침윤능을갖는것은매우이례적인것으로, 이는영양막세포가분비하는다양한 MMPs에의한것으로, 영양막세포에서의 MMPs 분비는활성화된 MMPs를포함하여 upa, plasminogen, thrombin, 그리고 elastase 등에의해조절될수있다. In vitro 연구를통해서도, 탈락막 (deciduas) 층을지나모체의혈관구조로의침윤에 MMP-2와 MMP-9의발현이중요한역할을하는것이확인되 었다. 21 이러한, 영양막세포의침윤을조절하는대표적인신호전달체계로는 Janus kinase/signal transducers and activators of transcription (JAKs-STAT) pathway가알려져있는데, 착상과정시주변자궁내막층에서분비되는다양한사이토카인과영양막세포에서분비되는사이토카인들, 특히, IL-6, IL-11, human hepatocyte growth factor, leukaemia inhibitory factor, 그리고 granulocytes-macrophage-colony stimulating factors 같은다양한사이토카인에의해서 JAKs- STAT pathway 가활성화되면서, 인산화된 STAT3 에의해서영양막세포의침윤이증가된다 태반발달단계에서의영양막세포의역할태반은복잡한혈관구조로형성된장기로, 임신기간동안태아의발달에필요한여러영양분과노폐물, 그리고산소등을운반한다. 따라서, 임신초기활발한혈관형성기전을통하여임신기간동안형성된혈관들의기능은태아의발달뿐아니라태반발달과기능에중요한역할을하므로, 혈관형성과기능의중요성으로볼때임신상태를일종의 pro-angiogenic state라고도할수있다. 23 따라서, 착상후태아가발달되면서이에따라자궁내태반의성장도임신말기에는태아체중의약 25% 전후까지비율이증가되므로, 임신기간동안의부적절한혈관형성은산과질환을유발하는대표적요인으로보고되고있다. 24 영양막세포의침윤은정상적인태반형성 (placentation) 의중요한요인으로, intervillous space와 maternal blood flow간의적절한혈관구조를형성한다. 특히, 모체의탈락막조직 (decidual tissues) 과자궁내막층에존재하는관상동맥 (spiral artery) 으로의융모외성영양막세포침윤은암세포의침윤과도유사한형태지만, 임신초기에만국한되어있는특징을갖고있으며자궁내막층의하단의 1/3 부위까지만진행되는제한된침윤으로, 과도한침윤은양성종양의일종인융모암 (choriocarcinoma) 으로진행된다. 25 특히, 이러한임신초기영양막세포의침윤은착상이처음이루어

Brown colors are trophoblast cells for positive to cytokeratin 7 antibody, which is a marker of trophoblast.

6 착상및태반발달과정에따른영양막세포의역할 대한생식의학회지 * * Figure 2. Remodeling of spiral artery in placental bed biopsy tissues between normal and pre-eclampsia. Transformation of spiral artery in placental bed biopsy between normal (A) and pre-eclampsia (B). *means spiral artery. Spiral artery stained by Periodic acid-schiff (PAS) staining. Brown colors are trophoblast cells for positive to cytokeratin 7 antibody, which is a marker of trophoblast. Arrowhead and arrow mean endovascular trophoblast in the endothelium of spiral artery and interstitial trophoblast, respectively ( 200). Gi Jin Kim. Role of Trophobolast in Implantation and Placenta Development. Korean J Reprod Med A B 지는위치인 placental bed에서혈관의확장 (spiral artery remodeling) 에중요한역할을하는데, 정상적인임신상태에서는이관상동맥 (spiral artery) 의확장이영양막세포가혈관내피세포로의침윤을통하여이루어진다. 따라서, placental bed 부위에서의부적절한혈관내영양막세포의침윤으로인한혈관확장의실패는곧태반의혈관형성및혈류공급에영향을주므로 IUGR 혹은자간전증 (preeclampsia) 등과같은초기발병되는산과질환의유발하는주요원인이된다. 26 임신초기혈관내영양막세포의관상동맥 (spiral artery) 으로의침윤불충분으로혈관확장이이루어지지않는상태에서는혈류량의감소로인한저산소상태가오래유지되면서태반내산화적스트레스로인해 soluble Flt-1이증가되고, 모체의자궁내막세포의변화, 과도한합포영양막세포의세포자멸사 (apoptosis), 그리고모체에서의면역체계에서의이상등이유발되면서결국임신중반이후에자간전증의증상인고혈압 (140/90 mm Hg), 단백뇨 (300 mg 이상 /24시간뇨 ), 그리고부종등이유발된다. 특히, 자간전증은임신중반이후산모에게서나타나는고혈압, 단백뇨, 그리고부종등을통하여진단되며, 전체임신부의약 5% 이상의발현빈도를나타내며, 산모와신생아의사망률이높은대표적인고위험산과질환이다. 27,28 현재까지알려진자간전증관련병인학적원인은임신초기유전적인요인, 산모의면역학적요인, 낮은산소분압과같은외부환경적인요인등으로구분될수있다. 또한아직까지잘밝혀지지않은요인들로인한태반의기능저하에따른혈관내피세포의기능저하, 그리고영양막세포의세포사멸과세포증식간의부조화등에의해자간전증이유발된다고알려져있으나, 가장큰병인학적요인으로영양막세포의부적절한침윤관련혈관내피세포의기능부전이다 (Figure 2). 하지만, 현재까지자간전증의진단및치료를위한진단마커및치료방법이없는실정으로더많은연구가필요한실정이다. 29,30 그외에도모체와태아간의중간매개체인태반에서의영양막세포의기능은모체의자궁내막층과혈액내존재하는면역세포들과의상호작용을통하여임신유지뿐아니라태아의발달을조절하는역할을한다. 특히, 영양막세포에서의 human leukocyte antigen-g 발현은모체의면역시스템에서외부물질 (foreign body) 로인식되는태아를회피혹은모체의면역세포의공격을억제하는역할을하는요인으로성공적인임신유지에중요한요

7 제 37 권제 3 호, 2010 김기진 인이며, 영양막세포의표면에서의 CXC-chemokine receptor (CXCR)1과 CXCR3 등의발현과 CXCR8, CCL3, 그리고 CXCL12 등과같은사이토카인의분비는영양막세포의이동 (migration) 에중요한역할을하는요인들이다. 31,32 그러나, 태반발달의시기및위치별역동적인역할을하는영양막세포에대한연구는여전히많은부분연구할분야로남아있다. 맺음말영양막세포는태반의발달에중요한역할을하는대표적인세포로, 이세포들은임신초기착상시기부터임신말기태반에이르기까지지속적인증식, 분열, 분화, 세포사멸등의역동적인단계를거쳐태반의발달과기능을조절하는중요한역할을한다. 따라서, 다양한기능을갖는영양막세포에관련된연구는증식, 이동, 침윤, 세포간융합을통한염색체이수성 (aneuploidy), 그리고분화에따른세포자멸사등에관한기전연구가진행되어왔다. 그러나, 아직도정확한분자생물학적기전규명이확립되지않은채로더많은연구가필요한분야이다. 또한, 인체유래태반조직확보의제한으로인체유래태반내영양막세포에대한연구는한정되어있는실정이다. 특히, 인체유래태반과설치류를포함한실험동물유래의태반은해부학적및구조학적큰차이를갖기때문에동물유래태반내에존재하는영양막세포의종류와기능에도차이가있어, 동물태반을이용한영양막세포의기능이인간유래태반내존재하는영양막세포의기능을대변할수있는지는아직도학계에서논란중이다. 33,34 따라서, 이러한제한을극복하고자최근영양막줄기세포에관한관심이증가되고있다. 영양막줄기세포는자가증식능 (self-renewal) 을갖고있으며, 합포영양막세포 (syntithiotrophoblast), 간질성영양막세포 (interstitial trophoblast), 혈관내영양막세포 (endovascular trophoblasts) 등과같은다양한영양막 세포로분화가능하기때문에분화된영양막세포의기능분석및분화과정별기전연구에활용할수있는장점을갖고있다. 35 또한, 영양막줄기세포를이용한연구분야는임신초기배아발생기전, 영양막세포의분화조절기전, 침윤기전, 산과질환관련기전, 그리고착상장애등을유발하는불임기전을연구할수있는좋은모델로활용가능하다. 특히, 인간배아줄기세포로부터유래된세포영양막줄기세포 (cytotrophoblast stem cells) 은착상시와유사한침윤능을보임으로써착상기전연구를포함한산과질환관련임상연구의새로운분야를제시하였다. 36 이처럼, 영양막세포의기능과기전연구에필요한새로운 in vitro 시스템을통한관련인자들의상호관계를규명할수있다면, 임신초기착상단계로부터태아의발달및산과질환으로의진행을예측하고예방할수있는기초자료로활용될수있을것이다. 참고문헌 1. Moore KL, Persaud TVN, Torchia MG. The developing human: clinically or ientated embryology. 8th ed. Philadelphia: Elsevier Saunders; Craven CM, Zhao L, Ward K. Lateral placental growth occurs by trophoblast cell invasion of decidual veins. Placenta 2000; 21: Benirschke K, Kaufmann P. Pathology of the human placenta. 4th ed. New York: Springer Verlag; Spitalieri P, Cortese G, Pietropolli A, Filareto A, Dolci S, Klinger FG, et al. Identification of multipotent cytotrophoblast cells from human first trimester chorionic villi. Cloning Stem Cells 2009; 11: Harris LK. Review: Trophoblast-vascular cell interactions in early pregnancy: how to remodel a vessel. Placenta 2010; 31(Suppl): S Jeon SY, Lee HJ, Park JM, Jung HM, Yoo JK, Lee JS, et al. Increased immortalization-upregulated protein 2 (IMUP-2) by hypoxia induces apoptosis of the trophoblast and pre-eclampsia. J Cell Biochem 2010; 110: Morrish DW, Dakour J, Li H. Life and death in the placenta:

8 착상및태반발달과정에따른영양막세포의역할 대한생식의학회지 new peptides and genes regulating human syncytiotrophoblast and extravillous cytotrophoblast lineage formation and renewal. Curr Protein Pept Sci 2001; 2: Lunghi L, Ferretti ME, Medici S, Biondi C, Vesce F. Control of human trophoblast function. Reprod Biol Endocrinol 2007; 5: Caniggia I, Taylor CV, Ritchie JW, Lye SJ, Letarte M. Endoglin regulates trophoblast differentiation along the invasive pathway in human placental villous explants. Endocrinology 1997; 138: Adjaye J, Huntriss J, Herwig R, BenKahla A, Brink TC, Wierling C, et al. Primary differentiation in the human blastocyst: comparative molecular portraits of inner cell mass and trophectoderm cells. Stem Cells 2005; 23: Lash GE, Otun HA, Innes BA, Percival K, Searle RF, Robson SC, et al. Regulation of extravillous trophoblast invasion by uterine natural killer cells is dependent on gestational age. Hum Reprod 2010; 25: Gonen-Gross T, Goldman-Wohl D, Huppertz B, Lankry D, Greenfield C, Natanson-Yaron S, et al. Inhibitory NK receptor recognition of HLA-G: regulation by contact residues and by cell specific expression at the fetal-maternal interface. PLoS One 2010; 5: e Clark DA, Chaouat G, Wong K, Gorczynski RM, Kinsky R. Tolerance mechanisms in pregnancy: a reappraisal of the role of class I paternal MHC antigens. Am J Reprod Immunol 2010; 63: Red-Horse K, Zhou Y, Genbacev O, Prakobphol A, Foulk R, McMaster M, et al. Trophoblast differentiation during embryo implantation and formation of the maternal-fetal interface. J Clin Invest 2004; 114: Blomberg L, Hashizume K, Viebahn C. Blastocyst elongation, trophoblastic differentiation, and embryonic pattern formation. Reproduction 2008; 135: Franchi A, Zaret J, Zhang X, Bocca S, Oehninger S. Expression of immunomodulatory genes, their protein products and specific ligands/receptors during the window of implantation in the human endometrium. Mol Hum Reprod 2008; 14: Caniggia I, Winter J, Lye SJ, Post M. Oxygen and placental development during the first trimester: implications for the pathophysiology of pre-eclampsia. Placenta 2000; 21(Suppl A): S James JL, Stone PR, Chamley LW. The regulation of trophoblast differentiation by oxygen in the first trimester of pregnancy. Hum Reprod Update 2006; 12: Dubinsky V, Poehlmann TG, Suman P, Gentile T, Markert UR, Gutierrez G. Role of regulatory and angiogenic cytokines in invasion of trophoblastic cells. Am J Reprod Immunol 2010; 63: Jovanovic M, Stefanoska I, Radojcic L, Vicovac L. Interleukin- 8 (CXCL8) stimulates trophoblast cell migration and invasion by increasing levels of matrix metalloproteinase (MMP)2 and MMP9 and integrins alpha5 and beta1. Reproduction 2010; 139: Isaka K, Usuda S, Ito H, Sagawa Y, Nakamura H, Nishi H, et al. Expression and activity of matrix metalloproteinase 2 and 9 in human trophoblasts. Placenta 2003; 24: Fitzgerald JS, Poehlmann TG, Schleussner E, Markert UR. Trophoblast invasion: the role of intracellular cytokine signalling via signal transducer and activator of transcription 3 (STAT3). Hum Reprod Update 2008; 14: Grazul-Bilska AT, Borowicz PP, Johnson ML, Minten MA, Bilski JJ, Wroblewski R, et al. Placental development during early pregnancy in sheep: vascular growth and expression of angiogenic factors in maternal placenta. Reproduction 2010; 140: Reynolds LP, Grazul-Bilska AT, Redmer DA. Angiogenesis in the female reproductive organs: pathological implications. Int J Exp Pathol 2002; 83: Shih IM, Kurman RJ. The pathology of intermediate trophoblastic tumors and tumor-like lesions. Int J Gynecol Pathol 2001; 20: Brosens IA. Morphological changes in the utero-placental bed in pregnancy hypertension. Clin Obstet Gynaecol 1977; 4: Whitley GS, Dash PR, Ayling LJ, Prefumo F, Thilaganathan B, Cartwright JE. Increased apoptosis in first trimester extravillous trophoblasts from pregnancies at higher risk of developing preeclampsia. Am J Pathol 2007; 170: Verlohren S, Geusens N, Morton J, Verhaegen I, Hering L, Herse F, et al. Inhibition of trophoblast-induced spiral artery remodeling reduces placental perfusion in rat pregnancy. Hypertension 2010; 56: Dekker GA, Sibai BM. Etiology and pathogenesis of preeclampsia: current concepts. Am J Obstet Gynecol 1998;

9 제 37 권제 3 호, 2010 김기진 179: Kalkunte S, Lai Z, Norris WE, Pietras LA, Tewari N, Boij R, et al. Novel approaches for mechanistic understanding and predicting preeclampsia. J Reprod Immunol 2009; 83: Apps R, Murphy SP, Fernando R, Gardner L, Ahad T, Moffett A. Human leucocyte antigen (HLA) expression of primary trophoblast cells and placental cell lines, determined using single antigen beads to characterize allotype specificities of anti-hla antibodies. Immunology 2009; 127: Li C, Houser BL, Nicotra ML, Strominger JL. HLA-G homodimer-induced cytokine secretion through HLA-G receptors on human decidual macrophages and natural killer cells. Proc Natl Acad Sci U S A 2009; 106: Carter AM. Animal models of human placentation: a review. Placenta 2007; 28(Suppl A): S Beghin D, Delongeas JL, Claude N, Farinotti R, Forestier F, Gil S. Comparative effects of drugs on P-glycoprotein expression and activity using rat and human trophoblast models. Toxicol In Vitro 2010; 24: Oda M, Shiota K, Tanaka S. Trophoblast stem cells. Methods Enzymol 2006; 419: Harun R, Ruban L, Matin M, Draper J, Jenkins NM, Liew GC, et al. Cytotrophoblast stem cell lines derived from human embryonic stem cells and their capacity to mimic invasive implantation events. Hum Reprod 2006; 21: = 국문초록 = 태반 (placenta) 은임신기간동안에만존재하는태아유래일시적인기관으로, 모체와태아간의정확한조절기전을통해태아의발달을수행하는중요한기관이다. 영양막세포 (trophoblast) 는임신초기빠른분열및분화과정을거쳐태반을형성하는주요세포이다. 영양막세포의역할은초기배아착상시기부터 40주간의임신기간동안태반의형성과정에서다양하게변화된다. 착상은모체자궁내막층으로의포배의가장밖에존재하는분화된영양막세포 ( 예, 합포영양막세포 ) 의침윤에의해이루어진다. 또한, 영양막세포은임신기간동안배아의성숙과발달에필요한영양분과노폐물등을모체와태아양방향으로적절하게전달할뿐아니라태반내에서침윤과다양한물질들의합성혹은분비에관련된대사작용에관여한다. 이기간동안영양막세포의기능이상은태아의선천적인기형뿐아니라자간전증등을포함하는다양한산과질환을유발하기도한다. 그러므로, 영양막세포는태반과태아의발달에결정적인요인으로작용한다. 본고찰에서는다양한영양막세포들의기능을이해하기위해분류및그종류별특징등을살펴보고, 착상단계와태반발달에따른영양막세포의고유한역할에대해알아보고향후활용될수있는연구분야에대해알아보고자한다. 중심단어 : 태반, 영양막세포, 착상, 침윤, 불임

Kaes010.hwp

Kaes010.hwp 갑상선자극호르몬이갑상선암세포의 VEGF, 신생혈관형성, 성장, 침윤및전이에미치는영향 Effects of TSH on the Production of VEGF, Angiogenesis, Growth, Invasion and Metastasis in Thyroid Cancer Cells Euy Young Soh, M.D., Hee Boong Park, M.D.,