臺灣博碩士論文加值系統

胚胎著床的機制很複雜，目前仍未完全清楚。在哺乳類動物的胚胎著床時期，在侵入期，胚胎外圍的滋養層細胞（trophoblast cells）會侵入穿越子宮內膜上皮層（endometrial epithelium）而進入子宮內膜基質（endometrial stroma）。動物實驗發現，在胚胎著床處的子宮內膜上皮細胞有凋亡（apoptosis）徵象；體外實驗也發現，囊胚（blastocyst）和子宮內膜上皮單細胞層共同培養後，囊胚的滋養層細胞會逐漸向外生長，而滋養層細胞附近的子宮內膜上皮細胞亦表現凋亡的特徵。這顯示滋養層細胞可能會造成子宮內膜上皮細胞凋亡，以利滋養層細胞入侵；但是滋養層細胞引起子宮內膜上皮細胞凋亡的訊息傳導路徑目前仍不清楚。當子宮內膜發生蜕膜化反應（decidualization）後，會活化子宮的蛋白酶MAPKs （mitogen-activated protein kinases），而許多研究也發現MAPK是細胞凋亡的訊息傳導路徑之ㄧ，而且在滋養層細胞與子宮內膜上皮細胞進行共同培養的實驗中，發現滋養層細胞會活化子宮內膜上皮細胞的p38 MAPK，而導致子宮內膜上皮細胞凋亡，以利滋養層細胞穿越子宮內膜上皮障礙，進而入侵子宮內膜基質。文獻中可知在細胞及組織內所發生的細胞凋亡反應的過程中，Fas/FasL凋亡系統扮演一個重要的機轉，而且在胚胎與子宮內膜上皮的接觸面會發現有Fas/FasL系統活化的現象。然而，在其他種類的細胞中發現蛋白酶MAPKs活化的作用是與Fas/FasL凋亡系統的反應習習相關的。因此本論文的目的即在探討JNK訊息的路徑以及Fas/FasL凋亡系統於胚胎著床時所扮演的角色。將滋養層細胞株，BeWo，做成約如囊胚大小的球體和子宮內膜上皮細胞株，RL95-2，做成的單細胞層共同培養，來模仿囊胚與子宮內膜的交互作用。首先，用西方墨漬法顯示，子宮內膜上皮細胞的JNK於共同培養後會有被活化的現象。而且，SP600125（一種JNK抑制劑）可以經由避免子宮內膜上皮細胞及滋養層細胞內JNK的活化來抑制滋養層細胞於子宮內膜上皮單細胞層的擴張。接著，藉由MTT的方法顯示，RL95-2所表現的Fas和FasL是具有可被Fas引發發生細胞凋亡的功能性，但在BeWo中並沒有發現。之後發現Anti-Fas neutralizing Ab無法顯著地抑制滋養層細胞於子宮內膜上皮單細胞層的擴張，但是Anti-Fas activating Ab卻會明顯地促進滋養層細胞於子宮內膜上皮單細胞層的擴張，再著，利用annexin V及VAD-FMK （valyl-alanyl-aspartyl-[O-methyl]-fluoromethylketone；可結合caspases）染色法顯示，滋養層細胞的擴張會造成其附近的子宮內膜上皮細胞凋亡，而且當有Anti-Fas activating Ab存在下，被偵測到的細胞凋亡數量以及caspases活化的現會有顯著地增多，之後，使用Z-VAD (pan-caspase 的抑制劑)只會發現有微弱地滋養層細胞於子宮內膜上皮單細胞層的擴張，但是Z-VAD會抑制由Anti-Fas activating Ab所促使的滋養層細胞擴張的現象。此外我們也發現Anti-Fas activating Ab會活化子宮內膜上皮單細胞層的p38 MAPK及JNK訊號，而SB203580(p38 MAPK的抑制劑)及SP600125(JNK的抑制劑)皆分別具有抑制由Anti-Fas activating Ab所促使的滋養層細胞擴張的現象。進一步利用VAD-FMK染色技術顯示，當有Anti-Fas activating Ab存在時，滋養層細胞與子宮內膜上皮單細胞層接觸的區域會有較多的caspase-positive cells，而此現象也可分別受SB203580及SP600125的抑制。總結上述結果，本論文研究發現在胚胎著床的過程中，滋養層細胞會活化子宮內膜上皮細胞的JNK，而導致子宮內膜上皮細胞凋亡，以利滋養層細胞穿越子宮內膜上皮障礙，進而入侵子宮內膜基質。然而，也發現滋養層細胞與子宮內膜上皮單細胞層並非主要藉由它們彼此間的Fas 及FasL 間的接觸作用而成的，但是可以藉由Anti-Fas activating Ab引發子宮內膜上皮單細胞內的p38 MAPK及JNK的活化，再經由caspase-dependent或caspase-independent路逕調控，使細胞凋亡的現象發生，而促進胚胎侵入子宮的能力，使之胚胎著床更容易成功。

During embryo implantation in mammals, trophoblast cells of the attached blastocyst penetrate the endometrial epithelium of the uterus before invasion into the endometrial stroma. Signaling of apoptosis was demonstrated in endometrial epithelial cells (EEC) surrounding the trophoblast cells; however, the signaling mechanisms leading to apoptosis in EEC remain unclear. Since mitogen-activated protein kinases (MAPKs) were shown to mediate apoptosis in several model systems and found to be activated in the uterus during decidualization, and then evidenced the important role of induction of p38 MAPK-mediated apoptosis involved in outgrowth of trophoblast cells on EEC in a model of human trophoblast-endometrial interactions, rather not ERK. The Fas-Fas Ligand (FasL) system is one of the major for the induction of apoptosis in cells and tissues. However, the Fas/FasL death system was found to be active at the embryo-endometrial interface, and in various cell models, activation of members of the MAPK superfamily was demonstrated to either mediate Fas-induced apoptosis or enhance FasL expression. The objective of this study were to investigate the roles of JNK activation and Fas/FasL system during embryo implantation using a co-culture model by co-culturing BeWo human trophoblast spheroids with RL95-2 human EEC monolayers to mimic the blastocyst-endometrial interaction. First, immunoblotting analysis showed that JNK were activated in EEC after co-culture. However, SP600125 (a JNK inhibitor) inhibited trophoblast outgrowth on EEC monolayers through the suppression of JNK activation in EEC and trophoblast cells. Second, MTT assay showed that Fas and FasL expressed on RL95-2 cells were functional to Fas-mediated apoptosis by using anti-Fas activating Ab, but BeWo cells was not observed. Then, trophoblast spheroid outgrowth on EEC monolayers was not significantly inhibited by anti-Fas neutralizing Ab, but spheroid outgrowth on EEC was notably increased by anti-Fas activating Ab. Furthermore, trophoblast expansion on EEC in the presence of anti-Fas activating Ab caused prominent EEC apoptosis at the spheroid-EEC interface compare with in the absence of anti-Fas activating Ab, as detected by annexin V labeling and valyl-alanyl-aspartyl-[O-methyl]-fluoromethylketone (VAD-FMK, which binds activated caspases) staining. Then, Z-VAD (pan-caspase inhibitor) appeared to have minimal effect on spheroid outgrowth, whereas Z-VAD significantly inhibited spheroid expansion on EEC monolayers that anti-Fas activating Ab was existed. In addition, SB203580 and SP600125 inhibited spheroid outgrowth enhanced by anti-Fas activating Ab on EEC monolayers, respectively, and p38 MAPK and JNK were both activated in EEC exposed to anti-Fas activating Ab. Then, using VAD-FMK staining technique for detecting caspase activation, marked activated caspase-positive cells along the spheroid-EEC interface in the presence of anti-Fas activating Ab that could be significantly suppressed by SB203580 and SP600125, respectively. Our results based on a model of human trophoblast-EEC interactions establish that trophoblast cells cause activation of JNK in EEC and trophoblast cells. In addition, our results also suggests that Fas/FasL system was not one of major for the mechanism of attachment between trophoblast cells and EEC, but may play an important role in trophoblast invasion, such as using anti-Fas activating Ab in our study. The signal was transferred by activating p38 MAPK and JNK in EEC, respectively, and then inducing apoptosis in EEC at the inter-implantation site and implantation site through the caspase-dependent pathway and caspase-independent pathway, therefore EEC were easy to be displaced and trophoblast spheroids outgrowth were easy successful.

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