Caniggia I, Taylor C V, Ritchie J W, Lye S J, Letarte M
Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Department of Obstetrics and Gynecology, University of Toronto, Ontario, Canada.
Endocrinology. 1997 Nov;138(11):4977-88. doi: 10.1210/endo.138.11.5475.
Successful invasion of the maternal vascular system by trophoblast cells is a prerequisite for the establishment of a normal hemochorial placenta. Transforming growth factor-beta (TGFbeta) has been implicated in the regulation of trophoblast invasiveness into the uterus. Endoglin is a component of the TGFbeta receptor complex that binds beta1 and beta3 isoforms and is expressed at high levels on syncytiotrophoblast throughout pregnancy and is also transiently up-regulated on extravillous trophoblasts differentiating along the invasive pathway. We investigated the role of endoglin in a serum-free human villous explant culture system that allows the study of trophoblast outgrowth, migration, and invasion and mimics events occurring in anchoring villi during the first trimester of gestation. Addition to explant cultures from 5-8 weeks gestation of a monoclonal antibody to endoglin or of antisense endoglin oligonucleotides significantly stimulated trophoblast outgrowth and migration. These responses were specific, as incubation of explants with nonimmune IgG or sense and scrambled oligonucleotides had no effect. Antisense endoglin-induced trophoblast outgrowth and migration were accompanied by cell division of villous-associated trophoblasts within the proximal region of the forming column and by the characteristic switch in integrins observed in anchoring villi in situ. Treatment of villous explants with antibody and antisense oligonucleotides to endoglin also resulted in an increased fibronectin release into the culture medium. The stimulatory effect of antisense endoglin on fibronectin production was overcome by the addition of exogenous TGFbeta2, but not TGFbeta1 and -beta3. These findings suggest that endoglin expression in the transition from polarized to nonpolarized trophoblasts in anchoring villi is necessary for mediation of the inhibitory effect of TGFbeta1 and/or TGFbeta3 on trophoblast differentiation along the invasive pathway.
滋养层细胞成功侵入母体血管系统是建立正常血绒毛膜胎盘的前提条件。转化生长因子-β（TGFβ）与滋养层细胞侵入子宫的调节有关。内皮糖蛋白是TGFβ受体复合物的一个组成部分，可结合β1和β3亚型，在整个孕期的合体滋养层细胞上高水平表达，并且在沿着侵入途径分化的绒毛外滋养层细胞上也会短暂上调。我们在无血清人绒毛外植体培养系统中研究了内皮糖蛋白的作用，该系统可用于研究滋养层细胞的生长、迁移和侵袭，并模拟妊娠头三个月在固定绒毛中发生的事件。向妊娠5 - 8周的外植体培养物中添加抗内皮糖蛋白单克隆抗体或反义内皮糖蛋白寡核苷酸可显著刺激滋养层细胞的生长和迁移。这些反应具有特异性，因为用非免疫IgG或正义及随机寡核苷酸孵育外植体没有效果。反义内皮糖蛋白诱导的滋养层细胞生长和迁移伴随着在形成柱近端区域与绒毛相关的滋养层细胞的细胞分裂，以及在原位固定绒毛中观察到的整合素特征性转换。用抗内皮糖蛋白抗体和反义寡核苷酸处理绒毛外植体也导致纤连蛋白释放到培养基中的量增加。添加外源性TGFβ2可克服反义内皮糖蛋白对纤连蛋白产生的刺激作用，但TGFβ1和 -β3则不能。这些发现表明，在固定绒毛中从极化滋养层细胞向非极化滋养层细胞转变过程中内皮糖蛋白的表达对于介导TGFβ1和/或TGFβ3对滋养层细胞沿侵入途径分化的抑制作用是必要的。
