Human placental development is impaired by abnormal human chorionic gonadotropin signaling in trisomy 21 pregnancies
Human placental development is impaired by abnormal human chorionic gonadotropin signaling in trisomy 21 pregnancies
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DOI：
10.1210/en.2007-0589
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发表时间：
2007-11-01
期刊：
影响因子：
4.8
通讯作者：
Frendo, Jean-Louis
中科院分区：
文献类型：
--
作者：
Pidoux, Guillaume;Gerbaud, Pascale;Frendo, Jean-Louis
怀有 21 三体胎儿的女性胎盘发育明显异常，合体滋养层 (ST) 形成和功能有缺陷。 ST 由细胞滋养层 (CT) 融合产生，通过分泌人绒毛膜促性腺激素 (hCG) 发挥重要作用，而 hCG 对胎盘发育至关重要。在 21 号染色体三体 (T21) 妊娠中，CT 无法正确融合并分化为 ST，导致分泌异常且生物活性较弱的 hCG。在这项研究中，我们首次报告，受 T21 影响的 CT 表面表达的成熟 hCG 受体 (LH/CG-R) 分子的数量显着减少。根据测序结果显示，LH/CG-R 似乎具有功能，显示没有突变或缺失，并且重组 hCG 以及内源性 hCG 没有结合。我们推测生物活性较弱的 hCG 和较低的 LH/CG-R 表达可能与 ST 形成缺陷有关。有趣的是，通过使用 LH/CG-R 小干扰 RNA 在正常 CT 培养物中模拟有缺陷的 ST 形成，从而导致 hCG 分泌较低。此外，用重组 hCG 治疗受 T21 影响的 CT 在体外克服了 T21 表型，使 CT 能够融合并形成一个大的 ST。这些结果首次在 21 三体病理学中说明异常的内源性 hCG 信号传导如何损害人类胎盘发育。
Placental development is markedly abnormal in women bearing a fetus with trisomy 21, with defective syncytiotrophoblast (ST) formation and function. The ST occurs from cytotrophoblast (CT) fusion and plays an essential role by secreting human chorionic gonadotropin (hCG), which is essential to placental development. In trisomy of chromosome 21 (T21) pregnancies, CTs do not fuse and differentiate properly into STs, leading to the secretion of an abnormal and weakly bioactive hCG. In this study we report for the first time, a marked decrease in the number of mature hCG receptor (LH/CG-R) molecules expressed at the surface of T21-affected CTs. The LH/CG-R seems to be functional based on sequencing that revealed no mutations or deletions and binding of recombinant hCG as well as endogenous hCG. We hypothesize that weakly bioactive hCG and lower LH/CG-R expression may be involved in the defect of ST formation. Interestingly, the defective ST formation is mimicked in normal CT cultures by using LH/CG-R small interfering RNA, which result in a lower hCG secretion. Furthermore, treatment of T21-affected CTs with recombinant hCG overcomes in vitro the T21 phenotype, allowing CTs to fuse and form a large ST. These results illustrate for the first time in trisomy 21 pathology, how abnormal endogenous hCG signaling impairs human placental development.