School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.
PLoS One. 2013 Jun 12;8(6):e65402. doi: 10.1371/journal.pone.0065402. Print 2013.
Monocarboxylate transporter 8 (MCT8) is a well-established thyroid hormone (TH) transporter. In humans, MCT8 mutations result in changes in circulating TH concentrations and X-linked severe global neurodevelopmental delay. MCT8 is expressed in the human placenta throughout gestation, with increased expression in trophoblast cells from growth-restricted pregnancies. We postulate that MCT8 plays an important role in placental development and transplacental TH transport. We investigated the effect of altering MCT8 expression in human trophoblast in vitro and in a Mct8 knockout mouse model. Silencing of endogenous MCT8 reduced T3 uptake into human extravillous trophoblast-like cells (SGHPL-4; 40%, P<0.05) and primary cytotrophoblast (15%, P<0.05). MCT8 over-expression transiently increased T3 uptake (SGHPL-4∶30%, P<0.05; cytotrophoblast: 15%, P<0.05). Silencing MCT8 did not significantly affect SGHPL-4 invasion, but with MCT8 over-expression T3 treatment promoted invasion compared with no T3 (3.3-fold; P<0.05). Furthermore, MCT8 silencing increased cytotrophoblast viability (∼20%, P<0.05) and MCT8 over-expression reduced cytotrophoblast viability independently of T3 (∼20%, P<0.05). In vivo, Mct8 knockout reduced fetal:placental weight ratios compared with wild-type controls at gestational day 18 (25%, P<0.05) but absolute fetal and placental weights were not significantly different. The volume fraction of the labyrinthine zone of the placenta, which facilitates maternal-fetal exchange, was reduced in Mct8 knockout placentae (10%, P<0.05). However, there was no effect on mouse placental cell proliferation in vivo. We conclude that MCT8 makes a significant contribution to T3 uptake into human trophoblast cells and has a role in modulating human trophoblast cell invasion and viability. In mice, Mct8 knockout has subtle effects upon fetoplacental growth and does not significantly affect placental cell viability probably due to compensatory mechanisms in vivo.
单羧酸转运蛋白 8（MCT8）是一种成熟的甲状腺激素（TH）转运蛋白。在人类中，MCT8 突变会导致循环 TH 浓度发生变化，并导致 X 连锁严重的全球神经发育迟缓。MCT8 在整个妊娠期间在人胎盘表达，在生长受限的妊娠滋养层细胞中表达增加。我们假设 MCT8 在胎盘发育和胎盘 TH 转运中发挥重要作用。我们研究了改变人滋养层细胞中 MCT8 表达的体外和 Mct8 敲除小鼠模型的影响。内源性 MCT8 沉默降低了人绒毛外滋养细胞样细胞（SGHPL-4；40%，P<0.05）和原代滋养细胞（15%，P<0.05）中 T3 的摄取。MCT8 过表达瞬时增加了 T3 的摄取（SGHPL-4∶30%，P<0.05；滋养细胞：15%，P<0.05）。沉默 MCT8 对 SGHPL-4 的侵袭没有显著影响，但 MCT8 过表达 T3 处理与无 T3 相比促进了侵袭（3.3 倍；P<0.05）。此外，沉默 MCT8 增加了滋养细胞的活力（约 20%，P<0.05），而 MCT8 过表达独立于 T3 降低了滋养细胞的活力（约 20%，P<0.05）。在体内，与野生型对照组相比，Mct8 敲除小鼠在妊娠第 18 天的胎儿：胎盘重量比降低（25%，P<0.05），但胎儿和胎盘的绝对重量没有显著差异。胎盘母体-胎儿交换的有利区室（labyrinthine zone）的体积分数在 Mct8 敲除胎盘减少（10%，P<0.05）。然而，体内对小鼠胎盘细胞增殖没有影响。我们得出结论，MCT8 对 T3 摄取到人滋养层细胞中做出了重要贡献，并在调节人滋养层细胞侵袭和活力方面发挥了作用。在小鼠中，Mct8 敲除对胎-胎盘生长有细微影响，并且由于体内的代偿机制，对胎盘细胞活力没有显著影响。
