Shafiei Shiva, Dufort Daniel
Division of Experimental Medicine, McGill University, Montreal, Canada; Child Health and Human Development Program, Research Institute of the McGill University Health Centre, Montreal, Canada.
Division of Experimental Medicine, McGill University, Montreal, Canada; Child Health and Human Development Program, Research Institute of the McGill University Health Centre, Montreal, Canada; Department of Obstetrics and Gynecology, McGill University, Montreal, Canada; Department of Biology, McGill University, Montreal, Canada.
Placenta. 2021 Apr;107:13-23. doi: 10.1016/j.placenta.2021.02.016. Epub 2021 Mar 2.
The growth and survival of the mammalian fetus is highly dependent on the placenta. Several research groups have demonstrated the involvement of different transforming growth factor-beta (TGFβ) superfamily members and their related receptors in placentation. Cripto is a member of the epidermal growth factor-Cripto1/FRL1/Cryptic protein family and plays a critical role in embryonic development, stem cell maintenance and tumor progression through TGFβ-dependent and independent pathways. Several studies have suggested that Cripto may also have a role in female reproduction and pregnancy maintenance, but its specific role remains elusive.
We used a conditional knockout mouse model in which Cripto is deleted from the uterus using a loxP-Cre system. Cripto cKO females were mated with wildtype males and dissections were performed at different timepoints during pregnancy for assessment of the number and size of the implantation sites, resorption sites, fetal weight and placental development. Histology, IF staining and quantitative PCR were employed to analyze the placentation process.
We found that loss of maternal Cripto results in defective placentation, decreased vascularization within the placental labyrinth and leads to intrauterine growth restriction and fetal death. We further demonstrated that components of the VEGF and Notch signaling pathways are downregulated in Cripto cKO decidua and placenta potentially contributing to defects in the development of the vasculature at maternal-fetal interface.
These findings demonstrate that maternal Cripto is involved in the maternal-fetal communications required for proper development of the placenta and placental vasculature.
哺乳动物胎儿的生长和存活高度依赖于胎盘。多个研究小组已证明不同的转化生长因子-β（TGFβ）超家族成员及其相关受体参与胎盘形成过程。Cripto是表皮生长因子-Cripto1/FRL1/隐窝蛋白家族的成员，通过TGFβ依赖和非依赖途径在胚胎发育、干细胞维持和肿瘤进展中发挥关键作用。多项研究表明，Cripto可能在女性生殖和维持妊娠中也发挥作用，但其具体作用仍不清楚。
我们使用了一种条件性基因敲除小鼠模型，利用loxP-Cre系统从子宫中删除Cripto。将Cripto条件性基因敲除的雌性小鼠与野生型雄性小鼠交配，并在妊娠期间的不同时间点进行解剖，以评估着床位点的数量和大小、吸收位点、胎儿体重和胎盘发育情况。采用组织学、免疫荧光染色和定量PCR分析胎盘形成过程。
我们发现母体Cripto缺失会导致胎盘形成缺陷，胎盘迷路内血管化减少，并导致子宫内生长受限和胎儿死亡。我们进一步证明，VEGF和Notch信号通路的成分在Cripto条件性基因敲除的蜕膜和胎盘中下调，这可能导致母胎界面血管发育缺陷。
这些发现表明母体Cripto参与了胎盘和胎盘血管正常发育所需的母胎通讯。
