Duan Fu-Mei, Fu Li-Juan, Wang Yong-Heng, Adu-Gyamfi Enoch Appiah, Ruan Ling-Ling, Xu Zeng-Wei, Xiao Shi-Quan, Chen Xue-Mei, Wang Ying-Xiong, Liu Tai-Hang, Ding Yu-Bin
School of Public Health and Management, Chongqing Medical University, Chongqing, 400016, PR China.
Department of Herbal Medicine, School of Traditional Chinese Medicine, Chongqing Medical University, Chongqing, 400016, PR China.
Genes Dis. 2020 Jun 8;8(3):353-363. doi: 10.1016/j.gendis.2020.05.007. eCollection 2021 May.
Preeclampsia is a pregnancy complication which threatens the survival of mothers and fetuses. It originates from abnormal placentation, especially insufficient fusion of the cytotrophoblast cells to form the syncytiotrophoblast. In this study, we found that THBS1, a matricellular protein that mediates cell-to-cell and cell-to-matrix interactions, is downregulated during the fusion of primary cytotrophoblast and BeWo cells, but upregulated in the placenta of pregnancies complicated by preeclampsia. Also, THBS1 was observed to interact with CD36, a membrane signal receptor and activator of the cAMP signaling pathway, to regulate the fusion of cytotrophoblast cells. Overexpression of THBS1 inhibited the cAMP signaling pathway and reduced the BeWo cells fusion ratio, while the effects of THBS1 were abolished by a CD36-blocking antibody. Our results suggest that THBS1 signals through a CD36-mediated cAMP pathway to regulate syncytialization of the cytotrophoblast cells, and that its upregulation impairs placental formation to cause preeclampsia. Thus, THBS1 can serve as a therapeutic target regarding the mitigation of abnormal syncytialization and preeclampsia.
子痫前期是一种危及母婴生存的妊娠并发症。它源于胎盘形成异常，尤其是细胞滋养层细胞融合形成合体滋养层不足。在本研究中，我们发现血小板反应蛋白1（THBS1），一种介导细胞间和细胞与基质相互作用的基质细胞蛋白，在原代细胞滋养层与BeWo细胞融合过程中表达下调，但在子痫前期妊娠的胎盘中表达上调。此外，观察到THBS1与CD36相互作用，CD36是一种膜信号受体和cAMP信号通路的激活剂，可调节细胞滋养层细胞的融合。THBS1的过表达抑制了cAMP信号通路并降低了BeWo细胞融合率，而CD36阻断抗体消除了THBS1的作用。我们的结果表明，THBS1通过CD36介导的cAMP途径发出信号来调节细胞滋养层细胞的合体化，其上调会损害胎盘形成，从而导致子痫前期。因此，THBS1可作为减轻异常合体化和子痫前期的治疗靶点。
