The role of CD147 on human trophoblast functions

Abstract

Successful implantation and placental development depend on the invasion of extravillous trophoblasts (EVCTs) into the maternal endometrium followed by the remodeling of the maternal spiral artery that establish a sufficient blood flow to support the placenta and fetus growth throughout the pregnancy. Inadequate EVCT invasion and deficient remodeling of the maternal uterine arteries are associated with intermittent placental perfusion and increased risks of secondary pathologies such as preeclampsia. EVCT invasion and spiral artery remodeling are mediated by many decidual and trophoblastic factors such as matrix metalloproteinases (MMPs), Wnt/β-catenin signaling, and extracellular vesicles, etc. CD147 is a glycosylated membrane protein that regulates cell recognition and differentiation in many cell types. The glycosylation regulates the biological activity of CD147, including its well-known inductive action on the production of matrix metalloproteinase (MMP) in cancers. In mice, CD147 is expressed in the blastocysts and the endometrial epithelium. Mice deficient of CD147 have implantation problem. However, how CD147 affects implantation is not known. In human, CD147 is abundantly expressed on trophoblasts in the form of protein complexes. Its expression is upregulated in the first trimester of pregnancy coinciding with the time of active EVCT invasion. In this project, we hypothesized that CD147 regulates the invasion of EVCTs and the cross-talk between EVCTs and endothelial cells during pregnancy. Our results showed that: 1) CD147 suppression inhibited EVCT invasion through the down-regulation of Wnt/β-catenin signaling and MMP2 activities; 2) CD147 forms two protein complexes on EVCT plasma membrane. Integrin β1 was identified as a component of these complexes which interacted with CD147 to regulate EVCT invasion via Wnt/β-catenin signaling; 3) CD147 on microvesicles released from trophoblasts could be taken up by EVCTs which in turns regulated the EVCT invasion; 4) CD147 treatment was able to modulate the angiogenesis of human umbilical vein endothelial cells. The above observations clearly suggest that CD147 is involved in human implantation process and trophoblast functions. Inadequate implantation and/or trophoblast functions are causes of infertility which could lead to pregnancy complications such as preeclampsia. Results of this study enhanced our understanding on the regulation of human implantation and trophoblast functions. Further study may lead to development of new treatment strategies for women with implantation problem.