The Role of the Adhesion Receptor CD146 and Its Soluble Form in Human Embryo Implantation and Pregnancy

Abstract

CD146 is an adhesion molecule essentially located in the vascular system, which has been described to play an important role in angiogenesis. A soluble form of CD146, called sCD146, is detected in the bloodstream and is known as an angiogenic factor. During placental development, CD146 is selectively expressed in extravillous trophoblasts. A growing body of evidence shows that CD146 and, in particular, sCD146, regulate extravillous trophoblasts migration and invasion both in vitro and in vivo. Hereby, we review expression and functions of CD146/sCD146 in the obstetrical field, mainly in pregnancy and in embryo implantation. We emphasized the relevance of quantifying sCD146 in the plasma of pregnant women or in embryo supernatant in the case of in vitro fertilization (IVF) to predict pathological pregnancy such as preeclampsia or implantation defect. This review will also shed light on some major results that led us to define CD146/sCD146 as a biomarker of placental development and paves the way toward identification of new therapeutic targets during implantation and pregnancy.

Keywords: CD146/sCD146; biomarker; fertility; implantation; preeclampsia; pregnancy.

Figure 1

CD146 expression on human extravillous trophoblasts (EVTs) and embryos. (A, B) Characterization of EVTs in human placenta, from a normal term pregnancy. (A) EVTs are stained with hematoxylin and eosin (H&E) (objective 10×). (B) Immunohistochemistry with avidin–biotin–peroxidase complex, with CD146 antibody (monoclonal mouse antihuman, BioCytex S-Endo 1S-Endo1) (objective 20×). (C, D) Expression of CD146 on EVTs outgrowth from human placental villous explants culture (ex vivo model) [for model, see Kaspi et al., (18)]. (C) Cells were labeled with mouse IgG1 isotype control and (D) anti-CD146 antibody (Novocastra-Leica N1238). 4′,6-Diamidino-2-phenylindole (DAPI) was used to counterstain DNA (objective 20×). (E, F) Expression of CD146 on early embryo stage (day 2): immunostaining of (E) mouse IgG1 isotype control and (F) anti-CD146 (S-Endo1). DAPI was used to counterstain DNA. [Picture is from Bouvier et al, (24)] (objective 63×).

Figure 2

The general effects of CD146/sCD146 in obstetrics are summarized in three illustrations. (A) In pregnancy, sCD146 and galectin 1 (Gal1) plasma concentration varies throughout the different stages of pregnancy. In case of pregnancy complications, sCD146 concentration surges, which in turn hinders Gal1/membrane CD146 interaction, mutually known to activate trophoblasts migration toward the spiral arteries. (B) In implantation, sCD146 injection into female pregnant rats significantly decreases the number of embryos per litter. (C) In IVF, in vitro fertilized eggs producing high concentrations of sCD146 into their culture media fail implantation when transferred into the uterus, a boxplot of sCD146 concentrations between implanted (Yes, n = 37) and non-implanted embryos (No, n = 185) (p = 0.024) is shown. *p < 0.05.