Submitted November 4, 2007
Returned for revision December 5, 2007
Accepted March 11, 2008
Pregnancy
CX3CL1 and CCL14 Regulate Extracellular Matrix and Adhesion Molecules in the Trophoblast: Potential Roles in Human Embryo Implantation
Natalie J. Hannan *
and
Lois A. Salamonsen
* To whom correspondence should be addressed. E-mail: natalie.hannan{at}princehenrys.org.
Abstract
Embryo implantation is a complex process involving blastocyst attachment to endometrial epithelium, and subsequent trophoblast invasion of the decidua. We have previously shown that the chemokines, CX3CL1 and CCL14, are abundant in endometrial vasculature, epithelial and decidual cells at this time and that their receptors CX3CR1 and CCR1, are present on invading human trophoblast. CX3CL1 and CCL14 promote trophoblast migration. We hypothesized that these endometrial chemokines promote trophoblast migration by regulating adhesion molecules and extracellular matrix (ECM) components on the trophoblast, similar to mechanisms used in leukocyte trafficking. Trophoblast cells (AC1M-88) used previously, showed a marked increase in adhesion to fibronectin following treatment with CX3CL1 and CCL14. Alterations in trophoblast adhesion and (ECM) following chemokine stimulation were examined using pathway specific oligo-arrays and quantitative real-time RT-PCR. Over 30 genes were affected by CX3CL1 treatment and 15 genes were found to be regulated by CCL14 treatment. Real-time RT-PCR quantitation revealed significant changes in the mRNA transcripts of alpha-catenin (CTNNA1), extracellular matrix protein-1 (ECM1), osteopontin (SPP1), integrin alpha6 (ITGA6), matrix metalloproteinase-12 (MMP12) and integrin beta5 (ITGB5) following chemokine treatment. Several of these genes have previously been implicated in implantation. Immunohistochemistry confirmed the presence of integrin 
6 and SPP1 protein in first trimester human implantation sites. The temporal and spatial expression of chemokines, their receptors, adhesion and ECM at the maternal-fetal interface emphasizes an important role in the controlled directional migration of trophoblast through the maternal decidua. For the first time this study demonstrates direct effects of CX3CL1 and CCL14 on trophoblast adhesion molecules and ECM suggesting mechanisms by which trophoblast cells migrate during early pregnancy.
Key words:
Pregnancy •
Cytokines •
Placenta
