Kisspeptin-10, a KiSS-1/metastin-derived decapeptide, is a physiological invasion inhibitor of primary human trophoblasts

• DOI: 10.1242/jcs.00971
• Publication Date: 2004-03-13T00:03:11Z
• Authors: Martin Bilban; Nassim Ghaffari-T...; Edith Hintermann; Sandra Bauer; Sylvia Molzer; Cristina Zoratti; Roland Malli; Andrew Sharabi; Ursula Hiden; Wolfgang Graier; Martin Knöfler; Fritz Andreae; Oswald Wagner; Vito Quaranta; Gernot Desoye
• Keywords: 0301 basic medicine; Kisspeptins; Gene Expression Profiling; Placenta; Gene Expression; Proteins; Immunohistochemistry; Culture Media, Serum-Free; Trophoblasts; Pregnancy Trimester, First; 03 medical and health sciences; Organ Culture Techniques; Cell Movement; Pregnancy; Culture Media, Conditioned; Humans; Calcium; Female; RNA, Messenger; Peptides; Oligopeptides; Oligonucleotide Array Sequence Analysis

Trophoblast invasion of the uterine extracellular matrix, a critical process of human implantation and essential for fetal development, is a striking example of controlled invasiveness. To identify molecules that regulate trophoblast invasion, mRNA signatures of trophoblast cells isolated from first trimester (high invasiveness) and term placentae (no/low invasiveness) were compared using U95A GeneChip microarrays yielding 220 invasion/migration-related genes. In this `invasion cluster', KiSS-1 and its G-protein-coupled receptor KiSS-1R were expressed at higher levels in first trimester trophoblasts than at term of gestation. Receptor and ligand mRNA and protein were localized to the trophoblast compartment. In contrast to KiSS-1, which is only expressed in the villous trophoblast, KiSS-1R was also found in the extravillous trophoblast, suggesting endocrine/paracrine activation mechanisms. The primary translation product of KiSS-1 is a 145 amino acid polypeptide (Kp-145), but shorter kisspeptins (Kp) with 10, 13, 14 or 54 amino acid residues may be produced. We identified Kp-10, a dekapeptide derived from the primary translation product, in conditioned medium of first trimester human trophoblast. Kp-10, but not other kisspeptins, increased intracellular Ca2+ levels in isolated first trimester trophoblasts. Kp-10 inhibited trophoblast migration in an explant as well as transwell assay without affecting proliferation. Suppressed motility was paralleled with suppressed gelatinolytic activity of isolated trophoblasts. These results identifed Kp-10 as a novel paracrine/endocrine regulator in fine-tuning trophoblast invasion generated by the trophoblast itself.