Bilban Martin, Ghaffari-Tabrizi Nassim, Hintermann Edith, Bauer Sandra, Molzer Sylvia, Zoratti Cristina, Malli Roland, Sharabi Andrew, Hiden Ursula, Graier Wolfgang, Knöfler Martin, Andreae Fritz, Wagner Oswald, Quaranta Vito, Desoye Gernot
Department of Cell Biology, The Scripps Research Institute, North Torrey Pines Road, La Jolla, CA 92037, USA.
J Cell Sci. 2004 Mar 15;117(Pt 8):1319-28. doi: 10.1242/jcs.00971.
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 Ca(2+) 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 identified Kp-10 as a novel paracrine/endocrine regulator in fine-tuning trophoblast invasion generated by the trophoblast itself.
滋养层细胞侵入子宫细胞外基质是人类着床的关键过程，对胎儿发育至关重要，是可控侵袭性的一个显著例子。为了鉴定调节滋养层细胞侵袭的分子，使用U95A基因芯片微阵列比较了从孕早期（高侵袭性）和足月胎盘（无/低侵袭性）分离的滋养层细胞的mRNA特征，得到了220个与侵袭/迁移相关的基因。在这个“侵袭簇”中，KiSS-1及其G蛋白偶联受体KiSS-1R在孕早期滋养层细胞中的表达水平高于妊娠末期。受体和配体的mRNA及蛋白定位于滋养层细胞区室。与仅在绒毛滋养层表达的KiSS-1不同，KiSS-1R也存在于绒毛外滋养层，提示存在内分泌/旁分泌激活机制。KiSS-1的主要翻译产物是一种145个氨基酸的多肽（Kp-145），但也可能产生具有10、13、14或54个氨基酸残基的较短的亲吻素（Kp）。我们在孕早期人滋养层细胞的条件培养基中鉴定出了源自主要翻译产物的十肽Kp-10。Kp-10而非其他亲吻素可增加分离的孕早期滋养层细胞内的Ca(2+)水平。Kp-10在植块及Transwell实验中均抑制滋养层细胞迁移，而不影响其增殖。迁移受抑制与分离的滋养层细胞的明胶溶解活性受抑制平行。这些结果表明Kp-10是一种新型的旁分泌/内分泌调节因子，可微调滋养层细胞自身产生的侵袭。
