Control of Human Endometrial Stromal Cell Motility by PDGF-BB, HB-EGF and Trophoblast-Secreted Factors

Human implantation involves extensive tissue remodeling at the fetal-maternal interface. It is becoming increasingly evident that not only trophoblast, but also decidualizing endometrial stromal cells are inherently motile and invasive, and likely contribute to the highly dynamic processes at the implantation site. The present study was undertaken to further characterize the mechanisms involved in the regulation of endometrial stromal cell motility and to identify trophoblast-derived factors that modulate migration. Among local growth factors known to be present at the time of implantation, heparin-binding epidermal growth factor-like growth factor (HB-EGF) triggered chemotaxis (directed locomotion), whereas platelet-derived growth factor (PDGF)-BB elicited both chemotaxis and chemokinesis (non-directed locomotion) of endometrial stromal cells. Supernatants of the trophoblast cell line AC-1M88 and of first trimester villous explant cultures stimulated chemotaxis but not chemokinesis. Proteome profiling for cytokines and angiogenesis factors revealed neither PDGF-BB nor HB-EGF in conditioned media from trophoblast cells or villous explants, while placental growth factor, vascular endothelial growth factor and PDGF-AA were identified as prominent secretory products. Among these, only PDGF-AA triggered endometrial stromal cell chemotaxis. Neutralization of PDGF-AA in trophoblast conditioned media, however, did not diminish chemoattractant activity, suggesting the presence of additional trophoblast-derived chemotactic factors. Pathway inhibitor studies revealed ERK1/2, PI3 kinase/Akt and p38 signaling as relevant for chemotactic motility, whereas chemokinesis depended primarily on PI3 kinase/Akt activation. Both chemotaxis and chemokinesis were stimulated upon inhibition of Rho-associated, coiled-coil containing protein kinase. The chemotactic response to trophoblast secretions was not blunted by inhibition of isolated signaling cascades, indicating activation of overlapping pathways in trophoblast-endometrial communication. In conclusion, trophoblast signals attract endometrial stromal cells, while PDGF-BB and HB-EGF, although not identified as trophoblast-derived, are local growth factors that may serve to fine-tune directed and non-directed migration at the implantation site.

人类胚胎植入过程会在母胎界面引发广泛的组织重塑。越来越多研究证据表明，不仅滋养层细胞，蜕膜化子宫内膜间质细胞本身也具备运动性与侵袭特性，且可能参与植入位点的高度动态生物学过程。本研究旨在进一步阐明子宫内膜间质细胞运动的调控机制，并鉴定可调节其迁移的滋养层细胞源性因子。在已知于植入时段存在的局部生长因子中，肝素结合性表皮生长因子样生长因子（heparin-binding epidermal growth factor-like growth factor，HB-EGF）可触发趋化性（定向运动），而血小板衍生生长因子（platelet-derived growth factor，PDGF）-BB则可同时诱导子宫内膜间质细胞的趋化性与趋激性（非定向运动）。滋养层细胞系AC-1M88与妊娠早期绒毛外植体培养物的上清液可刺激趋化性，但无法诱导趋激性。对细胞因子与血管生成因子的蛋白质组分析显示，滋养层细胞或绒毛外植体的条件培养基中均未检测到PDGF-BB与HB-EGF，而胎盘生长因子、血管内皮生长因子及PDGF-AA被鉴定为主要的分泌产物。在这些因子中，仅PDGF-AA可触发子宫内膜间质细胞的趋化性。然而，在滋养层细胞条件培养基中中和PDGF-AA并未削弱其趋化活性，提示尚存在其他滋养层细胞源性的趋化因子。信号通路抑制剂实验显示，ERK1/2、PI3激酶/Akt及p38信号通路与趋化性运动相关，而趋激性则主要依赖PI3激酶/Akt的激活。抑制Rho相关卷曲螺旋蛋白激酶（Rho-associated coiled-coil containing protein kinase，ROCK）可同时增强趋化性与趋激性。针对滋养层细胞分泌物的趋化反应无法通过单一信号通路的抑制来阻断，这表明在滋养层-子宫内膜间质细胞通讯中存在多条重叠激活的信号通路。综上，滋养层细胞分泌的信号可招募子宫内膜间质细胞；尽管PDGF-BB与HB-EGF未被证实由滋养层细胞分泌，但它们作为局部生长因子，可在胚胎植入位点对定向与非定向迁移进行精细调控。