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.
Endokrinologikum Hamburg, Hamburg, Germany.
Maren
M
Schwenke
Martin
M
Knöfler
Philipp
P
Velicky
Charlotte H E
CH
Weimar
Michelle
M
Kruse
Annemarie
A
Samalecos
Anja
A
Wolf
Nick S
NS
Macklon
Ana-Maria
AM
Bamberger
Birgit
B
Gellersen
D000077214:Becaplermin; D015153:Blotting, Western; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects*; D002478:Cells, Cultured; D002633:Chemotaxis / Q000187:drug effects; D002824:Chorionic Villi / Q000378:metabolism; D017077:Culture Media, Conditioned / Q000494:pharmacology*; D004717:Endometrium / Q000166:cytology; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000072483:Placenta Growth Factor; D010982:Platelet-Derived Growth Factor / Q000378:metabolism / Q000494:pharmacology; D011247:Pregnancy; D011257:Pregnancy Proteins / Q000378:metabolism / Q000494:pharmacology; D011261:Pregnancy Trimester, First; D020543:Proteome / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D017154:Stromal Cells / Q000187:drug effects* / Q000378:metabolism; D046509:Tissue Culture Techniques; D014327:Trophoblasts / Q000166:cytology / Q000378:metabolism; D054460:rho-Associated Kinases / Q000378:metabolism
D017077:Culture Media, Conditioned; C587883:HBEGF protein, human; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; C000608036:PGF protein, human; D010982:Platelet-Derived Growth Factor; D011257:Pregnancy Proteins; D020543:Proteome; D020574:Proto-Oncogene Proteins c-sis; C075278:platelet-derived growth factor A; D000072483:Placenta Growth Factor; D000077214:Becaplermin; D019869:Phosphatidylinositol 3-Kinases; C512478:EGFR protein, human; D066246:ErbB Receptors; D054460:rho-Associated Kinases; D020928:Mitogen-Activated Protein Kinases