Wingless ligand 5a is a critical regulator of placental growth and survival.
The maternal uterine environment is likely critical for human placental morphogenesis and development of its different trophoblast subtypes. However, factors controlling growth and differentiation of these cells during early gestation remain poorly elucidated. Herein, we provide evidence that the ligand Wnt5a could be a critical regulator of trophoblast proliferation and survival. Immunofluorescence of tissues and western blot analyses of primary cultures revealed abundant Wnt5a expression and secretion from first trimester decidual and villous stromal cells. The ligand was also detectable in decidual glands, macrophages and NK cells. Wnt5a increased proliferation of villous cytotrophoblasts and cell column trophoblasts, outgrowth on collagen I as well as cyclin A and D1 expression in floating explant cultures, but suppressed camptothecin-induced apoptosis. Similarly, Wnt5a stimulated BrdU incorporation and decreased caspase-cleaved cytokeratin 18 neo-epitope expression in primary cytotrophoblasts. Moreover, Wnt5a promoted activation of the MAPK pathway in the different trophoblast models. Chemical inhibition of p42/44 MAPK abolished cyclin D1 expression and Wnt5a-stimulated proliferation. Compared to controls, MAPK phosphorylation and proliferation of cytotrophoblasts declined upon supplementation of supernatants from Wnt5a gene-silenced decidual or villous stromal cells. In summary, non-canonical Wnt5a signalling could play a role in early human trophoblast development by promoting cell proliferation and survival.
Department of Obstetrics and Gynecology, Reproductive Biology Unit; Medical University of Vienna, Vienna, Austria.
Gudrun
G
Meinhardt
Department of Obstetrics and Gynecology, Reproductive Biology Unit; Medical University of Vienna, Vienna, Austria.
Leila
L
Saleh
Department of Obstetrics and Gynecology, Reproductive Biology Unit; Medical University of Vienna, Vienna, Austria.
Gerlinde R
GR
Otti
Department of Obstetrics and Gynecology, Reproductive Biology Unit; Medical University of Vienna, Vienna, Austria.
Sandra
S
Haider
Department of Obstetrics and Gynecology, Reproductive Biology Unit; Medical University of Vienna, Vienna, Austria.
Philipp
P
Velicky
Gynmed Clinic, Vienna, Austria.
Christian
C
Fiala
Department of Obstetrics and Gynecology, Reproductive Biology Unit; Medical University of Vienna, Vienna, Austria.
Jürgen
J
Pollheimer
Department of Obstetrics and Gynecology, Reproductive Biology Unit; Medical University of Vienna, Vienna, Austria.
Martin
M
Knöfler
D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D002166:Camptothecin / Q000494:pharmacology; D002454:Cell Differentiation / Q000235:genetics*; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D002478:Cells, Cultured; D019938:Cyclin D1 / Q000096:biosynthesis; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors; D005260:Female; D006801:Humans; D053538:Keratin-18 / Q000096:biosynthesis; D020935:MAP Kinase Signaling System / Q000235:genetics; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors; D010766:Phosphorylation; D010920:Placenta / Q000502:physiology*; D010929:Placentation / Q000235:genetics*; D011247:Pregnancy; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D014327:Trophoblasts / Q000166:cytology*; D000071818:Wnt-5a Protein / Q000235:genetics* / Q000378:metabolism*; D000095043:Cyclin-Dependent Kinase-Activating Kinase
C530104:CCND1 protein, human; D053538:Keratin-18; D034741:RNA, Small Interfering; C085389:WNT5A protein, human; D000071818:Wnt-5a Protein; D019938:Cyclin D1; D018844:Cyclin-Dependent Kinases; D048052:Mitogen-Activated Protein Kinase 3; D002166:Camptothecin; D000095043:Cyclin-Dependent Kinase-Activating Kinase