Ratio of Wnt3a to BMP4 doses is critical to their synergistic effects on proliferation of differentiating mouse embryonic stem cells.
OBJECTIVE
To investigate potential interactions between bone morphogenetic protein (BMP) and Wnt signalling on differentiating mouse embryonic stem cells (mESC).


METHODS
Mouse embryonic stem cells were cultured with differing combinations of Wnt3a, BMP4 and inhibitors of Wnt, BMP, PI-3K (phosphoinositide 3-kinase), p38, ERK1/2 (extracellular signal-regulated kinase 1/2) and JNK (c-Jun N-terminal kinase) pathways.


RESULTS
We found that Wnt3a synergized with BMP4 to promote mESC proliferation. Furthermore, the relative ratio of Wnt3a to BMP4 doses was critical to their synergistic effects, which could be abolished by using Dkk-1, noggin or the inhibitors of PI-3K, p38, ERK1/2 and JNK pathways. We also demonstrated that combination of Wnt3a and BMP4 could suppress ectodermal differentiation of mESCs. Moreover, inhibitors of PI-3K, p38, ERK1/2 and JNK pathways could negate this effect.


CONCLUSIONS
Relative ratio of Wnt3a to BMP4 doses is critical to their synergistic effect on differentiating mESC proliferation, which may work through PI-3K, p38, ERK1/2 and JNK pathways.
Lin
S-Y
SY
Stem Cell Lab, Department of Medical Research, Mackay Memorial Hospital, Taipei, Taiwan. sylin@ms1.mmh.org.tw
Chen
C-L
CL
Wu
Y-L
YL
Yang
Y-C
YC
Hwu
Y-M
YM
D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins / Q000494:pharmacology*; D002352:Carrier Proteins / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects*; D019070:Cell Lineage / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000187:drug effects* / Q000201:enzymology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D050814:Octamer Transcription Factor-3 / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D051153:Wnt Proteins / Q000494:pharmacology*; D060508:Wnt3 Protein; D060509:Wnt3A Protein; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000099176:Noggin Protein
D000469:Alkaline Phosphatase; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; D002352:Carrier Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D050814:Octamer Transcription Factor-3; D019869:Phosphatidylinositol 3-Kinases; D047428:Protein Kinase Inhibitors; D051153:Wnt Proteins; D060508:Wnt3 Protein; D060509:Wnt3A Protein; D048051:p38 Mitogen-Activated Protein Kinases; D000099176:Noggin Protein; C525810:Bmp4 protein, mouse; C555511:Wnt3a protein, mouse