BMP inhibition stimulates WNT-dependent generation of chondrogenic mesoderm from embryonic stem cells.
WNT and bone morphogenetic protein (BMP) signaling are known to stimulate hemogenesis from pluripotent embryonic stem (ES) cells. However, osteochondrogenic mesoderm was generated effectively when BMP signaling is kept to a low level, while WNT signaling was strongly activated. When mesoderm specification from ES cells was exogenous factor dependent, WNT3a addition supported the generation of cardiomyogenic cells expressing lateral plate/extraembryonic mesoderm genes, and this process involved endogenous BMP activities. Exogenous BMP4 showed a similar effect that depended on endogenous WNT activities. However, neither factor induced robust chondrogenic activity. In support, ES cell differentiation in the presence of either WNT3a or BMP4 was associated with elevated levels of both Bmp and Wnt mRNAs, which appeared to provide sufficient levels of active BMPs and WNTs to promote the nonchondrogenic mesoderm specification. The osteochondrogenic mesoderm expressed PDGFRalpha, which also expressed genes that mark somite and rostral presomitic mesoderm. A strong WNT signaling was required for generating the mesodermal progeny, while approximately 50- to 100-fold lower concentration of WNT3a was sufficient for specifying axial mes(end)oderm. Thus, depending on the dose and cofactor (BMP), WNT signaling stimulates the generation of different biological activities and specification of different types of mesodermal progeny from ES cells.
Tanaka
Makoto
M
Peter MacCallum Cancer Institute, East Melbourne VIC 3002, Australia.
Jokubaitis
Vanta
V
Wood
Colin
C
Wang
Yi
Y
Brouard
Nathalie
N
Pera
Martin
M
Hearn
Milton
M
Simmons
Paul
P
Nakayama
Naoki
N
D015703:Antigens, CD / Q000378:metabolism; D055415:Bone Morphogenetic Protein 4 / Q000378:metabolism* / Q000494:pharmacology; D015820:Cadherins / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism; D006801:Humans; D008648:Mesoderm / Q000166:cytology* / Q000378:metabolism; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000378:metabolism; D015398:Signal Transduction; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism* / Q000494:pharmacology; D060508:Wnt3 Protein; D060509:Wnt3A Protein
D015703:Antigens, CD; D055415:Bone Morphogenetic Protein 4; C050361:CDH2 protein, human; D015820:Cadherins; C555510:WNT3A protein, human; D051153:Wnt Proteins; D060508:Wnt3 Protein; D060509:Wnt3A Protein; D020796:Receptor, Platelet-Derived Growth Factor alpha; D040301:Vascular Endothelial Growth Factor Receptor-2