Gremlin enhances the determined path to cardiomyogenesis.
BACKGROUND
The critical event in heart formation is commitment of mesodermal cells to a cardiomyogenic fate, and cardiac fate determination is regulated by a series of cytokines. Bone morphogenetic proteins (BMPs) and fibroblast growth factors have been shown to be involved in this process, however additional factors needs to be identified for the fate determination, especially at the early stage of cardiomyogenic development.


RESULTS
Global gene expression analysis using a series of human cells with a cardiomyogenic potential suggested Gremlin (Grem1) is a candidate gene responsible for in vitro cardiomyogenic differentiation. Grem1, a known BMP antagonist, enhanced DMSO-induced cardiomyogenesis of P19CL6 embryonal carcinoma cells (CL6 cells) 10-35 fold in an area of beating differentiated cardiomyocytes. The Grem1 action was most effective at the early differentiation stage when CL6 cells were destined to cardiomyogenesis, and was mediated through inhibition of BMP2. Furthermore, BMP2 inhibited Wnt/beta-catenin signaling that promoted CL6 cardiomyogenesis.


CONCLUSIONS
Grem1 enhances the determined path to cardiomyogenesis in a stage-specific manner, and inhibition of the BMP signaling pathway is involved in initial determination of Grem1-promoted cardiomyogenesis. Our results shed new light on renewal of the cardiovascular system using Grem1 in human.
Kami
Daisuke
D
Department of Reproductive Biology, National Institute for Child Health and Development, Tokyo, Japan.
Shiojima
Ichiro
I
Makino
Hatsune
H
Matsumoto
Kenji
K
Takahashi
Yoriko
Y
Ishii
Ryuga
R
Naito
Atsuhiko T
AT
Toyoda
Masashi
M
Saito
Hirohisa
H
Watanabe
Masatoshi
M
Komuro
Issei
I
Umezawa
Akihiro
A
D002454:Cell Differentiation / Q000187:drug effects; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D006321:Heart / Q000196:embryology*; D006801:Humans; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
C486399:GREM1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D004121:Dimethyl Sulfoxide