Biomedical Engineering Reference
In-Depth Information
inhibition is important for cardiac differentiation in early phases of
differentiationandthatBMPsignalingdoesnotjustpromotecardiac
differentiation.
In mouse ES cells, Cripto depletion results in a decrease in cardiac
marker gene expression and inhibition of cardiac differentiation
[34]. Although Cripto or overexpression of the activated receptor
rescues these phenotypes, the nodal inhibitor Cerberus-Short
(Cer-S) abolishes the rescued phenotype [35]. These data suggest
that signal transduction through nodal-dependent Cripto is crucial
for cardiac differentiation.
In human ES cells, there have been reports on cardiac
differentiation induced by activin and BMPs. BMP2 results in an
increase in mesoderm and cardiac marker gene expression [36].
Human ES cell embryoid bodies contain <10% beating areas [37].
Furthermore, the ratio of cardiomyocytes in embryoid bodies is
<1% [38]. Sequential treatment with activin A and then BMP4 in
monolayer culture effectively induces cardiac differentiation, and
thecardiomyocyteratiois>30%[39].Cardiacdifferentiationfrom
human iPS cells has been observed using the same methods [4]. In
addition to these observations, differentiated cardiomyocytes are
induced at >50% by activin A, BMP4, basic FGF (bFGF), vascular
endothelial growth factor (VEGF), and Dickkopf 1 (Dkk1) [40].
2b.3
The Wnt Signaling Pathway in Cardiac
Differentiation
Wnts are a growth factor family that regulates various biological
processes such as cell growth, adhesion, polarity, and mobility.
Nineteen Wnt molecules have been reported, and their signals are
mediated via two signaling pathways, the beta-catenin-related
canonical and the noncanonical (Fig. 2b.2). The canonical
Wnt pathway begins with ligand binding to the seven-pass
transmembraneproteinfrizzled(Frz)andlowdensitylipoprotein
receptor-related proteins 5 and 6 (Lrp5 and Lrp6) coreceptors.
Beta-catenin interacts with cadherin to regulate cell adhesion and
act as a signaling mediator in the canonical Wnt pathway. In the
absence of Wnts, beta-catenin forms a destruction complex with
axin, glycogen synthase kinase 3β (GSK3β), and adenomatous
polyposis coli (APC), which is phosphorylated for degradation in the
