Biomedical Engineering Reference
In-Depth Information
signaling is required for cardiac differentiation. In mouse ES cells,
FGFR ablation results in suppression of cardiac differentiation [71].
Either deletion of Erk2, a molecule downstream of FGF signaling, or
FGFR inhibition represses mesoderm formation [72]. In addition,
BMP2andFGF2efficientlyenhancecardiacdifferentiation[73].
2b.5
Other Factors Involved in Cardiac
Differentiation
RetinoicacidisavitaminAderivativesynthesizedbyretinaldehyde
dehydrogenase and is the ligand of cognate nuclear receptors such
as retinoic acid receptor (RAR) and retinoid X receptor (RXR), which
regulate target gene expression. Retinoic acid has also been reported
as being involved in heart development. Heart malformation found
inRAR-deficientmiceisembryoniclethal[74-77].InmouseP19
EC cells, retinoic acid induces cardiac differentiation in a time- and
dose-dependent manner [78]. In mouse ES cells, the effect of retinoic
acid on cardiac differentiation has been studied. Low concentrations
of retinoic acid during late phases of differentiation promote
cardiac differentiation, whereas high concentrations inhibit cardiac
differentiation[79].RXRagonisttreatmentalsoinducescardiac
differentiation[80].Moreover,retinoicacidtreatmentoffloating
culture systems induces cardiac differentiation [81].
Nitric oxide (NO) is a widespread signaling molecule with high
activities and short durations. NO synthesis is regulated by NO
synthase (NOS), and three isoforms have been reported thus far.
These isoforms are considered to be involved in development due
totissue-specificexpression.Duringembryonicdevelopment,both
inducible NOS expression and endothelial NOS (eNOS) expression
have been observed, and several congenital heart malformations
havebeenreportedineNOS-deficientmice[82-84].Inmouse
ES cells, NOS inhibition suppresses cardiac differentiation and is
rescued by NO donor treatment [82]. In addition to inducing cardiac
differentiation, NO may also induce noncardiac cell apoptosis [85].
Ascorbic acid is an antioxidant with various roles in metabolic
and biochemical processes. In mouse ES cells, differentiated
cardiomyocytes increase in the presence of ascorbic acid,
which cannot be reproduced by other antioxidants [86]. During
embryogenesis, mesoderm formation is induced by an interaction
