Biomedical Engineering Reference
In-Depth Information
The essential roles of BMP have been demonstrated in heart
development between species. In chick embryos, the cardiac gene
program induces the differentiation of the precardiac mesoderm
by BMP signaling from the adjacent ectoderm and endoderm.
The ectopic expression of cardiac markers, GATA-4 and
,
are initiated by BMP2 ectopic expression in the anterior medial
mesoderm [10]. Furthermore, it has been reported that the
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enhancer region contains Smad-binding sites [12]. In mice,
BMP expression has been observed in the anterior mesoderm that
contains the heart-forming region [13-15]. Moreover, amnion/
chorion malformation and disruption of cardiogenesis in BMP2-
deficientmiceareembryoniclethalatE7.5-E9[13].NullBMP4
mutations in mice result in extraembryonic and posterior/ventral
mesodermdisruptionandareembryoniclethalatE6.5-E9.5[16].In
BMP10-deficientmice,normalheartdevelopmentisinhibitedwith
subsequentcardiacdysfunctionatE9.5-E10.5[17].Therefore,BMP
signaling is considered as being critical for cardiac cell induction.
In addition, the importance of BMP signaling in gastrulation and
primitive mesoderm formation was elucidated by embryonic
lethalityduetothedeficiencyofseveralBMPreceptorsandrelated
molecules such as Smad4 [18-22].
Activin and nodal are well-known mesoderm-inducing factors in
various species. In avian explant cultures, cardiac differentiation is
induced in the pregastrula epiblast by activin and inhibited in the
posterior explant by the activin-binding protein follistatin [23, 24]. In
mouse embryos, nodal is essential for gastrulation via the formation
of the anterior-posterior and left-right axes, the primitive streak,
the mesoderm, and the endoderm [25, 26]. In addition, the nodal
coreceptor Cripto is important for gastrulation via the formation of
the anterior-posterior axis and the mesoderm [27, 28].
Cardiac differentiation is promoted by BMP or activin A and
reported to be suppressed by noggin, a BMP inhibitor, in mouse ES cells
andP19embryoniccarcinoma(EC)cells[29,30].Therefore,BMPs
havebeenhypothesizedtosimplyinducecardiacdifferentiation.
Incontrasttopreviousstudies,cardiacdifferentiationefficiency
is increased by noggin prior to early phases of differentiation in
mouseEScells[31].InP19cells,knownBMPinhibitorsGremlin
and Crossveinless-2 (Cv2), promote cardiac differentiation in early
phases of differentiation [32, 33]. During embryonic development,
transient noggin and Cv2 expression has been observed in the heart-
forming region. These observations suggest that BMP-signaling
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