Members of the transforming growth factor beta1 (TGF-beta) superfamily--namely, 
TGF-beta and BMP2--applied to undifferentiated murine embryonic stem cells 
up-regulated mRNA of mesodermal (Brachyury) and cardiac specific transcription 
factors (Nkx2.5, MEF2C). Embryoid bodies generated from stem cells primed with 
these growth factors demonstrated an increased potential for cardiac 
differentiation with a significant increase in beating areas and enhanced 
myofibrillogenesis. In an environment of postmitotic cardiomyocytes, stem cells 
engineered to express a fluorescent protein under the control of a cardiac 
promoter differentiated into fluorescent ventricular myocytes beating in 
synchrony with host cells, a process significantly enhanced by TGF-beta or BMP2. 
In vitro, disruption of the TGF-beta/BMP signaling pathways by 
latency-associated peptide and/or noggin prevented differentiation of stem 
cells. In fact, only host cells that secrete a TGF-beta family member induced a 
cardiac phenotype in stem cells. In vivo, transplantation of stem cells into 
heart also resulted in cardiac differentiation provided that TGF-beta/BMP2 
signaling was intact. In infarcted myocardium, grafted stem cells differentiated 
into functional cardiomyocytes integrated with surrounding tissue, improving 
contractile performance. Thus, embryonic stem cells are directed to 
differentiate into cardiomyocytes by signaling mediated through TGF-beta/BMP2, a 
cardiac paracrine pathway required for therapeutic benefit of stem cell 
transplantation in diseased heart.