Reprogramming of mouse fibroblasts toward a myocardial cell fate by forced 
expression of cardiac transcription factors or microRNAs has recently been 
demonstrated. The potential clinical applicability of these findings is based on 
the minimal regenerative potential of the adult human heart and the limited 
availability of human heart tissue. An initial but mandatory step toward 
clinical application of this approach is to establish conditions for conversion 
of adult human fibroblasts to a cardiac phenotype. Toward this goal, we sought 
to determine the optimal combination of factors necessary and sufficient for 
direct myocardial reprogramming of human fibroblasts. Here we show that four 
human cardiac transcription factors, including GATA binding protein 4, Hand2, 
T-box5, and myocardin, and two microRNAs, miR-1 and miR-133, activated cardiac 
marker expression in neonatal and adult human fibroblasts. After maintenance in 
culture for 4-11 wk, human fibroblasts reprogrammed with these proteins and 
microRNAs displayed sarcomere-like structures and calcium transients, and a 
small subset of such cells exhibited spontaneous contractility. These phenotypic 
changes were accompanied by expression of a broad range of cardiac genes and 
suppression of nonmyocyte genes. These findings indicate that human fibroblasts 
can be reprogrammed to cardiac-like myocytes by forced expression of cardiac 
transcription factors with muscle-specific microRNAs and represent a step toward 
possible therapeutic application of this reprogramming approach.