Cardiomyocytes induce endothelial cells to trans-differentiate into cardiac muscle: Implications for myocardium regeneration

The concept of tissue-restricted differentiation of postnatal stem cells ha s been challenged by recent evidence showing pluripotency for hematopoietic , mesenchymal, and neural stem cells. Furthermore, rare but well documented examples exist of already differentiated cells in developing mammals that change fate and transdifferentiate into another cell type. Here, we report that endothelial cells, either freshly isolated from embryonic vessels or e stablished as homogenous cells in culture, differentiate into beating cardi omyocytes and express cardiac markers when cocultured with neonatal rat car diomyocytes or when injected into postischemic adult mouse heart. Human umb ilical vein endothelial cells also differentiate into cardiomyocytes under similar experimental conditions and transiently coexpress von Willebrand fa ctor and sarcomeric myosin. In contrast, neural stem cells, which efficient ly differentiate into skeletal muscle, differentiate into cardiomyocytes at a low rate. Fibroblast growth factor 2 and bone morphogenetic protein 4, w hich activate cardiac differentiation in embryonic cells, do not activate c ardiogenesis in endothelial cells or stimulate trans-differentiation in coc ulture, suggesting that different signaling molecules are responsible for c ardiac induction during embryogenesis and in successive periods of developm ent. The fact that endothelial cells can generate cardiomyocytes sheds addi tional light on the plasticity of endothelial cells during development and opens perspectives for cell autologous replacement therapies.