Figure 5. Reprogramming different cardiac cell types.

Progress has been made in using transcriptional reprogramming to generate different specialized cell types that are essential for restoring cardiac function in an injured heart. For the conduction system, pacemaker cells and Purkinje fibres can be generated by reprogramming. Overexpression of the transcription factor T-box 18 (TBX18) directly reprogrammes rodent ventricular cardiomyocytes, in vitro and in vivo, into cells resembling pacemaker cells from the sinoatrial node, without passage of cells through a pluripotent state. The activation of Notch signalling in newborn rodent cardiomyocytes,in vitro and in vivo, confers a Purkinje cell-like phenotype. For the vasculature, smooth muscle cells and endothelial cells can be produced from fibroblasts by reprogramming. Smooth muscle cells can be generated by forced expression of the cardiovascular-specific co-activator myocardin. Myocardin activates smooth muscle-specific genes through association with the transcription factor serum response factor (SRF). Adult fibroblasts can also be reprogrammed into an incomplete induced pluripotent state by transient forced overexpression of the four induced pluripotent stem (iPS) cell factors OCT4, SOX2, Kruppel-like factor 4 (KLF4) and MYC (OSKM factors); endothelial cells then form under permissive culture conditions. Endothelial cells can also be generated from amniotic cells by forced overexpression of ETS transcription factors, in combination with the inhibition of transforming growth factor-β (TGFβ) signalling, without cells transiting through an iPS cell state. Finally, cardiomyocytes can be generated by reprogramming fibroblasts indirectly via an iPS cell state that is induced by OSKM factors, or directly with the cardiac-specific transcription factors GATA4, HAND2, myocyte-specific enhancer factor 2C (MEF2C) and T-box 5 (TBX5) (collectively referred to as GHMT) (see also FIG. 4).