Transcription factors (TFs) govern most developmental gene expression programs. The power of TFs to establish cellular identity has been recently exemplified by cellular reprogramming, in which the ectopic expression of TFs in somatic cells can generate many cell types. Examples include the generation of skeletal muscle cells from fibroblasts [46
], the complete reprogramming of somatic cells into iPS cells [47
] (Box 1
), and the conversion of mesoderm-derived fibroblasts into normally ectoderm-derived neurons [49
], demonstrating that the right combination of TFs can completely alter the state of a differentiated cell. These approaches demonstrate the possibility for directed trans-lineage reprogramming.
In the heart, a large group of TFs cooperate to control cardiac gene expression [29
]. These include members of the Nkx, Mesp, Gata, Islet, Tbx, Mef2, and Hand families. Similar to signaling pathways, understanding the TF networks that control cardiac development could yield effective means for generating desired therapeutic cell types in vitro
as well as mobilizing or transdifferentiating cells in vivo
either after injury or disease onset. Numerous cardiac factors might have this potential.
Mesp1, a basic helix-loop-helix TF, is transiently expressed in mesodermal populations that contribute to the majority of the heart [51
]. Owing to its expression within early cardiogenic mesoderm, it is an enticing candidate for a critical regulator of the cardiac transcriptional program. Several groups have overexpressed Mesp1 to probe its function in cardiogenesis. Mesp1 overexpression induces greater numbers of mesodermal-derived precursors [52
], an earlier advent of beating [53
], more beating areas [53
], and increased expression of cardiac markers [52
] during mESC differentiation. In addition, ectopic expression of Mesp1 in Xenopus
tadpoles produces ectopic contracting tissue [54
]. Together, these data suggest this factor might promote transdifferentiation into cardiac precursors (). Although these experiments are promising, the mechanism by which Mesp1 functions as a cardiogenic factor is uncertain, and additional research is necessary to fully define its role.
Cardiogenic transcriptional regulators can induce mesodermal derivatives to transdifferentiate into functional myocytes within the mouse embryo. The combination of factors that is effective in this process reveals important aspects of the biology of mammalian cardiac transcriptional regulation. Ectopic expression of three factors, Tbx5, Gata4, and Baf60c, drives cardiogenesis in non-cardiogenic posterior mesoderm as well as amniotic mesoderm [55
] (). Baf60c, a component of the conserved SWI-SNF-like Brg1/Brm-associated factor (BAF) chromatin-remodeling complex, might allow BAF complexes to recognize cardiac regulatory elements and facilitate TF binding by altering the local chromatin environment. Indeed, Gata4 and the BAF complex ATPase Brg1 were detected at cardiac promoters only when coexpressed with Baf60c [55
]. Understanding the cooperative roles that TFs and chromatin regulators play during cardiac differentiation will likely be pivotal in driving therapeutic cardiac cell fates.
Understanding the determinants of the cardiac transcriptional programs has raised the distinct possibility of direct transdifferentiation of adult cell types into functional cardiomyocytes. The induction of cardiac tissue from embryonic mesoderm helps define the minimal inputs required for cardiac differentiation, but does not necessarily provide a therapeutically useful approach to generate new cardiomyocytes. Recent work in the mouse demonstrates that cardiogenic transcription factors can reprogram fibroblasts into functional cardiomyocytes [56
]. The combination of Gata4, Tbx5, and Mef2c direct reprogramming of cardiac fibroblasts or tail-tip fibroblasts into cells that express cardiac markers, form sarcomeres, have a transcriptional profile that closely resembles that of cardiomyocytes, and demonstrate sponteous calcium flux, beating, and action potentials that resemble adult cardiomyocytes [56
] (). Two of the factors, Gata4, and Tbx5, are part of the combination that direct mesoderm to cardiomyocytes [55
], indicating a likely common mechanism of action. Importantly, it was found that the reprogramming of fibroblasts to cardiomyocytes does not proceed via dedifferentiation to a precursor state, but rather appears to be a direct conversion [56
]. These findings indicate that it is feasible to reprogram somatic cells into cardiomyocytes, providing an exciting potential for regenerative strategies that could involve conversion of resident fibroblasts to replace cardiomyocytes lost to ischemic injury.