Repairing hearts with AKT

Adult cardiomyocytes—the contractile units of the heart—have little regenerative capacity, and their loss, following ischemic injury and other insults, leads to cardiac dysfunction and heart failure, a degenerative condition with a poorer prognosis than many cancers. Despite intense efforts, there are presently no effective treatments for heart failure besides heart transplantation, itself limited by the number of organ donors and immunosuppressive therapies. Cell therapy has emerged as an attractive option for heart repair following myocardial infarction, which often progresses to heart failure. Over the past decade, many clinical trials have tested the ability of a variety of exogenous progenitor cells at repairing ischemic and failing hearts, but with little success; in most cases, cells transferred to the heart were unable to generate new cardiomyocytes (1). Alternative strategies, including in situ generation of cardiomyocytes at the infarcted area or in vitro reprogramming of cells into cardiomyocytes for organ grafting, are being explored. A promising avenue is the use of transcription factors to reprogram stem or somatic cells, such as fibroblasts, into beating cardiomyocytes. The discovery that transcription factor GATA4 cooperates with other cardiac transcriptional regulators to enhance cardiogenesis opened interesting avenues for heart repair (2⇓–4). In the past few years, several studies showed that a combination of cardiac transcription factors, GATA4, MEF2C and TBX5 (GMT) or GHMT (GMT + HAND2) can be used to directly reprogram mouse fibroblasts into cardiomyocytes (5⇓⇓–8). Notwithstanding these impressive advances, several limitations still need to be overcome for this approach to realize its clinical potential. Chief among them is the modest efficiency of the reprogramming process and the need to …