Challenges and new directions for cardiac reprogramming

Recent discoveries have highlighted the heart's natural ability to repair itself through mobilization of resident stem cells and regeneration from preexisting cardiomyocytes. However, these endogenous mechanisms are incapable of meaningful repair, since the regenerative response does not produce an adequate number of new cardiomyocytes to restore normal contractile activity in response to acquired cardiovascular disease. An entirely new heart repair strategy has recently been introduced to address this issue: direct reprogramming of fibroblasts toward a cardiac cell fate without transition through the stem cell state (referred to as "direct cardiac reprogramming"). Significant progress has been made toward achieving this new strategy: (i) in vitro reprogramming of mouse fibroblasts into beating cardiomyocytes by forced expression of various combination of cardiogenic transcription factors; (ii) in vivo reprogramming targeting activated cardiac fibroblasts after myocardial infarction, improving heart function and reducing scar formation; and (iii) identification of the optimal combination of factors that is necessary and sufficient to induce a contractile phenotype in human fibroblasts. In this chapter, we discuss current challenges in this field and new directions that will move this strategy toward clinical translation.