Less may be more: Using small molecules to reprogram human cells into functional cardiomyocytes.

The prospect of genetically reprogramming cardiac fibroblasts into induced cardiomyocytes by using cardio-differentiating transcription factors represents a significant advantage over previous strategies involving stem cell implantation or the delivery of angiogenic factors. Remarkably, intramyocardial administration of cardio-differentiating factors consistently results in 20% to 30% improvements in postinfarct ejection fraction and nearly a 50% reduction in myocardial fibrosis in murine models. Despite these encouraging observations, few breakthroughs have been made in the reprogramming of human cells, which have more rigorous epigenetic constraints and gene regulatory networks that oppose reprogramming. As a potential solution to this challenge, Cao and colleagues used a cocktail of 9 chemicals capable of reprogramming human fibroblasts into contractile cardiomyocyte-like cells, albeit at a low efficiency. This strategy would obviate the concerns with viral vectors and appears to partially overcome the epigenetic constraints in human cells. Nevertheless, significant challenges, including drug-drug interactions, low reprogramming efficiency, and lack of in vivo data must be overcome before future clinical application.