Reprogramming approaches to cardiovascular disease: From developmental biology to regenerative medicine

Abstract

Heart disease is a leading cause of death in adults and children. We, and others, have described complex signaling, transcriptional, and translational networks that guide early differentiation of cardiac progenitors and later morphogenetic events during cardiogenesis. We found that networks of transcription factors and miRNAs function through intersecting positive and negative feedback loops to reinforce differentiation and proliferation decisions. We have utilized a combination of major cardiac regulatory factors to induce direct reprogramming of cardiac fibroblasts into cardiomyocyte-like cells with global gene expression and electrical activity similar to cardiomyocytes. The in vivo efficiency of reprogramming into cells that are more fully reprogrammed was greater than in vitro and resulted in improved cardiac function after injury. We have also identified a unique cocktail of transcription factors and small molecules that reprogram human fibroblasts into cardiomyocyte-like cells and are testing these in large animals. Knowledge regarding the early steps of cardiac differentiation in vivo has led to effective strategies to generate necessary cardiac cell types for regenerative approaches and may lead to new strategies for human heart disease.