Reprogramming Approaches for Cardiovascular Disease

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. For example, we found the human mutations in the transcription factor GATA4 disrupt cardiogenesis, in part by affecting GATA4's interaction with TBX5. Many of the developmental cues have been leveraged to control differentiation of pluripotent stem cells into cardiac, endothelial and smooth muscle cells that may be useful for regenerative purposes. We have used similar approaches to direct differentiation of disease-specific human induced pluripotent stem cells in order to model human heart disease. Recently, we utilized a combination of major cardiac regulatory factors, Gata4/Mef2c/Tbx5, to induce direct reprogramming of cardiac fibroblasts into cardiomyocyte-like cells with global gene expression and electrical activity similar to cardiomyocytes. The reprogramming was a stable event at the epigenetic level. We have now used genetic lineage-tracing techniques to demonstrate that resident cardiac fibroblasts can be reprogrammed into induced cardiomyocytes in vivo using a gene therapy approach. The in vivo efficiency of reprogramming into cells that are more fully reprogrammed into beating cardiomyocytes was greater than in vitro and resulted in improved cardiac function after injury. Knowledge regarding the early steps of cardiac differentiation in vivo has led to effective strategies to generate necessary cardiac cell types for disease-modeling and regenerative approaches, and promise to lead to new strategies for human heart disease.