Direct cardiac reprogramming

Cardiovascular disease remains the number one cause of death in industrialized nations. The majority of cardiac pathologic conditions, in both adult and pediatric patients, can be characterized by hypocellularity. While cardiac muscle cells in humans have been confirmed to proliferate this occurs at a very low rate and is insufficient for functional recovery following myocardial injuries such as ischemia or infection. Identifying an ideal source for cardiomyocytes for cardiac repair or regeneration that is effective and safe is a major goal in regenerative medicine. A new strategy is currently being developed in which various cell types are being converted directly to cardiomyocytes. In efforts to understand cardiac development we have been using embryonic stem cell differentiation as a model and information gained on the genetic regulation of cardiomyogenesis is being used in efforts to reprogram mouse and human fibroblasts directly into cardiomyocytes. This is done by introducing combinations of small molecules and virally transduced transcription factors, known to be critical during cardiogenesis, into fibroblasts isolated from different anatomic locations. Treated cells are induced to express a broad cardiac transcriptional program including cardiac specific channels, transcription factors, sarcomeric proteins, etc. Downregulation of fibroblast specific gene expression occurs concurrently. Our approach suggests that expression of the cardiomyocyte transcriptional program is more effectively and completely achieved in cardiac fibroblasts than fibroblasts form other sources. Recently, the continuation of this work in our laboratory has demonstrated that primary mouse embryonic fibroblasts directly reprogrammed to cardiomyocytes contract spontaneously, have characteristic myocardial calcium currents and display a variety of proteins and transcripts characteristic of functional cardiomyocytes. Similar experiments with human cells demonstrate the capacity of skin fibroblasts and keratinocytes to display broad cardiac gene expression and histologic characteristics of immature cardiomyocytes.