A Tractable Model of Human Cardiac Development

Stem cell-derived cardiac cells hold great promise for the regeneration of damaged heart tissue after cardiovascular disease or injury; however, there are currently several issues that impede the immediate use of these cells in a therapeutic setting. One such issue is the heterogeneity of cell types formed during differentiation and the resulting poor generation efficiency of the desired cell type.

As outlined in the manuscript in the September 2011 issue of Molecular Therapy, Dr. James E. Dixon and colleagues have approached this problem by implementing a genetics-based screen to identify four key developmental factors (GATA4, TBX5, NKX2.5 and BAF60c) that can direct the differentiation of human embryonic stem (hES) cells toward cardiac cells. Upon viral overexpression of the aforementioned factors, Dixon et al report successful differentiation via a cardiac progenitor intermediate cell, a desired cell type for use in potential therapy. The authors also note that consistent expression of the four factors gives rise to slightly abnormal cardiac cells, a problem that continues to plague the field. Owing to the knowledge that hES cell differentiation is dynamic, rather than a static event, the authors performed additional experiments utilizing a virus that permitted the transient expression of the four factors. This tractable approach was capable of stimulating cardiac differentiation in hES cells, leading to both progenitor, intermediate and fully mature cardiac cells.

Nevertheless, it remains necessary to perform further experiments to elucidate the mechanism of action of these factors. Until the precise developmental stages have been identified and recapitulated in vitro to generate completely normal and durable cells, it is unlikely that current strategies will deliver cells which can be used in the clinic. Despite this, the work of Dixon and colleagues has advanced the field considerably closer to obtaining that goal.