Chemical genetics and its potential in cardiac stem cell therapy

Abstract

Over the last decade or so, intensive research in cardiac stem cell biology has led to significant discoveries towards a potential therapy for cardiovascular disease; the main cause of morbidity and mortality in humans. The major goal within the field of cardiovascular regenerative medicine is to replace lost or damaged cardiac muscle and coronaries following ischaemic disease. At present, de novo cardiomyocytes can be generated either in vitro, for cell transplantation or disease modelling using directed differentiation of embryonic stem cells or induced pluripotent stem cells, or in vivo via direct reprogramming of resident adult cardiac fibroblast or ectopic stimulation of resident cardiac stem or progenitor cells. A major bottleneck with all of these approaches is the low efficiency of cardiomyocyte differentiation alongside their relative functional immaturity. Chemical genetics, and the application of phenotypic screening with small molecule libraries, represent a means to enhance understanding of the molecular pathways controlling cardiovascular cell differentiation and, moreover, offer the potential for discovery of new drugs to invoke heart repair and regeneration. Here, we review the potential of chemical genetics in cardiac stem cell therapy, highlighting not only the major contributions to the field so far, but also the future challenges.

Figure 1

Chemical genetics potential in cardiac stem therapy. ES, iPS and cardiac progenitor's cells are at the present the favoured cell source for replacement of lost or damaged cardiac muscle and coronary vasculature post-ischaemic disease. These cells constitute a perfect platform for small molecule high-throughput screening experiments. Ideally, HTS studies can lead to the identification of small molecules that efficiently stimulate proliferation of these stem/progenitor cells and their self-renewal, specification and differentiation into the different cell lineages required for heart repair, including cardiomyocytes (in brown), endothelial cells (in red) and smooth muscle cells (in yellow).