Reprogramming the Beat

Abstract

The explosion of stem cell research in cardiology has yielded an increasing recognition that understanding developmental cell fate decisions is critical for everything from disease models to cellular therapeutics. However, the biology is particularly rich and complex and has not yielded easily to traditional investigative methods. One area of intense focus is the study of the cues responsible for the development of specialized conduction tissues in the heart. Direction of native cells or exogenous cells into the conduction system lineage might offer therapeutic insights into degenerative conduction disease. Article see p 1058 The most distal subendocardial fibers of the cardiac conduction system were first described by Jan Purkinje in 1839.1 Over 100 years ago, in painstakingly delicate dissections, Sunao Tawara2 characterized the cardiac conduction system further, describing the atrioventricular node, the penetrating bundle of His, the bundle branches, and the Purkinje fiber network. During the past 20 years, however, the pace of discovery of this highly specialized tissue has accelerated. Beginning with the observations that peripheral and central conduction tissue derives from cardiomyocyte progenitors in the chick,3,4 investigators have now identified key roles for many important molecular signals and transcription factors in conduction system development. Signaling molecules implicated in the formation of the conduction system include endothelin,5–9 neuregulin,10–13 Wnts,14 and bone morphogenetic proteins,15 and complex transcriptional roles have been identified for NKx2.5,16–20 members the T-box transcription factor family,18,21,22 shox2,23 msx2,24,25 and hop.26–28 In this issue of Circulation , Rentschler et al29 take a significant step toward understanding the determinants of conduction cell fate. In a series of elegant experiments, they demonstrate that activation of …