Normal rhythms originate in the sino-atrial node, a specialized cardiac tissue consisting of only a few thousands of nodal pacemaker cells. Malfunction of pacemaker cells due to diseases or aging leads to rhythm generation disorders (for example, bradycardias and sick-sinus syndrome (SSS)), which often necessitate the implantation of electronic pacemakers. Although effective, electronic devices are associated with such shortcomings as limited battery life, permanent implantation of leads, lead dislodging, the lack of autonomic responses and so on. Here, various gene-and cell-based approaches, with a particular emphasis placed on the use of pluripotent stem cells and the hyperpolarization-activated cyclic nucleotide-gated-encoded pacemaker gene family, that have been pursued in the past decade to reconstruct bio-artificial pacemakers as alternatives will be discussed in relation to the basic biological insights and translational regenerative potential. Gene Therapy (2012) 19, 588-595; doi:10.1038/gt.2012.33Keywords: human embryonic stem cells; pluripotent; bio-artificial; pacemaker; cardiac differentiation; electrophysiologyThe heart beats with a regular rhythm to pump blood throughout the body. These mechanical actions require the highly coordinated efforts of different types of cardiomyocytes (CMs) such as atrial, ventricular and pacemaker cells. Chamber-specific CM types differ substantially in their electrical properties, which in turn govern cardiac excitability. Normal heart (sinus) rhythms originate in the sino-atrial node (SAN), a specialized cardiac tissue consisting of only a few thousands nodal or so-called pacemaker cells. 1,2 The SAN spontaneously and rhythmically generates action potentials (APs) by the process of pacemaking. These rhythmic APs propagate through the atria to the atrioventricular node, and after a slow pause, subsequently to the ventricles via a unique conduction system for coordinated chamber contractions and therefore blood pumping. As such, the SAN is responsible for initiating and controlling the heart rate. CLASSICAL VIEW OF CARDIAC PACEMAKING: SAN IS A COMPLEX STRUCTURE THAT FUNCTIONS WITH A COMPLEX MECHANISMStructurally, the native SAN is a complex, three-dimensional tissue containing a heterogeneous population of pacemaker cells that display a range of phenotypic properties and anatomic boundary effects. 1,3 For instance, there are gradual gradient changes in the AP profile, 4,5 ionic current densities and gap-junction expression from central (dominant or the leading pacemaker site) to peripheral (subsidiary) SAN cells. 1 These differences and anatomic arrangements (for example, interdigitation) have been thought to ensure that the leading center cells are protected from any over-hyperpolarizing effects from the surrounding mass of atrial CMs and that the depolarization wave front is propagated in the proper directions. In addition to pacemaker cells, the SAN also contains atrial CMs, fibroblasts and adipocytes. The collagen content of the SAN region is relatively high. 6 Dur...
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