Heart circulates blood through the entire body with a regular and stable rhythm. For fulfillment of this regularity and stability it requires proper, accurate and coordinated activities of various types of cardiomyocytes such as atrial, ventricular and pacemaker cells. Original location of pacemaker cells is sinoatrial node (SAN) which establishes spontaneous and ordered action potentials. Unnatural formation and function of SAN can cause dysfunction of pacemaker cells that be followed by sinus arrhythmias including tachycardia (very fast heart beats) or bradycardia (very slow heart beats). Prolonged arrhythmias can result in heart failure which in serious conditions lead to death. Bradycardia can be fixed with electronic pacemakers. Although electronic pacemakers are effective for SAN dysfunction, they have some defects including inadequate autonomic modulation, limited battery life and infection which lead scientists to think of a more physiological alternative, like biological pacemakers. So far, different strategies have been devised for creation of biological pacemakers based on cell and gene therapy. Combinatorial strategies in which cells are being applied as a platform for carrying the desired genes, are more common. In this approach, stem cells such as mesenchymal stem cells, embryonic stem cells, cardiac stem cells and induced pluripotent stem cells (iPSCs) are mainly used. Desired genes are either transcription factors or pacemaker characteristic genes like Hyperpolarization-activated cyclic nucleotide–gated (HCN) channels, T-boxes gene family (Tbx2, Tbx3, andTbx18), connexins gene family (Cx40, Cx43 and Cx45) and Shox2. As HCN channels play a prominent role in generating pacemaker current (If, funny current). Different isoforms of this gene, alone or in combination with other genes can be used for producing pacemaker-like cells. Although, great progress has been made in creating biological pacemakers and many promising results have been achieved from in vivo studies in animals, there is still room to bring to light some critical aspects of clinical applications of biological pacemaker to determine the best strategy in this case.

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