Creation of a Biological Pacemaker by Cell Fusion

As an alternative to electronic pacemakers, we explored the feasibility of converting ventricular myocytes into pacemakers by somatic cell fusion. The idea is to create chemically induced fusion between myocytes and synge-neic fibroblasts engineered to express HCN1 pacemaker channels (HCN1–fibroblasts). HCN1–fibroblasts were fused with freshly isolated guinea pig ventricular myo-cytes using polyethylene-glycol 1500. In vivo fused myo-cyte–HCN1–fibroblast cells exhibited spontaneously os-cillating action potentials; the firing frequency increased with -adrenergic stimulation. The heterokaryons cre-ated ectopic ventricular pacemaker activity in vivo at the site of cell injection. Coculture of nonfused HCN1– fibroblasts and myocytes without polyethylene-glycol 1500 revealed no evidence of dye transfer, demonstrating that the If-mediated pacemaker activ-ity arises from heterokaryons rather than electro-tonic coupling. This nonviral, non–stem cell ap-proach enables autologous, adult somatic cell therapy to create biopacemakers. Cardiac rhythm disorders are caused by malfunctions ofimpulse generation and/or conduction. Present therapies for deficient impulse generation, eg, electronic pacemakers, remain palliative. Here we continue to develop the alternative concept of biological therapy for cardiac arrhythmias; the objective is to achieve functional reengineering of cardiac tissue, so as to alter a specific electrical property of the tissue in a salutary manner. In this study, engineered cells were introduced to create a biological pacemaker in normally quiescent myocardium. A key ionic current present in sino-atrial nodal pacemaker cells, but largely absent in atrial and ventricular myocytes, is the pacemaker current, If.1 We used polyethylene glycol–induced fibroblast–myocyte fusion as a method to deliver If to myocardium to create a biological pacemaker