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Creation of a Biological Pacemaker by Cell Fusion

From the Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD. Present address for H.C.C.: Excigen Inc, Baltimore, Md. Present address for Y.K.: Okayama Innovation Center for Nanobio-targeted Therapy, School of Medicine, Okayama University, Japan.

Correspondence to Eduardo Marbán, MD, PhD, Chief of Cardiology, 858 Ross Bldg, 720 Rutland Ave, Baltimore, MD 21205. E-mail marban{at}jhmi.edu

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 syngeneic fibroblasts engineered to express HCN1 pacemaker channels (HCN1-fibroblasts). HCN1-fibroblasts were fused with freshly isolated guinea pig ventricular myocytes using polyethylene-glycol 1500. In vivo fused myocyte-HCN1-fibroblast cells exhibited spontaneously oscillating action potentials; the firing frequency increased with ß-adrenergic stimulation. The heterokaryons created 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 I_f-mediated pacemaker activity arises from heterokaryons rather than electrotonic coupling. This nonviral, non-stem cell approach enables autologous, adult somatic cell therapy to create biopacemakers.

Key Words: arrhythmia • biological pacemaker • cell fusion • cell transplantation • heart rate • ion channels • pacemaker

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