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(Circulation. 2007;116:706-713.)
© 2007 American Heart Association, Inc.

Arrhythmia/Electrophysiology

Xenografted Adult Human Mesenchymal Stem Cells Provide a Platform for Sustained Biological Pacemaker Function in Canine Heart

Alexei N. Plotnikov, MD; Iryna Shlapakova, MD; Matthias J. Szabolcs, MD; Peter Danilo, Jr, PhD; Beverly H. Lorell, MD; Irina A. Potapova, PhD; Zhongju Lu, MD, PhD; Amy B. Rosen, PhD; Richard T. Mathias, PhD; Peter R. Brink, PhD; Richard B. Robinson, PhD; Ira S. Cohen, MD, PhD; Michael R. Rosen, MD

From the Center for Molecular Therapeutics (A.N.P., I.S., P.D., R.B.R., I.S.C., M.R.R.), Department of Pharmacology (A.N.P., I.S., P.D., R.B.R., I.S.C., M.R.R.), Department of Pediatrics (M.R.R.), and Department of Pathology (M.J.S), Columbia University, New York, NY; King & Spalding, LLP, Washington, DC (B.H.L.); and Institute of Molecular Cardiology (I.A.P., Z.L., A.B.R., R.T.M., I.S.C., M.R.R.), Departments of Physiology and Biophysics, SUNY–Stony Brook, Stony Brook, NY.

Correspondence to Michael R. Rosen, MD, Gustavus A. Pfeiffer Professor of Pharmacology, Professor of Pediatrics, Director, Center for Molecular Therapeutics, College of Physicians and Surgeons of Columbia University, 630 W 168 St, PH7 West-321, New York, NY 10032. E-mail mrr1{at}columbia.edu

Received January 31, 2007; accepted June 11, 2007.

Background— Biological pacemaking has been performed with viral vectors, human embryonic stem cells, and adult human mesenchymal stem cells (hMSCs) as delivery systems. Only with human embryonic stem cells are data available regarding stability for >2 to 3 weeks, and here, immunosuppression has been used to facilitate survival of xenografts. The purpose of the present study was to determine whether hMSCs provide stable impulse initiation over 6 weeks without the use of immunosuppression, the "dose" of hMSCs that ensures function over this period, and the catecholamine responsiveness of hMSC-packaged pacemakers.

Methods and Results— A full-length mHCN2 cDNA subcloned in a pIRES2-EGFP vector was electroporated into hMSCs. Transfection efficiency was estimated by GFP expression. I_HCN2 was measured with patch clamp, and cells were administered into the left ventricular anterior wall of adult dogs in complete heart block and with backup electronic pacemakers. Studies encompassed 6 weeks. I_HCN2 for all cells was 32.1±1.3 pA/pF (mean±SE) at –150 mV. Pacemaker function in intact dogs required 10 to 12 days to fully stabilize and persisted consistently through day 42 in dogs receiving 700 000 hMSCs (40% of which carried current). Rhythms were catecholamine responsive. Tissues from animals killed at 42 days manifested neither apoptosis nor humoral or cellular rejection.

Conclusions— hMSCs provide a means for administering catecholamine-responsive biological pacemakers that function stably for 6 weeks and manifest no cellular or humoral rejection at that time. Cell doses >700 000 are sufficient for pacemaking when administered to left ventricular myocardium.

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CLINICAL PERSPECTIVE

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