Muscle Cell Grafting for the Treatment and Prevention of Heart Failure CHARLES E. MURRY,*† MARSHAL. WHITNEY,*† HANS REINECKE* Seattle, Washington ABSTRACT Background: The review aims to highlight recent advances in cardiac and skeletal muscle cell grafting for myocardial infarct repair. Results: Fetal and neonatal cardiomyocytes form new myocardium in normal or injured hearts, and this new myocardium differentiates toward an adult phenotype. Unfortunately, formation of new myocardium is limited by graft cell death, in large part because of ischemic injury. In contrast, skeletal myoblasts are ischemia-resistant and form larger grafts of mature skeletal muscle in the injured heart. Although contractile under field stimulation, skeletal muscle grafts do not express gap junction proteins and remain electrically insulated, suggesting they may not beat with host myocardium. When placed in coculture, however, cardiac and skeletal muscle form synchronously beating networks, where cardiomyocytes capture and pace skeletal muscle cells via intercalated disk-like structures containing gap junctions. This suggests that engineering skeletal muscle to express gap junction proteins in vivo may induce similar coupling with host myocardium. One major challenge to myocardial repair is getting sufficient graft cell mass without risking a tumor-like overgrowth. Recent experiments suggest it may be possible to control skeletal muscle graft size using a small, synthetic ligand, which activates the fibroblast growth factor signaling pathway only in genetically modified graft cells. Finally, a review of functional studies is presented that provides clear evidence that skeletal myoblast grafting is beneficial by limiting remodeling of the heart after infarction. Conclusion: Given that clinical trials of skeletal myoblast grafting for myocardial repair are under way, it will be critically important to determine if these cells beat after grafting in the heart. Key Words: Myocardial infarction, cell transplantation, skeletal myoblast, cell death, cell proliferation, gap junction Myocardial infarction and subsequent heart failure can be viewed as a disease of cellular deficiency. It has long been recognized that there is no functional regeneration of the myocardium after infarction. 1 Inability of the heart to regenerate stems from two factors: the apparent absence of a myogenic stem cell component in the infarct and the inability of surviving cardiomyocytes to reenter the cell cycle. 2 It has been suggested in studies that there may be a stem cell population that contributes new myocytes after infarction, 3-6 and, similarly, that there can be limited DNA synthesis in surviving myocytes. 7 If such responses truly exist, they clearly are physiologi- cally insignificant in comparison to the mechanical requirements of the infarcted heart. For this reason, our group and others have explored cellular grafting as a strategy for repairing the infarcted heart. From the *Departments of Pathology and †Bioengineering, Univer- sity of Washington School of Medicine, Seattle, Washington. These studies were supported, in part by NIH grants K08 HL03094, P01 HL03174, R01 HL61553, and R24 HL64387. Many of these studies were performed while Dr. Murry was the recipient of a Burroughs Wellcome Career Award in the Biomedical Sciences. Reprint requests: Charles E. Murry, MD, PhD, Department of Pathology, Box 357470, Room D-514 HSB, University of Washington, Seattle, WA 98195. Copyright 2002, Elsevier Science (USA). All rights reserved. 1071-9164/02/0806-0056$35.00/0 doi:10.1054/jcaf.2002.129268 Journal of Cardiac Failure Vol. 8 No. 6 Suppl. 2002 S532