Transmural replacement of myocardium after skeletal myoblast grafting intothe heart: Too much of a good thing?

Skeletal myoblasts form stable grafts in the heart and may improve myocardi al performance after infarction. The current study compared the ability of different immortalized myoblast lines, or primary myoblast isolates, to for m grafts in the normal or cryoinjured heart. With a constant dose of 6 X 10 (6) cells, primary rat myoblasts and mouse C2C12 myoblasts formed similarly large skeletal muscle grafts in recipient rat hearts. Grafts often caused transmural replacement of the myocardium in normal hearts and almost comple tely replaced the damaged region in cryoinjured hearts. To test for possibl e artifacts due to immunosuppression and xenografting (mouse C2C12 cells in to rat hearts), we grafted 1 X 10(6) mouse MM14 or C2C12 myoblasts into nor mal hearts of nude mice. Again, the C2C12 grafts caused transmural replacem ent of the left ventricular wall and distorted the epi- and endocardial con tours. The MM14 cells, however, formed relatively small grafts. The C2C12 g rafts showed substantially higher BrdU incorporation rates at day 4 compare d with MM14 cells, suggesting that ongoing proliferation was responsible fo r the increased graft size. None of the three skeletal muscle cell types ex pressed detectable amounts of the gap junction protein connexin43 after gra fting. The intercellular adhesion protein N-cadherin was not expressed in p rimary skeletal muscle grafts, but was spotty or abundant in C2C12- and MM1 4-derived grafts, respectively. The absence of connexin43 precluded electri cal coupling between graft and host muscle cells. Thus, when sufficient amo unts of proliferation occur after grafting, skeletal muscle cells can effec tively replace the volume of lost myocardium. Excess proliferation, however , can cause grafts to expand the ventricular wall and possibly impair pump function. Optimal cardiac repair strategies may need to incorporate methods to control graft cell proliferation. (C) 2000 by Elsevier Science Inc.