Survival, integration, and differentiation of cardiomyocyte grafts - A study in normal and injured rat hearts

Background-Cardiomyocyte grafting augments myocyte numbers in the heart. We investigated (1) how developmental stage influences graft survival; (2) wh ether acutely necrotic or healing cardiac lesions support grafts; and (3) t he differentiation and integration of cardiomyocyte grafts in injured heart s. Methods and Results-Cardiomyocytes from fetal, neonatal, or adult inbred ra ts were grafted into normal myocardium, acutely cryoinjured myocardium, or granulation tissue (6 days after injury). Adult cardiomyocytes did not surv ive under any conditions. In contrast, fetal and neonatal cardiomyocytes fo rmed viable grafts under all conditions. Time-course studies with neonatal cardiomyocytes showed that the grafts recapitulated many aspects of normal development. The adherens junction protein N-cadherin was distributed circu mferentially at day 1 but began to organize into intercalated disk-like str uctures by day 6. The gap junction protein connexin43 followed a similar bu t delayed pattern relative to N-cadherin. From 2 to 8 weeks, there was prog ressive hypertrophy and the formation of mature intercalated disks. In some hearts, graft cells formed adherens and gap junctions with host cardiomyoc ytes, suggesting electromechanical coupling. More commonly, however, grafts were separated from the host myocardium by scar tissue. Gap and adherens j unctions formed between neonatal and adult cardiomyocytes in coculture, as evidenced by dye transfer and localization of cadherin and connexin43 at in tercellular junctions. Conclusions-Grafted fetal and neonatal cardiomyocytes form new, mature myoc ardium with the capacity to couple with injured host myocardium. Optimal re pair, however, may require reducing the isolation of the graft by the inter vening scar tissue.