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The Expedited Review from Pagani et al. (1)and the Research Letter from Hagege et al. in The Lancet(2)are the first reports that provide evidence about the fate of human myoblasts posttransplantation. Before these reports appeared there was no histological evidence on the viability and in vivo behavior of the human myoblasts after engraftment into the myocardium. These are significant findings and may provide clues to the unanswered questions impeding the progress in heart cell therapy using myoblasts. Moreover, these reports will provide impetus to the efforts in defining the basic mechanism underlying cardiac function improvement in postmyoblast transplantation.
Pagani et al. (1)showed that transplanted myoblasts developed into myotubes and expressed human myosin heavy chain (slow isoform) in the myocardium. The myofibers originating from the myoblasts aligned in accordance with the heart muscle architecture. These results may resolve the controversy surrounding the milieu-dependent trans-differentiation of myoblasts into cardiomyocytes. The absence of connexin-43 expression, however, confirms the lack of electrical integration between the skeletal myofibers and the surrounding cardiac tissue. Without such linkage, it will be difficult for the cell graft to synchronize its contractility with the myocardium.
Considering the difficulties of using human subjects as a model, we developed a porcine heart model of myocardial infarction with immune tolerance in order to study the in vivo behavior of the human myobalsts and to define the underlying mechanism of global improvement in the left ventricular pump function. We observed the persistence of lac-z reporter gene carrying human myoblasts for up to seven months in the porcine heart (3). The xenografted myoblasts expressed human skeletal muscle myosin heavy chain (slow isoform) at the site of transplantation. Similar to the results obtained by Pagani et al. (1), we observed that the cells followed the geometric organization of the host tissue. An interesting finding of our study—based on histochemistry and fluorescent in situ hybridization analysis using a cocktail of probes specific for human and porcine chromosomes—is the presence of heterokaryons in the host myocardium resulting from the fusion between the donor myoblasts and the recipient cardiomyocytes. This hypothesis is substantiated by the long-term survival of the xenograft even after the discontinuation of immunosuppression (3). The observation of myofibers expressing both slow and fast isoforms of myosin by Hagege et al. (2)may be due to spontaneous fusion between myoblasts and the cardiomyocytes. We believe that together with other proposed mechanisms, formation of mosaic muscle fibers is the underlying mechanism in the improvement of cardiac function.
- American College of Cardiology Foundation
- Pagani F.D.,
- DerSimonian H.,
- Zawadzka A.,
- et al.
- ↵Haider HK, Ye L, Jiang SJ, et al. Transient immunosuppression is effective for the xenotransplantation of human myoblasts for cardiac repair in a porcine heart model. Circulation 2002;106 Suppl 19:II15