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Ann Thorac Surg 2007;83:1234
© 2007 The Society of Thoracic Surgeons
a Division of Cardiovascular Surgery, Toronto General Hospital, 4N-470, 200 Elizabeth Street, Toronto, Ontario, M5G2C4 Canada
b Department of Surgery, University of Toronto, 4N-470, 200 Elizabeth Street, Toronto, Ontario, M5G2C4 Canada
(Email: terry.yau{at}uhn.on.ca).
As Ye and colleagues [1] note, the concept of expressing proangiogenic genes in transplanted cells to enhance their efficacy for myocardial repair is not new, having first been reported in 2001 by Suzuki and colleagues [2] and by ourselves [3] in the same issue of the same journal.
While cells may express cytokines after implantation to enhance their own survival, we and others have demonstrated that this adaptive response may be enhanced by targeted transgene expression. Cell-based gene therapy to augment angiogenesis has been evaluated in a host of studies, with uniformly positive results. There are a few reports evaluating this approach to modify donor cell survival, myogenesis, or infarct morphology. We have reported transplanted bone marrow cells (BMC) expressing vascular endothelial growth factor and insulin-like growth factor-1 (IGF-1) reduced apoptosis, enhanced BMC survival, and improved left ventricular (LV) function and myogenesis [4]. Elastin-expressing endothelial cells limited adverse LV remodeling and improved function [5], but unmodified endothelial cells do not. Targeted transgene expression can thus improve the outcomes of cell transplantation in many ways.
Although Ye and colleagues [1] assert that our study [6] demonstrates "extensive survival of cells from an allogenic source in an immunocompetent host," such is not the case. As stated in our article, we used syngeneic Lewis rats as donors and recipients to avoid rejection of the implanted cells. Allogeneic cell transplantation results in loss of the implanted cells by 20 weeks, despite cyclosporine [7]. Despite sporadic reports that the barriers to xenotransplantation have been overcome, these findings have not been reproduced by most investigators.
Detection of Y-chromosomal DNA in gender-mismatched transplants allows more accurate quantitation of donor cells than has previously been possible, but does not permit simultaneous visualization of the cell for morphometry or co-localization. This can be accomplished by fluorescent in-situ hybridization (FISH) for Y-chromosomal DNA, but many XY cells will not be detected by serial sections and FISH. In addition, total sry DNA reflects both the originally transplanted cells and their progeny. However, the effect of cell transplantation should be proportional to the total number of donor-derived cells, whether original or progeny, and this distinction may have little influence on the outcome.
Correlation of the results of PCR for Y-chromosomal DNA with other methodologies to evaluate cell survival and mechanisms of cell loss will strengthen confidence in these findings. In our study [6], differences in apoptosis, evaluated by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining and DNA fragmentation, paralleled the differences in cell survival and suggest that reduced apoptosis explains the differences in cell survival. The magnitude of the pro-survival effect was almost identical in skeletal myoblasts and cardiomyocytes, cell types in which rates of donor cell proliferation after implantation may well be expected to differ. Finally, histologic analysis of BrdU-prelabelled transplanted bromodeoxyuridine-prelabelled demonstrated the same effect of VEGF expression on cell survival in both cell types. Identical findings by PCR, TUNEL staining, DNA fragmentation and histology in our study suggest that our findings are accurate.
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