Ann Thorac Surg 2005;79:2063-2064
© 2005 The Society of Thoracic Surgeons
Original article: Cardiovascular
Invited commentary
Frank W. Sellke, MD
Division of Cardiothoracic Surgery, Beth Israel-Deaconess Medical Center, Harvard Medical School, 110 Francis St, Lowry Medical Office Building, Suite 2a, Boston, MA 02215
(E-mail: fsellke{at}caregroup.harvard.edu).
In this study, Yau and colleagues evaluated the effect of transplanted cell type, time, and region of the heart on expression of the vascular endothelial growth factor (VEGF) receptors fms-like tyrosine kinase-1(flt-1) and fetal liver kinase (flk-1). They observed that overexpression of VEGF by transplanted heart cells or skeletal myoblasts that resulted in elevated flk-1 and flt-1 expression compared with unmodified cells. The authors concluded that flk-1 and flt-1 upregulation may mediate the angiogenic effect of cell transplantation and are augmented by VEGF transgene expression. Optimizing the angiogenic response to cell transplantation may maximize the benefit of cell transplantation.
This group has been at the forefront of investigating methods of cell transplanation for the treatment of ischemic heart disease and heart failure. They previously reported that VEGF transfected heart cells induced both greater regional blood flow and greater vascular densities than unmodified heart cells or injection of culture medium alone. This study extends to findings that enhanced VEGF receptor expression may contribute to the beneficial effect. Although the findings suggest that this effect was mediated in part by flk-1 and flt-1 upregulation, it may be naive to believe that altered receptor expression is the only mechanism involved. There are certainly other, and very likely more important, mechanisms contributing to this effect.
By conventional wisdom, VEGF receptors are present predominantly on endothelial cells. Yet in the present study, the expression is not only present but enhanced in response to VEGF transfection in both myocytes and skeletal muscle cells. How are the cells transformed such that the flt-1 and flk-1 receptors are present in high numbers on nonendothelial cells and may produce such a pronounced effect? Another question is whether these receptors are fully functional. The authors have not clearly explained how increased VEGF expression affects flt-1 and flk-1 receptor expression. In other words, they have provided no mechanistic information other than the finding of increased VEGF receptor density. A rat model using cryoinjury was used in this study. Findings from rat experiments are a long way from clinical studies, and this model (rat cryoinjury) may affect how the findings can be extrapolated to patients. Finally, almost all preliminary studies of cell transplantation have failed to demonstrate any clinical benefit and in certain cases have led to serious arrhythmias and other problems. The conventional wisdom today is that embryonal stem cells or other cell types with a high degree of plasticity will offer the best chance for the cell-based treatment of heart failure. However, stem cells are in short supply, and it remains uncertain whether this will change in the near future, or even if primitive stem cells will offer more than adult cells with less plasticity if modified in the correct manner. For this reason, studies such as this reported by Yau and colleagues are critical to the evolution and advancement of the field. Although subject to the usual criticism, this study and others from the same group have helped greatly to further the field of study. However, it is also clear that we have a long way to go before we have a clinically applicable cell-based treatment for the failing heart.
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