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Eur J Cardiothorac Surg 2004;25:350-351
© 2004 Elsevier Science NL
Pr Deville, Department of Cardiovascular Surgery, Haut-Lévêque Hospital, 33600 Pessac, France
* Tel.: +33-557-65-6565; fax: +33-556-36-8979
e-mail: lesbarandon{at}wanadoo.fr
In the last decade, improvements in cell biology, cell selection and cell culture have led to the development and refinement of a new strategy to treat ischemic and post-infarction heart diseases [1]. The goal for cell therapy or cellular cardiomyoplasty is to repopulate the scar, to develop new contractile activity, and eventually to improve scar perfusion. Cell therapy offers cardiac surgeons new fields of experimental and clinical research for treating infarcted and ischemic cardiac tissues [2]. Two of the most widely used cell types in this new strategy are skeletal muscle-derived progenitors or myoblasts and mononuclear bone marrow-derived cells (BM-MDC). These cells are autologous and easily expandable in vitro. The relative limitation of myoblasts is maintained in muscle phenotype [2]. However, they are well integrated in the scar and are able to improve cardiac function. In contrast, BM-MDC are potentially interesting for their capacity to transdifferentiate into cardiomyocytes and endothelial cells. BM-MDC are a non-homogeneous population containing very different lineages such as hematopoietic, mesenchymal stem cells [3], but they have been demonstrated both in vitro and in vivo to be beneficial in ischemic myocardium by stimulating myogenesis and angiogenesis [4]. The choice of cell type, date of implantation, injection pathway and number of cells to be transplanted are a matter of debate, and the data are still controversial regarding in situ cell differentiation and contractility [5]. However, immediate cell survival and grafting is an important limitation to this approach, due to cell trauma and inflammation. There is now some evidence that cell therapy could be an interesting option in cardiac regeneration, but several questions remain with regard to the long-term outcome and effects of these cells [6].
Ozbaran et al. report the injection of peripheral blood-derived mononuclear cells in six ischemic heart patients. The concept is both interesting and exciting, at a time when so much is being written and so many controversies remain unsolved. I will not discuss the ethical issue of this study, nor the curious study design in which unsuitable patients (see Materials and Methods section) were revascularized with coronary by-pass surgery, presumably in order to improve cell survival. Moreover, it is only in passing that I will mention the impossibility to demonstrate any in vitro data about their BM-MDC. It is now clear that peripheral or central derived bone marrow cells are not homogeneous, so it would be useful to characterize transplanted cell type better than just by using CD-34 immunostaining. In other words, did the authors have any idea about the transdifferentiation potential of their transplanted cells? A fundamental issue in this study is that the in vitro properties of the transplanted cells should be clearly understood and defined. It would be useful to show for the reader's benefit, e.g. for cardiac surgeons, the in vitro potential for endothelial lineage differentiation [7] of the transplanted cells. In fact, the real question is: "Do the authors know what they are injecting?". Another debatable point is the strategy adopted. Why did they use different pathways to inject their BM-MDC? What would be needed is the same injection type (intra-myocardial or intra-coronary but not both) in order to have a realistic idea about the number of transplanted cells. Although the study does not purport to be a pharmacodynamical one, it would be interesting to know where the cells were exactly injected and in what proportion. Moreover, the volume of transplanted cells injected was regrettably not the same (or in the same ratio) in each patient, so comparisons cannot readily be made. Another major point is that the authors had access to necropsy data. In Fig. 1 in DOI: 10.1016/j.ejcts.2003.11.038, which presents histologic immunostaining with CD-34, CD-31 and Factor-VIII antibodies, it is not possible to conclude that the transplanted cells are present in the scar, or whether they eventually transdifferentiated into endothelial cells. In fact, the same zone is not shown and co-immunostaining would be required to confirm transdifferentiation. It would be very interesting to demonstrate this eventual in vivo property because it has not been clearly demonstrated to date.
My concluding remarks concern the improvement in cardiac function. How can one explain or understand this improvement in scar perfusion when it is very difficult to demonstrate the outcome of transplanted cells and their eventual transdifferentiation? [8]. The real effect of the cell therapy administered by Ozbaran et al. is not clear, and the improvement claimed in cardiac function is probably dependent on myocardial revascularization. Cardiac surgeons play a crucial role in cardiac research and development [9] and consequently in cellular cardiomyoplasty [10]. Real progress in cell therapy can be made only if the fundamental research is carried out rigorously.
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