J Thorac Cardiovasc Surg 2003;126:2117
© 2003 The American Association for Thoracic Surgery
Reply to the Editor
Ray C.-J. Chiu, MD, PhD
Senior author, McGill University, Montreal, Quebec, Canada
Dr Taheri made an important point in his comment, which we probably should have discussed in our article. However, first I, on behalf of my coauthors, wish to clarify that we did not inject "isogenic myofibril grafts," which would represent a differentiated anatomic unit of a muscle tissue. Instead, we transplanted either skeletal myoblasts, which are immature progenitor cells, or marrow stromal cells, which contain a pluripotent cell population. Such immature cells are able to migrate and self-assemble with preexisting supracellular structure, as we reported.
The hypothesis we postulated to explain the mechanism of this phenomenon should indeed predict that those donor cells, if implanted as an isolated island within a scar tissue, would lack the microenvironment to allow them to integrate into the preexisting native myocardial syncytium. We and others have pointed out that how such cells surrounded by scar contribute to the myocardial function, as has been reported experimentally and in some early clinical trials, remains unclear at present.1 It is of some interest to recall how the strategy of implanting cells into scar started. In our studies in the early 1990s,2,3 which were the first attempts to use cell therapy for myocardial regeneration, we lacked the tools for cell labeling and thus created a homogeneous scar induced by cryoinjury. By implanting myoblasts within such a scar, we were able to show that the new myofibers surrounded by the scar tissue originated from our donor cells. Because turning noncontractile scar tissue into potentially contractile muscle tissue is an intuitively appealing idea, many investigators in the subsequent studies, both experimental and clinical, have continued to use the model of implanting cells within the scar tissue, even though there has been no convincing evidence that these isolated muscle fibers can actually contribute to the synchronized contractile function of the myocardium.
In studying the pathophysiologic roles of marrow stromal cells, it has been shown that tissue injuries, such as myocardial infarction, can send a signal to recruit marrow stromal cells from the bone marrow, which traffic through the bloodstream to target the infarcted segment of the myocardium. There they undergo milieu-dependent differentiation, expressing a number of phenotypes.4 We have suggested that some of these cells that reached the peri-infarct zone became endothelial and vascular smooth muscle cells to participate in vasculogenesis and enhance collateral circulation. Some cells, which reached the scar tissue through patent collateral vessels, may express a myofibroblastic phenotype and participate in scar maturation to reduce scar expansion and rupture. The marrow cells in the peri-infarct zone that are in contact with viable and contracting host myofibers may differentiate into cardiomyocytes and integrate into the existing myofibers as we reported1, and this may play a role in modulating the postinfarct remodeling process of the ventricle. Yet other mechanisms are possible. The neocardiomyocytes, which have received phenotypic signals from native cardiomyocytes at the peri-infarct zone, may then migrate toward the myocardial scar to reduce infarct size. Various transforming growth factors and cytokines coming from the surrounding cells and extracellular matrix may also play important roles, as suggested by Dr Taheri. Clearly, much needs to be learned, and from such understanding better clinical strategies to use cell therapy for myocardial injury may yet evolve in the future.
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References
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- Chiu RC. Therapeutic cardiac angiogenesis and myogenesis: The promises and challenges on a new frontier. J Thorac Cardiovasc Surg. 2001;122:851–852[Free Full Text]
- Marelli D, Desrosiers C, El-Alfy M, Kao RL, Chiu RC. Cell transplantation for myocardial repair: an experimental approach. Cell Transplant. 1992;1:383–390[Medline]
- Chiu RC, Zibaitis A, Kao RL. Cellular cardiomyoplasty: myocardial regeneration with satellite cell implantation. Ann Thorac Surg. 1995;60:12–18[Abstract/Free Full Text]
- Bittira B, Shum-Tim D, Al-Khaldi A, Chiu RC. Mobilization and homing of bone marrow stromal cells in myocardial infarction. Eur J Cardiothorac Surg. 2003;24:393-8
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