Myocardial-cell replacement: the science, the clinic and the future

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Abstract
The traditional view of the heart is of an organ incapable of self-renewal. Hypotheses on the genesis of pump dysfunction in heart failure include emerging concepts of myocyte deficiency due to attritional ischemia and chronic apoptotic cell loss. In the adult heart, inadequate regenerative capacity was presumed to exist to counterbalance such extensive myocyte depletion. Preliminary animal and human studies now challenge the paradigm of myocardial regenerative inadequacy, with findings suggesting that noncardiac cells implanted in the dysfunctional heart augment myocyte deficiency and contractile mass. Data from these studies remain inconclusive and have generated much debate in the basic science and clinical communities. Controversial issues center on the scientific basis for regeneration in the heart, the mechanism of cell-therapy benefit and the safety and appropriateness of clinical trials based on these concepts. This review will evaluate the scientific basis for myocardial-cell replacement, with emphasis on current experimental and human data. We will explore unresolved questions of experimental design, mechanism of action, therapeutic strategies and safety concerns in an era of rising numbers of human cell-therapy trials. Prospects for more widespread clinical application of myocardial-cell replacement and future hurdles to be overcome in this field will also be addressed.