The Elusive Mechanism of Cell Therapy

The notion of cell transplantation into the heart as a means of reversing ischemic injury is now nearly a decade old. The first clinical application of bone marrow mononuclear cells (BMCs) for myocardial infarction was in 2001,1 presumably motivated at least in part by the premise that BMCs injected into the heart can directly regenerate new, functional myocardium.2 Although subsequent investigators questioned the ability of BMCs to transdifferentiate into cardiomyocytes3,4 (but in all fairness, others did support the idea5,6), the horse was out of the barn, and the treatments continued apace. Fortunately, injection of autologous BMCs as adjunctive treatment for convalescent myocardial infarction has proven to be remarkably safe.7–9 Although the overall efficacy is modest, certain subgroups (particularly those with large functional deficits at baseline) do experience clinically meaningful increments in ejection fraction.10,11 A related consideration arises in the choice of cell type to transplant. BMCs, although easy to harvest, are almost certainly not the best candidate cells for cardiomyoplasty, because they are not specialized to regrow normal healthy heart muscle. An attractive alternative arose with the recognition that the adult heart contains its own reservoir of progenitor cells,12–15 some of which express the stem cell antigen c-kit.12,14 Such cardiac progenitor cells (CPCs) presumably function physiologically to mediate a low basal turnover rate of cardiomyocytes in the adult heart16 but may be expanded and exploited iatrogenically for more focused (and, mechanistically, more rational) benefit than may be possible with BMCs. When injected into the injured heart, CPCs increase tissue viability12,14,17–20 and improve ventricular function.12,14,17,20