Stem-cell homing and tissue regeneration in ischaemic cardiomyopathy

Abstract

In endstage cases, the last option for treatment is cardiac transplantation, which is limited by the small number of organs available. This situation raises the urgent need for alternative treatments. In recent years experimental models have suggested the possibility of stem-cell transplantation and endogenous stem-cell mobilisation as alternatives. The principle of translocation of bone-marrow-derived stem cells into cardiac tissue was shown by Quaini and colleagues 2 in men who had received a female donor heart: primitive cells bearing Y-chromosomes were present in the donor heart and expressed markers of cardiomyocytes, endothelial cells, and smooth-muscle cells. Furthermore, in female patients who had undergone sex-mismatched bonemarrow transplantation, Y-chromosome-positive cells were present in the host heart and developed into de-novo cardiomyocytes. 3 And transplantation of primitive Lin-ckit+ bone-marrow stem-cells into mice resulted in increased cardiac function. 4 In addition, administration of granulocyte colony-stimulating factor led to mobilisation of primitive bone-marrow stem-cells into the circulation, resulting in reduced mortality and improved cardiac function in infarcted mice. 5 All these findings encourage the development of strategies for stem-cell therapy. As mobilised peripheral-blood stem-cells (CD34+) are increasingly used for clinical cell transplantation, it is becoming clear that proteolytic degradation of the chemokine, stromal cell-derived factor (SDF-1), and its receptor, CXCR-4, on stem cells could be an important step in stemcell release and homing. 6 Further, administration of granulocyte colony-stimulating factor activates neutrophil elastases, which then cleave the membrane-bound SDF-1 of endothelial or stromal cells of the bone marrow and provoke an efflux of stem cells that express CXCR-4. Presumably, circulating stem cells home to loci of high SDF-1 concentration, which is lent support by in-vitro data showing transmigration capacity towards SDF-1 gradients. 7