Stem cell repair in ischemic heart disease: an experimental model.

Bone marrow stem cells (BMSC) from adult mice are now believed to generate non-hematopoietic cell types. This newly defined property is referred to as stem cell plasticity. We tested the potential of lineage negative c-kit positive (Lin- c-kit+), GFP+ BMSC to differentiate into cardiac myocytes in myocardial infarcts produced by ligation of the left coronary artery. At 9 days post-transplant the hearts showed a band of developing GFP+ myocytes within the damaged myocardium. These GFP+ myocytes were positive for cardiac specific myosin and early expressed transcription factors. Endothelial cells and smooth muscle cells also developed from the donor bone marrow cells. Left ventricular end diastolic pressure (LVEDP) and left ventricular developed pressure (LVDP) were improved. Lin-c- kit- cells did not regenerate myocardium. We next tested the ability of cytokine-mobilized BMSC to regenerate myocardium. Nuclei in regenerating cardiomyocytes were positive for Csx/Nkx 2.5, GATA-4 and MEF2. Cytoplasmic proteins included desmin, nestin and connexin 43. Regenerating arterioles consisted of endothelial cells and smooth muscle cells positive for Ki67, and flkl. These regenerating vessels contained circulating TER119 positive red blood cells. Repair of infarcted myocardium resulted in improved heart function and survival. At day 27 after cytokine treatment and surgery, 11 of 15 mice survived compared with 9 of 52 non-treated mice. Left ventricular ejection fraction in infarcted hearts in cytokine-treated mice was 48%, 62% and 114% higher than the ejection fraction in non-treated mice at 9, 16 and 26 days following coronary artery occlusion. These findings demonstrate that circulating autologous stem cells traffic to the ischemic, infarcted myocardium and undergo differentiation into cardiomyocytes and vascular structures. We conclude that adult BMSC have the potential for repair in acute, ischemic heart disease.