Transplanted Adult Bone Marrow Cells Repair Myocardial Infarcts in Mice

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Abstract
Occlusion of the anterior descending left coronary artery leads to ischemia, infarction, and loss of function in the left ventricle. We have studied the repair of infarcted myocardium in mice using highly enriched stem/progenitor cells from adult bone marrow. The left coronary artery was ligated and 5 hours later Lin− c‐kit+ bone marrow cells obtained from transgenic male mice expressing enhanced green fluorescent protein (EGFP) were injected into the healthy myocardium adjacent to the site of the infarct. After 9 days the damaged hearts were examined for regenerating myocardium. A band of new myocardium was observed in 12 surviving mice. The developing myocytes were small and resembled fetal and neonatal myocytes. They were positive for EGFP, Y chromosome, and several myocyte‐specific proteins including cardiac myosin, and the transcription factors GATA‐4, MEF2, and Csx/Nkx2.5. The cells were also positive for connexin 43, a gap junction/intercalated disc component indicating the onset of intercellular communication. Myocyte proliferation was demonstrated by incorporation of BrdU into the DNA of dividing cells and by the presence of the cell cycle‐associated protein Ki67 in their nuclei. Neo‐vascularization was also observed in regenerating myocardium. Endothelial and smooth muscle cells in developing capillaries and small arterioles were EGFP‐positive. These cells were positive for Factor VIII and α smooth muscle actin, respectively. No myocardial regeneration was observed in damaged hearts transplanted with Lin− c‐kit− bone marrow cells, which lack bone marrow‐regenerating activity. Functional competence of the repaired left ventricle was improved for several hemodynamic parameters. These in vivo findings demonstrate the capacity of highly enriched Lin− c‐kit+ adult bone marrow cells to acutely regenerate functional myocardium within an infarcted region.