Effect of Adult Bone Marrow Stem Cells on Myocardial Regeneration in Doxorubicin-Induced Mouse Cardiomyopathy

ABSTRACT

BACKGROUND AND OBJECTIVES: Bone marrow cells have been shown to differentiate into various cell lineages, including cardiomyocytes, in recent studies. This study evaluates the hypothesis that intravenous injection of bone marrow mononuclear cells (BMNCs) into rats with doxorubicin-induced cardiomyopathy can induce myocardial regeneration and improve myocardial contractility. MATERIALS AND METHODS: Adult male Sprague-Dawley rats were induced to develop cardiomyopathy by treatment with doxorubicin (2.5 mg/kg, 6 times, 2-week period). Stem cell enriched BMNCs were injected into the tail vein of the rats after cessation of the doxorubicin injections. One week after the injection of PKH-67-labeled BMNCs, the localization of transplanted cells was evaluated. Immunohistochemical studies and Western blots were performed two weeks after BMNCs injection. RESULTS: Cell-treated animals showed significant improvement in left ventricular fractional shortening as compared to untreated (control) rats (cell treated group vs. control group 47.2+/-4.9% vs. 34.4+/-3.6%, p<0.01). Histological analyses showed that in the cell-treated animals there was an increase in ventricular interstitial collagen deposition and the cell-treated animals had an improved number of capillary endothelial cells as compared with the control rats. PKH-67-labeled BMNCs and cell proliferation by BrdU was noted in the cell-treated hearts. Cardiac CXCR4 protein expression increased at day 7 and 14 in the cell-treated rats, but only at day 14 in the control animals. CONCLUSION: These results suggest that intravenous injection of BMNCs effectively induce engraftment of BMNCs into the myocardium and attenuation of fibrosis. Intravenous injection of BMNCs also improved myocardial contractility in doxorubicininduced cardiomyopathy.