Abstract 2967: Transplantation of Bone Marrow Derived Mononuclear Cells Improves the Cardiac Function of Dilated Cardiomyopathy Models via Myeloid Lineage Cells-secreted Factors
Bone marrow mononuclear cells (BMMNC) transplantation has been reported to improve cardiac function of ischemic cardiomyopathy. The aim of this study is to elucidate the effect of BMMNC transplantation to DCM mice and the precise mechanisms, including paracrine action. We used two kinds of DCM mice, including doxorubicin-induced DCM mice and cardiac specific dominant negative epidermal growth factor receptor expressing mice. When BMMNC was transplanted intravenously to DCM mice, significant improvement of fractional shortening (FS) and +dp/dt were observed compared with PBS group (FS: BMMNC, 0.33±0.01; PBS, 0.29±0.01, p<0.05, n=8) 3 days after transplantation, but not at 14 days. In contrast, almost of transplanted BMMNC existed in peripheral blood but not in heart, suggesting BMMNC transplantation might improve the cardiac function via paracrined mechanisms. When neonatal rat cardiomyocytes were cultured in serum free medium with BMMNC-derived conditioned medium (CM), percentage of cell shortening (%CS) and beating rate (BR) were significantly improved compared with control (%CS: BMMNC, 11.0±0.7; control, 2.5±0.1, p<0.01, n=5). When we compared the effects of CM from each population in BMMNC, including Gr-1(+) cells (myeloid), B220(+) cells (lymphoid), TER(+) cells (erythroid) and lineage negative (LN) population, Gr-1(+) cells-derived CM improved %CS and BR as well as BMMNC-derived CM. Gr-1(+) cells-derived CM increased cyclic AMP and phosphorylated PKA in cardiomyocytes. Furthermore, when cultured with Gr-1(+) cell-derived CM, cardiomyocytes exhibited hypertrophy in accompanied with phosphorylation of Akt and Erk1/2. Finally we examined the effects of Gr-1(+)-derived CM in vivo. When Gr-1(+) cell-derived CM was infused intravenously to DCM mice, FS and +dp/dt were significantly improved 1 and 3 days after treatment as well as BMMNC transplantation (FS: Gr-1(+) cells-derived CM, 0.32±0.01; PBS, 0.28±0.01, +dp/dt: 9238.7±320.4; 7487.9±279.4, p<0.05, n=7). These findings suggest that the improvement of cardiac function of non-ischemic cardiomyopathy by BMMNC transplantation might be mainly mediated by Gr-1(+) cells-secreted factors and identification of the key molecule and the mechanism remains to be determined.