We used a heterotopic transplanted working heart model to probe the collaborative role of bone marrow-derived progenitor cells (BPCs) and stromal cell-derived factor (SDF)-1alpha in attenuating tissue remodeling in recipient and transplanted hearts. BPCs from male transgenic rats expressing green fluorescent protein (GFP(+) BPCs, 2 x 10(6) cells) were injected intravenously into myeloablated female rats. One month later, heterotopic heart transplantation was performed. The left anterior descending coronary artery (LAD) of the recipient heart was occluded permanently. Mesenchymal stem cells (MSCs; 2 x 10(6) cells) with a null gene (null group) or overexpressing SDF-1alpha (SDF-1alpha group) were injected intramyocardially in the LAD perfusion region of both recipient and transplanted hearts. Recipient and transplanted hearts (n = 10 hearts/group) were harvested 21 days later for analysis. The survival of transplanted hearts was assessed daily by palpation in additional animals (n = 7). Five days after LAD occlusion, subpopulations of GFP(+) BPCs in the circulation were significantly higher in the SDF-1alpha group. Y chromosome, 5-bromo-2'-deoxyuridine, Ki67-positive nuclei, newly formed vessels, and GFP(+) cells significantly increased in transplanted hearts of the SDF-1alpha group at 21 days after the injection of MSCs overexpressing SDF-1alpha, whereas fewer TUNEL-positive nuclei were found. The survival of transplanted hearts was also markedly increased in the SDF-1alpha group (P < 0.05). Supplementation of endogenous cytokines released from the ischemic myocardium with exogenous MSCs overexpressing SDF-1alpha significantly increased BPC homing to acutely ischemic recipient and progressively ischemic transplanted hearts. BPC recruitment resulted in the regeneration of new cardiomyocytes and blood vessels and extended survival of the transplanted hearts.