We used a heterotopic transplanted working heart model to probe the collaborative role of bone marrow-derived progenitor cells (BPC) and stromal-derived factor-1 alpha (SDF-1) in attenuating tissue remodeling in recipient and transplanted hearts. BPC from male transgenic rats expressing green fluorescent protein (GFP⁺-BPC, 2x10⁶) were injected intravenously into myeloablated female rats. One month later, heterotopic heart transplantation was performed. The left anterior descending artery (LAD) of the recipient heart was occluded permanently. Mesenchymal stem cells (MSCs, 2 x 10⁶) with a null gene (null group) or overexpressing SDF-1 (SDF-1 group) were injected intramyocardially in the LAD perfusion region of both recipient and transplanted hearts. Recipient and transplanted hearts (n=10 per group) were harvested 21 days later for analysis. Survival of transplanted hearts was assessed daily by palpation in additional animals (n=7). Five days after LAD occlusion, the subpopulations of GFP⁺-BPC in circulation were significantly higher in the SDF-1 group. Y-chromosome, BrdU, Ki67 positive nuclei, newly formed vessels, and GFP cells significantly increased in transplanted hearts of the SDF-1 group at 21 days after injection of MSCs overexpressing SDF-1, while fewer of TUNEL-positive nuclei were found. Survival of transplanted hearts was also markedly increased in SDF-1 group (p<0.05). The supplementation of endogenous cytokines released from ischemic myocardium with exogenous MSCs overexpressing SDF-1 significantly increased BPC homing to acutely ischemic recipient and progressively ischemic transplanted hearts. BPC recruitment resulted in regeneration of new cardiomyocytes and blood vessels and extended survival of the transplanted hearts.