The aim of this study was to investigate whether supplemental IGF-1Ea transgene expression induces activation of local cardiac and bone marrow stem cell population to mediate mammalian heart repair. In physiologic conditions, cardiac overexpression of the IGF-1Ea propeptide is associated with an enrichment of c-Kit/Sca-1 positive side population cells in the bone marrow and the occurrence of an endothelial-primed CD34 positive side population in the heart. This cellular profile is shown here to correlate with the expression of cytokines involved in stem cell mobilization and vessel formation. This molecular and cellular interplay favored IGF-1Ea-mediated vessel formation in injured hearts. The physiologic and pathologic connection between cytokines and stem cells in response to IGF-1Ea may represent an important model to understand how to elicit endogenous reparative signaling. (C) 2011 Elsevier Inc. All rights reserved.