Background-We hypothesized that the function of the receptor for stem cell factor (SCF), c-kit, on endothelial progenitor cells (EPCs) is necessary for the endogenous mobilization of these cells from the bone marrow to the injured heart, where they play a reparative role after myocardial infarction (MI). Methods-Coronary snaring was used to induce MI in 5 groups of mice: C57BV6, rnrnp-9-/-, c-kit mutant KitW/KitW-", wild-type Kit+'' congenic littermates, and KitW/KitW-" whose bone marrow was replaced by Kitc'+ cells (BMT) (total n=212 mice). mRNA and protein levels of proteinases and factors and EPC trafficking in the peripheral circulation and the injured myocardium were evaluated. Cardiac function was assessed by echocardiography and pressure-volume loop analysis. *P<0.05. Results-MI in C57BV6 mice increased bone marrow soluble SCF (sSCF) 1.6-fold* and decreased membrane SCF (mSCF) 0.6-fold.* The SCF oscillations were associated with c-kit phosphorylation. These events corresponded to 2.1 -fold* upregulation of MMP-9 but not MMP-2 or tissue inhibitors of MMPs. One day after MI, circulating EPCs increased 2.4-foW and myocardial EPCs 14-fold.* In mmp-9-/animals, MI did not cause conversion of mSCF to sSCF, c-kit remained unphosphorylated, and circulating or myocardial EPCs did not increase. In KitW/KitW-" mice, neither MI nor recombinant SCF caused c-kit phosphorylation, and the circulating EPCs and myocardial EPCs did not increase. This was not caused by strain differences, because in Kit+'+ controls circulating EPCs increased 3.4-fold* and myocardial EPCs 9-fold.* In the BMT group, where c-kit phosphorylation in the bone marrow alone was restored, circulating EPCs increased 1.6-fold* and myocardial EPCs 9-fold.* When followed up over 2 weeks, MI caused a 2.3-fold* higher mortality in the KitW/Kit"" compared with Kit+'+. The surviving mice had 1.8-fold* larger ventricular volumes, 0.7-fold* lower ejection fraction, 0.7fold' reduced dP/dt,, and other parameters consistent with dilated cardiomyopathy. ConclusionActivation of c-kit by an MMP-9-dependent pathway is required for mobilization of bone marrow EPCs in response to ischemic cardiac injury. The recruitment of these cells to the heart is critical in preventing rapid cardiac failure after MI.