Despite promising pre-clinical results, administration of granulocyte-colony stimulating factor (G-CSF) for improving heart function in humans after acute myocardial infarction has been disappointing. Therefore, a better understanding of the mechanism(s) of heart repair by G-CSF is urgently required. To address the potential mechanism of G-CSF, we have generated chimeric mice using G-CSF receptor knockout mice to distinguish the hematopoietic benefits of G-CSF from the direct effects of G-CSF on cardiomyocytes and blood vessels. Lethally irradiated wild-type mice were reconstituted with G-CSFR −/− bone marrow (BM) cells to generate G-CSFR BM −/− chimeras. Alternatively, lethally irradiated G-CSFR −/− mice were reconstituted with wild-type BM cells to generate G-CSFR cardiac −/− chimeras. Myocardial ischemic injury was induced by transient (60 minutes) occlusion of the left coronary artery. Mice were treated daily with saline or G-CSF for 5 days beginning 4 hours after ischemic injury. Mice were sacrificed 28 days post-injury for assessment of cardiac function and cellular repair. As previously reported in wild-type mice, G-CSFR −/− cardiac chimeras had 30–50% improved cardiac function compared with saline-treated G-CSFR −/− cardiac chimeras (ANOVA; P<0.05). This suggests that the benefits of G-CSF are NOT due to direct effects on cardiomyocytes or blood vessels, as previously proposed by Harada et al. (

Nature Medicine 2005; 11: 305–311
). In contrast, G-CSF BM −/− chimeras had dramatically impaired cardiac repair following ischaemic injury. The most striking finding was that saline-treated G-CSFR BM −/− mice had 20% worse cardiac function and cellular repair than saline-treated control G-CSFR BM +/+ mice (ANOVA; P<0.05). Furthermore, G-CSF treatment in G-CSFR BM −/− mice produced no significant benefit on cardiac function or cellular repair. The lack of benefit of G-CSF in these mice was due to an inability of G-CSF to mobilise hematopoietic progenitors because treatment of G-CSFR BM −/− mice with the CXCR4 antagonist, AMD3100 improved cardiac function and cellular repair as well as G-CSF in control G-CSFR BM +/+ mice. Together, these results suggest that mobilization of hematopoietic progenitors is a critical component of not only the therapeutic but also physiologic effects of G-CSF for repair after acute myocardial ischemic injury.

Topics:
granulocyte colony-stimulating factor, myocardial ischemia, myocardium, receptors, colony-stimulating factor, saline solutions, ischemia, antagonists, cxcr4 receptors, granulocyte colony-stimulating factor receptors, myocardial infarction, acute

Disclosures: No relevant conflicts of interest to declare.

Author notes

Corresponding author

2008, The American Society of Hematology
2008
Sign in via your Institution