Abstract 3820: Loss of CD 26 Function Accumulates Cardiac SDF-1 Protein Yielding Enhanced Stem Cell Homing and Attenuation of Ischemic Cardiomyopathy after Treatment with G-CSF
G-CSF treatment after myocardial infarction (MI) is known to improve survival and myocardial function in mice. However, double-blind clinical trials revealed no significant effect on ejection fraction. Recently, we have shown that G-CSF treatment even impaired the chemotactic response towards the SDF1-CXCR4 axis after MI. Therefore, inhibition of the extracellular protease CD26, which is responsible for cleavage of SDF-1, may preserve cardiac SDF-1 protein and improve homing of circulating stem cells. This prompted us to investigate in a genetic CD26−/− mouse model the expression of SDF-1 and to analyze stem cell homing to the heart after MI.
Methods: MI was induced by ligation of the LAD in CD26−/− or C57/Bl6 (wt) mice (n=20), treated either with G-CSF (100 μg/kg/d) or saline for up to 6 days. Functional and immunohistochemical analyses were performed at day 6 and 30 after MI. SDF-1 mRNA and protein expression in the heart was analyzed by RT-PCR and Western-Blot, respectively. Stem cells in the peripheral blood (PB) and the myocardium were analysed by FACS.
Results: CD26 was highly expressed on CD34+ progenitors in the PB. Compared to wt, G-CSF treatment of CD26−/− animals improved survival, myocardial function, ameliorated LV wall thinning, associated with an increased neovascularization. In contrast to wt, cardiac SDF-1 accumulated on the protein level in CD26−/− mice yielding enhanced recruitment of c-kit and Sca-1 positive CD34+/CXCR4+ progenitors to the heart. This SDF-1 dependent homing was reversed by the CXCR4 antagonist AMD3100.
In conclusion, loss of CD26 function preserves cardiac SDF-1 protein, leading to enhanced homing of stem cells, thereby promoting cardiac repair. Based on these preclinical data, the use of CD26 inhibitors may represent a novel concept of stem cell therapy in ischemic heart disease.