Abstract 1843: Combined Application Of G-csf And A Cd26-inhibitor Improves Stem Cell Homing, Cardiac Function And Survival After Myocardial Infarction In A Mouse Model
Background: The key issue of therapeutic stem cell approaches emerges to be the process of cardiac homing of stem cells via the SDF-1-CXCR4 axis. Myocardial SDF-1, which is crucial for incorporation of progenitors, is degradeted by the extracellular protease CD26. We hypothesized that inhibition of CD26 by Diprotin A leads to an increase of myocardial SDF-1 thus improving the homing of G-CSF-mobilized stem cells after myocardial infarction in a mouse model.
Methods: We induced acute myocardial infarction (AMI) in 8–12 weeks old male C57BL/6 mice using surgical occlusion of the left descending artery (LAD). Mice were then treated either with G-CSF (100 μg/kg/d s.c.) in combination with Diprotin A (140/kg/d μg p.i., “G-CSF+DipA”), G-CSF (“G-CSF”) alone or saline (“control”). Myocardial SDF-1 was assessed on protein level by Western blot after 2 days. FACS analyses were used to determine stem cell populations in peripheral blood and myocardium after 6 days. Cardiac function parameters were assessed using a Millar-Tip catheter system. Survival was analyzed by Kaplan-Meier-method for 30 days (n=20 in each group).
Findings: Circulation of CD34+CXCR-4 stem cells was enhanced in G-CSF+Diprotin A treated mice. Furthermore, myocardial SDF-1 on protein level was only increased in G-CSF+DipA mice leading to a significantly improved cardiac homing of CD34+CXCR-4 stem cells. This led to a relevant induction of resident cardiac stem cells (CD34-CD45-Sca1+ and CD34-CD45-ckit+) in the G-CSF+DipA group compared to G-CSF alone. Cardiac regeneration was improved in G-CSF+DipA mice as shown by a significant improvement of left ventricular ejection fraction (35±4% versus 27±2% in G-CSF mice and 16±2% in the saline group after 30 days). Finally, G-CSF+DipA mice showed a dramatical increase of survival after 30 days (65% versus 40% in G-CSF mice and 32% in the saline group)
Interpretation: This is the first study showing that combined application of G-CSF and a CD26-inhibitor improves cardiac function and survival after myocardial infarction by an enhanced cardiac homing of stem cells due to inhibition of SDF-1 degradation.