Abstract 13878: Stem Cell Mobilization and DPP-IV/CD26 Inhibition Enhances Myocardial Regeneration in Mice With Targeted Expression of Cyclin D2 in Adult Cardiomyocytes
Objective: Although pharmacologic interventions that mobilize stem cells and enhance their homing to damaged tissue can limit adverse post-myocardial infarction remodeling, cardiomyocyte (CM) renewal with this approach is limited. While experimental cell cycle induction can promote CM renewal following MI, this process must compete with the more rapid processes of scar formation and adverse remodeling. The current study tested the hypothesis whether the combination of enhanced stem cell mobilization/homing and CM cell cycle induction would result in increased myocardial regeneration in injured hearts.
Methods: Myocardial infarction (MI) was induced by coronary artery ligation in adult MHC-cycD2 transgenic mice (which exhibit constitutive CM cell cycle activity) and their non-transgenic (NON-TXG) littermates. Mice were then treated with saline or with granulocyte colony stimulating factor (G-CSF) plus the dipeptidylpeptidase-IV inhibitor Diprotin A (DipA) for 7 days.
Results: Although infarct size at day 60 after MI was similar in mice with stem cell mobilization/homing and/or cell cycle induction, vessel density and infarct thickness were significantly increased in MHC-cycD2 mice with G-CSF plus DipA-treatment (Tab. 1). 3H-Thymidine proliferation index of CMs was over 200 fold increased in transgenic mice. Quantification of CMs in the infarct area at day 7 and day 60 revealed a 3 fold increase in MHC-cycD2 mice with G-CSF plus DipA-treatment. Compared to NON-TXG mice receiving saline, infarct CMs numbers were more than 9 fold increased in MHC-cycD2 mice receiving G-CSF plus DipA (Tab. 1). Finally, echocardiographic analyses at 60 days post-MI revealed that stem cell mobilization/homing and CM cell cycle activation had an additive effect on functional recovery (Tab. 1).
Conclusion: These data strongly suggest that G-CSF plus DPP-IV inhibition, combined with CM cell cycle activation, leads to enhanced myocardial regeneration following MI.
- © 2011 by American Heart Association, Inc.