title: Granulocyte colony-stimulating factor treatment plus dipeptidylpeptidase-IV inhibition augments myocardial regeneration in mice expressing cyclin D2 in adult cardiomyocytes.
abstract: OBJECTIVE
  Although pharmacological interventions that mobilize stem cells and enhance their homing to damaged tissue can limit adverse post-myocardial infarction (MI) remodelling, cardiomyocyte renewal with this approach is limited. While experimental cell cycle induction can promote cardiomyocyte renewal following MI, this process must compete with the more rapid processes of scar formation and adverse remodelling. The current study tested the hypothesis that the combination of enhanced stem cell mobilization/homing and cardiomyocyte cell cycle induction would result in increased myocardial renewal in injured hearts.
  
  
  RESULTS
  Myocardial infarction was induced by coronary artery ligation in adult MHC-cycD2 transgenic mice (which exhibit constitutive cardiomyocyte cell cycle activity) and their non-transgenic littermates. Mice were then treated with saline or with granulocyte colony-stimulating factor (G-CSF) plus the dipeptidylpeptidase-IV (DPP-IV) inhibitor Diprotin A (DipA) for 7 days. Infarct thickness and cardiomyocyte number/infarct/section were significantly improved in MHC-cycD2 mice with G-CSF plus DipA treatment when compared with MHC-cycD2 transgene expression or G-CSF plus DipA treatment alone. Echocardiographic analyses revealed that stem cell mobilization/homing and cardiomyocyte cell cycle activation had an additive effect on functional recovery.
  
  
  CONCLUSIONS
  These data strongly suggest that G-CSF plus DPP-IV inhibition, combined with cardiomyocyte cell cycle activation, leads to enhanced myocardial regeneration following MI. The data are also consistent with the notion that altering adverse post-injury remodelling renders the myocardium more permissive for cardiomyocyte repopulation.
authors.affiliation: Medical Department I, Klinikum Grossh, Ludwig-Maximilians University, Marchioninistrasse 15, Munich 81377, Germany. marc-michael.zaruba@med.uni-muenchen.de
authors.forename: Marc-Michael
authors.initials: MM
authors.lastname: Zaruba
authors.forename: Wuqiang
authors.initials: W
authors.lastname: Zhu
authors.forename: Mark H
authors.initials: MH
authors.lastname: Soonpaa
authors.forename: Sean
authors.initials: S
authors.lastname: Reuter
authors.forename: Wolfgang-Michael
authors.initials: WM
authors.lastname: Franz
authors.forename: Loren J
authors.initials: LJ
authors.lastname: Field
mesh_terms: D000818:Animals; D056742:Cyclin D2 / Q000378:metabolism; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology*; D004338:Drug Combinations; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology*; D006321:Heart / Q000502:physiology*; D019650:Hematopoietic Stem Cell Mobilization / Q000379:methods; D051379:Mice; D008822:Mice, Transgenic; D009203:Myocardial Infarction / Q000503:physiopathology*; D032383:Myocytes, Cardiac / Q000378:metabolism; D011897:Random Allocation; D012038:Regeneration / Q000502:physiology*; D013318:Stroke Volume / Q000502:physiology
chemical_list: D056742:Cyclin D2; D054873:Dipeptidyl-Peptidase IV Inhibitors; D004338:Drug Combinations; D016179:Granulocyte Colony-Stimulating Factor