title: Dual stem cell therapy after myocardial infarction acts specifically by enhanced homing via the SDF-1/CXCR4 axis.
abstract: BACKGROUND
  G-CSF based stem cell mobilization and stabilization of cardiac SDF-1 by DPP-IV-inhibition (dual stem cell therapy) improve heart function and survival after myocardial infarction. However, it is barely understood whether this new approach acts specifically through the SDF-1/CXCR4 axis, stimulation of resident cardiac stem cells and improved myocardial perfusion. Therefore, we aimed to clarify the role of the SDF1/CXCR4 axis with respect to the benefits of a dual stem cell based therapy.
  
  
  RESULTS
  After surgically induced ligation of the LAD, SDF-1/CXCR4 interactions were specifically blocked by the CXCR4 receptor antagonist AMD3100 in G-CSF and Diprotin A treated C57BL/6 mice. G-CSF+DipA treated and non-treated animals served as controls. Because AMD3100 is known to mobilize bone marrow derived stem cells (BMCs) in high concentrations, the optimal dosage (1.25mg per kg body weight) sufficient to block CXCR4 without stimulating mobilization was established. AMD3100 treatment of G-CSF and Diprotin A stimulated mice significantly decreased myocardial homing of circulating stem cells (FACS analysis) and inverted the beneficial effects of (i) cardiac remodeling (histological analyses), (ii) heart function (Millar tip catheterization) and (iii) survival (Kaplan-Meier curves). G-CSF treatment in combination with DPP-IV inhibition enhanced neovascularization at the infarct border zone which was related to an improved myocardial blood flow as measured by SPECT. Moreover, dual stem cell treatment effectively stimulated the pool of resident cardiac stem cells (FACS) which was reversed by AMD3100 treatment.
  
  
  CONCLUSIONS
  Our data give final proof that homing through the SDF-1/CXCR-4 axis is essential for the success of dual stem cell therapy.
authors.affiliation: Medical Department I, Klinikum Grosshadern, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: Hans D
authors.initials: HD
authors.lastname: Theiss
authors.forename: Markus
authors.initials: M
authors.lastname: Vallaster
authors.forename: Christoph
authors.initials: C
authors.lastname: Rischpler
authors.forename: Lisa
authors.initials: L
authors.lastname: Krieg
authors.forename: Marc-Michael
authors.initials: MM
authors.lastname: Zaruba
authors.forename: Stefan
authors.initials: S
authors.lastname: Brunner
authors.forename: Yordan
authors.initials: Y
authors.lastname: Vanchev
authors.forename: Rebekka
authors.initials: R
authors.lastname: Fischer
authors.forename: Michael
authors.initials: M
authors.lastname: Gröbner
authors.forename: Bruno
authors.initials: B
authors.lastname: Huber
authors.forename: Timm
authors.initials: T
authors.lastname: Wollenweber
authors.forename: Gerald
authors.initials: G
authors.lastname: Assmann
authors.forename: Josef
authors.initials: J
authors.lastname: Mueller-Hoecker
authors.forename: Markus
authors.initials: M
authors.lastname: Hacker
authors.forename: Wolfgang-M
authors.initials: WM
authors.lastname: Franz
mesh_terms: D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D001596:Benzylamines; D054377:Chemokine CXCL12 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000080027:Cyclams; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D006334:Heart Function Tests / Q000187:drug effects; D019650:Hematopoietic Stem Cell Mobilization; D006571:Heterocyclic Compounds / Q000494:pharmacology; D017493:Leukocyte Common Antigens / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D009203:Myocardial Infarction / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D018919:Neovascularization, Physiologic / Q000187:drug effects; D009842:Oligopeptides / Q000494:pharmacology; D010477:Perfusion; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D033581:Stem Cell Transplantation; D016019:Survival Analysis
chemical_list: D018952:Antigens, CD34; D001596:Benzylamines; D054377:Chemokine CXCL12; D000080027:Cyclams; D006571:Heterocyclic Compounds; D009842:Oligopeptides; D019718:Receptors, CXCR4; D016179:Granulocyte Colony-Stimulating Factor; C041445:diprotin A; D019009:Proto-Oncogene Proteins c-kit; D017493:Leukocyte Common Antigens; D018819:Dipeptidyl Peptidase 4; C088327:plerixafor