title: Mechanism of improved cardiac function after bone marrow mononuclear cell therapy: role of cardiovascular lineage commitment.
abstract: BACKGROUND
  Cell therapy is a promising option to improve functional recovery after ischemia. Several subsets of bone marrow-derived cells were shown to reduce infarct size and increase ejection fraction in experimental models of ischemia. The mechanisms underlying the functional improvement are diverse and have been shown to include paracrine effects of the injected cells, as well as a variable degree of differentiation to endothelial cells, pericytes, smooth muscle, and cardiac muscle.
  
  
  RESULTS
  To elucidate the true nature of such plasticity and contribution to recovery, we engineered vectors that encoded inducible suicide genes under the control of endothelium (endothelial nitric oxide synthase)-, smooth muscle (SM22alpha)-, and cardiomyocyte (alpha-MHC)-specific promoters, thereby allowing selective depletion of the individual cell lineage acquired by the transplanted undifferentiated bone marrow-derived cells. Lentivirally delivered thymidine kinase, which converts the prodrug ganciclovir into a cytotoxic agent, was used to selectively eliminate cells 2 weeks after transplantation of bone marrow mononuclear cells in an acute myocardial infarction model. We demonstrate that elimination of transplanted endothelium-committed or SM22alpha-expressing cells, but not cardiac-committed cells, induced a significant deterioration of ejection fraction. Moreover, elimination of endothelial nitric oxide synthase-expressing cells 2 weeks after injection reduced capillary and arteriole density.
  
  
  CONCLUSIONS
  This study demonstrates that elimination of bone marrow mononuclear cells reexpressing endothelial nitric oxide synthase particularly induced a deterioration of cardiac function, which indicates a functional contribution of the vascular cell fate decision of human bone marrow-derived mononuclear cells in vivo.
authors.affiliation: Institute of Cardiovascular Regeneration, Centre for Molecular Medicine, University of Frankfurt, Germany.
authors.forename: Chang-Hwan
authors.initials: CH
authors.lastname: Yoon
authors.forename: Masamichi
authors.initials: M
authors.lastname: Koyanagi
authors.forename: Kazuma
authors.initials: K
authors.lastname: Iekushi
authors.forename: Florian
authors.initials: F
authors.lastname: Seeger
authors.forename: Carmen
authors.initials: C
authors.lastname: Urbich
authors.forename: Andreas M
authors.initials: AM
authors.lastname: Zeiher
authors.forename: Stefanie
authors.initials: S
authors.lastname: Dimmeler
mesh_terms: D000818:Animals; D001011:Aorta / Q000166:cytology; D001854:Bone Marrow Cells / Q000166:cytology* / Q000502:physiology*; D016026:Bone Marrow Transplantation; D019070:Cell Lineage / Q000502:physiology; D042783:Endothelial Cells / Q000166:cytology; D004847:Epithelial Cells / Q000166:cytology / Q000502:physiology; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D006085:Graft Survival; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D016086:Lentivirus / Q000235:genetics; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D009203:Myocardial Infarction / Q000473:pathology* / Q000503:physiopathology / Q000628:therapy*; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000502:physiology; D051381:Rats; D020127:Recovery of Function / Q000502:physiology; D013318:Stroke Volume / Q000502:physiology; D013937:Thymidine Kinase / Q000235:genetics; D014183:Transplantation, Heterologous; D014471:Umbilical Veins / Q000166:cytology
chemical_list: D049452:Green Fluorescent Proteins; D013937:Thymidine Kinase