title: Profoundly reduced neovascularization capacity of bone marrow mononuclear cells derived from patients with chronic ischemic heart disease.
abstract: BACKGROUND
  Cell therapy with bone marrow-derived stem/progenitor cells is a novel option for improving neovascularization and cardiac function in ischemic heart disease. Circulating endothelial progenitor cells in patients with coronary heart disease are impaired with respect to number and functional activity. However, whether this impairment also extends to bone marrow-derived mononuclear cells (BM-MNCs) in patients with chronic ischemic cardiomyopathy (ICMP) is unclear.
  
  
  RESULTS
  BM-MNCs were isolated from bone marrow aspirates in 18 patients with ICMP (ejection fraction, 38+/-11%) and 8 healthy control subjects (controls). The number of hematopoietic stem/progenitor cells (CD34+/CD133+), CD49d(+) (VLA-4) cells, and CXCR4+ cells did not differ between the 2 groups. However, the colony-forming capacity of BM-MNCs from patients with ICMP was significantly lower compared with BM-MNCs from healthy controls (37.3+/-25.0 versus 113.8+/-70.4 granulocyte-macrophage colony-forming units; P=0.009). Likewise, the migratory response to stromal cell-derived factor 1 (SDF-1) and vascular endothelial growth factor (VEGF) was significantly reduced in BM-MNCs derived from patients with ICMP compared with BM-MNCs from healthy controls (SDF-1, 46.3+/-26.2 versus 108.6+/-40.4 cells/microscopic field, P<0.001; VEGF, 34+/-24.2 versus 54.8+/-29.3 cells/microscopic field, P=0.027). To assess the in vivo relevance of these findings, we tested the functional activity of BM-MNCs to improve neovascularization in a hindlimb animal model using nude mice. Two weeks after ligation of the femoral artery and intravenous injection of 5x10(5) BM-MNCs, laser Doppler-derived relative limb blood flow in mice treated with BM-MNCs from patients with ICMP was significantly lower compared with mice treated with BM-MNCs from healthy controls (0.45+/-0.14 versus 0.68+/-0.15; P<0.001). The in vivo neovascularization capacity of BM-MNCs closely correlated with the in vitro assessment of SDF-1-induced migration (r=0.78; P<0.001) and colony-forming capacity (r=0.74; P<0.001).
  
  
  CONCLUSIONS
  BM-MNCs isolated from patients with ICMP have a significantly reduced migratory and colony-forming activity in vitro and a reduced neovascularization capacity in vivo despite similar content of hematopoietic stem cells. This functional impairment of BM-MNCs from patients with ICMP may limit their therapeutic potential for clinical cell therapy.
authors.affiliation: Molecular Cardiology, Department of Internal Medicine IV, University of Frankfurt, Frankfurt, Germany.
authors.forename: Christopher
authors.initials: C
authors.lastname: Heeschen
authors.forename: Ralf
authors.initials: R
authors.lastname: Lehmann
authors.forename: Jörg
authors.initials: J
authors.lastname: Honold
authors.forename: Birgit
authors.initials: B
authors.lastname: Assmus
authors.forename: Alexandra
authors.initials: A
authors.lastname: Aicher
authors.forename: Dirk H
authors.initials: DH
authors.lastname: Walter
authors.forename: Hans
authors.initials: H
authors.lastname: Martin
authors.forename: Andreas M
authors.initials: AM
authors.lastname: Zeiher
authors.forename: Stefanie
authors.initials: S
authors.lastname: Dimmeler
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D001853:Bone Marrow / Q000473:pathology*; D001854:Bone Marrow Cells / Q000166:cytology*; D002452:Cell Count; D019070:Cell Lineage; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000494:pharmacology; D003114:Colony-Forming Units Assay; D005260:Female; D006614:Hindlimb / Q000098:blood supply; D006801:Humans; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000187:drug effects; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D017202:Myocardial Ischemia / Q000473:pathology*; D018919:Neovascularization, Physiologic; D014183:Transplantation, Heterologous; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology
chemical_list: C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse; D042461:Vascular Endothelial Growth Factor A