title: Interleukin-10 deficiency impairs bone marrow-derived endothelial progenitor cell survival and function in ischemic myocardium.
abstract: BACKGROUND
  Endothelial progenitor cell (EPC) survival and function in the injured myocardium is adversely influenced by hostile microenvironment such as ischemia, hypoxia, and inflammatory response, thereby compromising full benefits of EPC-mediated myocardial repair.
  
  
  OBJECTIVE
  We hypothesized that interleukin-10 (IL-10) modulates EPC biology leading to enhanced survival and function after transplantation in the ischemic myocardium.
  
  
  RESULTS
  Myocardial infarction (MI)-induced mobilization of bone marrow EPC (Sca-1+Flk1+cells) into the circulation was significantly impaired in IL-10 knockout (KO) mice. Bone marrow transplantation to replace IL-10 KO marrow with wild-type (WT) marrow attenuated these effects. Impaired mobilization was associated with lower stromal cell-derived factor (SDF)-1 expression levels in the myocardium of KO mice. Interestingly, SDF-1 administration reversed mobilization defect in KO mice. In vitro, hypoxia-mediated increases in CXCR4 expression and cell survival were lower in IL-10-deficient EPCs. Furthermore, SDF-1-induced migration of WT EPCs was inhibited by AMD3100, an inhibitor of CXCR4. To further study the effect of IL-10 on in vivo EPC survival and engraftment into vascular structures, GFP-labeled EPC were injected intramyocardially after induction of MI, and the mice were treated with either saline or recombinant IL-10. The IL-10-treated group showed increased retention of transplanted EPCs in the myocardium and was associated with significantly reduced EPC apoptosis after MI. Interestingly, increased EPC retention and their association with the vascular structures was observed in IL-10-treated mice. Increased EPC survival and angiogenesis in the myocardium of IL-10-treated mice corroborated with improved left ventricular function, reduced infarct size, and fibrosis in the myocardium. In vitro, IL-10-induced increase in VEGF expression in WT EPC was abrogated by STAT3 inhibitor, suggesting IL-10 signals through STAT3 activation.
  
  
  CONCLUSIONS
  Taken together, our studies demonstrate that MI-induced EPC mobilization was impaired in IL-10 KO mice and that IL-10 increases EPC survival and function possibly through activation of STAT3/VEGF signaling cascades, leading to attenuation of MI-induced left ventricular dysfunction and remodeling.
authors.affiliation: Feinberg Cardiovascular Research Institute, Feinberg School of Medicine, Northwestern University, Chicago IL 60611, USA. p-krishnamurthy@northwestern.edu
authors.forename: Prasanna
authors.initials: P
authors.lastname: Krishnamurthy
authors.forename: Melissa
authors.initials: M
authors.lastname: Thal
authors.forename: Suresh
authors.initials: S
authors.lastname: Verma
authors.forename: Eneda
authors.initials: E
authors.lastname: Hoxha
authors.forename: Erin
authors.initials: E
authors.lastname: Lambers
authors.forename: Veronica
authors.initials: V
authors.lastname: Ramirez
authors.forename: Gangjian
authors.initials: G
authors.lastname: Qin
authors.forename: Douglas
authors.initials: D
authors.lastname: Losordo
authors.forename: Raj
authors.initials: R
authors.lastname: Kishore
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D015687:Cell Hypoxia; D002470:Cell Survival; D054377:Chemokine CXCL12 / Q000494:pharmacology; D042783:Endothelial Cells / Q000473:pathology*; D006085:Graft Survival; D006321:Heart / Q000502:physiology; D018380:Hematopoietic Stem Cell Transplantation; D016753:Interleukin-10 / Q000172:deficiency* / Q000235:genetics / Q000494:pharmacology / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000473:pathology*; D018919:Neovascularization, Physiologic; D019718:Receptors, CXCR4 / Q000096:biosynthesis / Q000235:genetics; D011994:Recombinant Proteins / Q000494:pharmacology; D012038:Regeneration; D050796:STAT3 Transcription Factor / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology; D020257:Ventricular Remodeling / Q000502:physiology*
chemical_list: C514936:CXCR4 protein, mouse; D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; C556062:IL10 protein, mouse; D019718:Receptors, CXCR4; D011994:Recombinant Proteins; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D016753:Interleukin-10