title: MicroRNA-126 modulates endothelial SDF-1 expression and mobilization of Sca-1(+)/Lin(-) progenitor cells in ischaemia.
abstract: OBJECTIVE
  MicroRNA-126 (miR-126), which is enriched in endothelial cells, plays a role in angiogenesis. Based on the seed sequence, miR-126 can also be predicted to regulate vasculogenesis by modulating the endothelial expression of stromal cell-derived factor-1 (SDF-1).
  
  
  RESULTS
  Using miR-reporter constructs, we first validated that miR-126 inhibits SDF-1 expression in endothelial cells in vitro. Next, we investigated the potential relevance of this observation with respect to the mobilization of progenitor cells. For this, we studied the migration of human CD34+ progenitor cells towards chemotactic factors present in endothelial cell-conditioned medium. Antagomir-induced silencing of miR-126 elevated SDF-1 expression by human umbilical vein endothelial cells and enhanced migration of the CD34+ cells. In a murine model of hind limb ischaemia, a striking increase in the number of circulating Sca-1(+)/Lin(-) progenitor cells in antagomir-126-treated mice was observed when compared with scramblemir-treated controls. Immunohistochemical staining of capillaries in the post-ischaemic gastrocnemius muscle of miR-126-silenced mice revealed elevated SDF-1 expressing CD31-positive capillaries, whereas a mobilizing effect of miR-126 inhibition was not detected in healthy control animals.
  
  
  CONCLUSIONS
  miR-126 can regulate the expression of SDF-1 in endothelial cells. In the context of an ischaemic event, systemic silencing of miR-126 leads to the mobilization of Sca-1(+)/Lin(-) progenitor cells into the peripheral circulation, potentially in response to elevated SDF-1 expression by endothelial cells present in the ischaemic tissue.
authors.affiliation: Department of Nephrology,  LUMC, Albinusdreef 2, 2333 ZA, Leiden,  The Netherlands.
authors.forename: Coen
authors.initials: C
authors.lastname: van Solingen
authors.forename: Hetty C
authors.initials: HC
authors.lastname: de Boer
authors.forename: Roel
authors.initials: R
authors.lastname: Bijkerk
authors.forename: Matthieu
authors.initials: M
authors.lastname: Monge
authors.forename: Annemarie M
authors.initials: AM
authors.lastname: van Oeveren-Rietdijk
authors.forename: Leonard
authors.initials: L
authors.lastname: Seghers
authors.forename: Margreet R
authors.initials: MR
authors.lastname: de Vries
authors.forename: Eric P
authors.initials: EP
authors.lastname: van der Veer
authors.forename: Paul H A
authors.initials: PH
authors.lastname: Quax
authors.forename: Ton J
authors.initials: TJ
authors.lastname: Rabelink
authors.forename: Anton Jan
authors.initials: AJ
authors.lastname: van Zonneveld
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D000950:Antigens, Ly / Q000378:metabolism*; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000235:genetics / Q000378:metabolism*; D002633:Chemotaxis; D017077:Culture Media, Conditioned / Q000378:metabolism; D004195:Disease Models, Animal; D017930:Genes, Reporter; D006614:Hindlimb; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D007511:Ischemia / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000098:blood supply*; D018919:Neovascularization, Physiologic; D009841:Oligonucleotides / Q000008:administration & dosage; D013234:Stem Cells / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection
chemical_list: D020413:3' Untranslated Regions; D018952:Antigens, CD34; D000950:Antigens, Ly; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D017077:Culture Media, Conditioned; C515256:Cxcl12 protein, mouse; C074650:Ly6a protein, mouse; C527111:MIRN126 microRNA, human; C545201:MIRN126 microRNA, mouse; D008565:Membrane Proteins; D035683:MicroRNAs; D009841:Oligonucleotides