title: Cyclophilin A modulates bone marrow-derived CD117(+) cells and enhances ischemia-induced angiogenesis via the SDF-1/CXCR4 axis.
abstract: BACKGROUND
  Critical limb ischemia (CLI) is a major health problem with no adequate treatment. Since CLI is characterized by insufficient tissue vascularization, efforts have focused on the discovery of novel angiogenic factors. Cyclophilin A (CyPA) is an immunophilin that has been shown to promote angiogenesis in vitro and to enhance bone marrow (BM) cell mobilization in vivo. However, its potential as an angiogenic factor in CLI is still unknown. Thus, this study aimed to evaluate whether CyPA might induce neo-angiogenesis in ischemic tissues.
  
  
  RESULTS
  Wild-type C57Bl/6j mice underwent acute hind-limb ischemia (HLI) and received a single intramuscular administration of recombinant CyPA or saline. Limb perfusion, capillary density and arteriole number in adductor muscles were significantly increased after CyPA treatment. Interestingly, BM-derived CD117(+) cell recruitment was significantly higher in ischemic adductor tissue of mice treated with CyPA versus saline. Therefore, the effect of CyPA on isolated BM-derived CD117(+) cells in vitro was evaluated. Low concentrations of CyPA stimulated CD117(+) cell proliferation while high concentrations promoted cell death. Moreover, CyPA enhanced CD117(+) cell adhesion and migration in a dose-dependent manner. Mechanistic studies revealed that CyPA up-regulated CXCR4 in CD117(+) cells and in adductor muscles after ischemia. Additionally, SDF-1/CXCR4 axis inhibition by the CXCR4 antagonist AMD3100 decreased CyPA-mediated CD117(+) cell recruitment in the ischemic limb.
  
  
  CONCLUSIONS
  CyPA induces neo-angiogenesis by recruiting BM-derived CD117(+) cell into ischemic tissues, at least in part, through SDF-1/CXCR4 axis.
authors.affiliation: Department of Clinical Sciences and Community Health, University of Milan, Via Festa del Perdono 7, 20122 Milan, Italy; Unit of Vascular Biology and Regenerative Medicine, Centro Cardiologico Monzino-IRCCS, Via C. Parea 4, 20138 Milan, Italy.
authors.forename: Gianluca L
authors.initials: GL
authors.lastname: Perrucci
authors.affiliation: Laboratory of Vascular Pathology, Istituto Dermopatico dell'Immacolata-IRCCS, Via Monti di Creta 104, 00167 Rome, Italy; Explora Biotech S.r.l., Via G. Peroni 386, 00131 Rome, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Straino
authors.affiliation: Unit of Vascular Biology and Regenerative Medicine, Centro Cardiologico Monzino-IRCCS, Via C. Parea 4, 20138 Milan, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Corlianò
authors.affiliation: Unit of Vascular Biology and Regenerative Medicine, Centro Cardiologico Monzino-IRCCS, Via C. Parea 4, 20138 Milan, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Scopece
authors.affiliation: Laboratory of Vascular Pathology, Istituto Dermopatico dell'Immacolata-IRCCS, Via Monti di Creta 104, 00167 Rome, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Napolitano
authors.affiliation: Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA.
authors.forename: Bradford C
authors.initials: BC
authors.lastname: Berk
authors.affiliation: Department of Clinical Sciences and Community Health, University of Milan, Via Festa del Perdono 7, 20122 Milan, Italy; Unit of Cardiology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Via Francesco Sforza 35, 20122 Milano, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Lombardi
authors.affiliation: Department of Clinical Sciences and Community Health, University of Milan, Via Festa del Perdono 7, 20122 Milan, Italy; Unit of Vascular Biology and Regenerative Medicine, Centro Cardiologico Monzino-IRCCS, Via C. Parea 4, 20138 Milan, Italy; Department of Cardiovascular Surgery, Centro Cardiologico Monzino-IRCCS, Via C. Parea 4, 20138 Milan, Italy.
authors.forename: Giulio
authors.initials: G
authors.lastname: Pompilio
authors.affiliation: Laboratory of Vascular Pathology, Istituto Dermopatico dell'Immacolata-IRCCS, Via Monti di Creta 104, 00167 Rome, Italy.
authors.forename: Maurizio C
authors.initials: MC
authors.lastname: Capogrossi
authors.affiliation: Unit of Vascular Biology and Regenerative Medicine, Centro Cardiologico Monzino-IRCCS, Via C. Parea 4, 20138 Milan, Italy. Electronic address: patrizia.nigro@ccfm.it.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Nigro
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000378:metabolism; D021984:Cyclophilin A / Q000008:administration & dosage* / Q000494:pharmacology; D004195:Disease Models, Animal; D006614:Hindlimb / Q000098:blood supply* / Q000187:drug effects; D006801:Humans; D007511:Ischemia / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: C514936:CXCR4 protein, mouse; D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D019718:Receptors, CXCR4; D019009:Proto-Oncogene Proteins c-kit; D021984:Cyclophilin A
keywords: CD117(+) cells; Cyclophilin A; Hind-limb ischemia; Neo-angiogenesis; SDF-1/CXCR4 axis