title: Homeostatic and tissue reparation defaults in mice carrying selective genetic invalidation of CXCL12/proteoglycan interactions.
abstract: BACKGROUND
  Interaction with heparan sulfate proteoglycans is supposed to provide chemokines with the capacity to immobilize on cell surface and extracellular matrix for accomplishing both tissue homing and signaling of attracted cells. However, the consequences of the exclusive invalidation of such interaction on the roles played by endogenous chemokines in vivo remain unascertained.
  
  
  RESULTS
  We engineered a mouse carrying a Cxcl12 gene (Cxcl12(Gagtm)) mutation that precludes interactions with heparan sulfate structures while not affecting CXCR4-dependent cell signaling of CXCL12 isoforms (α, β, γ). Cxcl12(Gagtm/Gagtm) mice develop normally, express normal levels of total and isoform-specific Cxcl12 mRNA, and show increased counting of circulating CD34(+) hematopoietic precursor cells. After induced acute ischemia, a marked impaired capacity to support revascularization was observed in Cxcl12(Gagtm/Gagtm) animals associated with a reduced number of infiltrating cells in the ischemic tissue despite the massive expression of CXCL12 isoforms. Importantly, exogenous administration of CXCL12γ, which binds heparan sulfate with the highest affinity ever reported for a cytokine, fully restores vascular growth, whereas heparan sulfate-binding CXCL12γ mutants failed to promote revascularization in Cxcl12(Gagtm/Gagtm) animals.
  
  
  CONCLUSIONS
  These findings prove the role played by heparan sulfate interactions in the functions of CXCL12 in both homeostasis and physiopathological settings and document for the first time the paradigm of chemokine immobilization in vivo.
authors.affiliation: Institut Pasteur, Unité de Pathogénie Virale, Département de Virologie, INSERM U819, Paris, France.
authors.forename: Patricia
authors.initials: P
authors.lastname: Rueda
authors.forename: Adèle
authors.initials: A
authors.lastname: Richart
authors.forename: Alice
authors.initials: A
authors.lastname: Récalde
authors.forename: Pamela
authors.initials: P
authors.lastname: Gasse
authors.forename: José
authors.initials: J
authors.lastname: Vilar
authors.forename: Coralie
authors.initials: C
authors.lastname: Guérin
authors.forename: Hugues
authors.initials: H
authors.lastname: Lortat-Jacob
authors.forename: Paulo
authors.initials: P
authors.lastname: Vieira
authors.forename: Franoise
authors.initials: F
authors.lastname: Baleux
authors.forename: Fabrice
authors.initials: F
authors.lastname: Chretien
authors.forename: Fernando
authors.initials: F
authors.lastname: Arenzana-Seisdedos
authors.forename: Jean-Sébastien
authors.initials: JS
authors.lastname: Silvestre
mesh_terms: D000818:Animals; D054377:Chemokine CXCL12 / Q000096:biosynthesis / Q000235:genetics*; D006493:Heparin / Q000031:analogs & derivatives* / Q000378:metabolism; D006614:Hindlimb / Q000098:blood supply; D006706:Homeostasis; D007511:Ischemia / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D023421:Models, Animal; D018482:Muscle, Skeletal / Q000098:blood supply*; D018919:Neovascularization, Physiologic / Q000235:genetics*; D020033:Protein Isoforms / Q000235:genetics; D011509:Proteoglycans / Q000378:metabolism*; D012333:RNA, Messenger; D014158:Transcription, Genetic
chemical_list: D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D020033:Protein Isoforms; D011509:Proteoglycans; D012333:RNA, Messenger; C036090:heparin proteoglycan; D006493:Heparin