title: Plasminogen activator inhibitor-1 controls bone marrow-derived cells therapeutic effect through MMP9 signaling: role in physiological and pathological wound healing.
abstract: We assessed the role of plasminogen activator inhibitor-1 (PAI-1) and matrix metalloproteinase 9 (MMP9) in wound healing process and in the bone marrow mononuclear cells (BMMNC)-related effects on physiological and pathological wound healing. A full thickness excision wound was created by removal of the skin on the midback of irradiated and nonirradiated animals. Angiogenesis and re-epithelialization were markedly increased in PAI-1-/- mice compared to wild-type (WT) animals. We revealed high MMP activity in tissue of PAI-1-/- animals. Of interest, the wound healing process was reduced in PAI-1-/-:MMP9-/- animals compared to PAI-1-/- mice, suggesting a key role of MMP9 in beneficial effect of PAI-1 deficiency on wound closure. To unravel the role of PAI-1 in BMMNC relative effects, mice were treated with or without local injection of BMMNC isolated from WT, PAI-1-/-, and PAI-1-/-: MMP9-/- animals for 14 days (10(6) cells, n = 6 per group). In WT nonirradiated mice, transplantation of BMMNC isolated from PAI-1-/- animals enhanced wound formation when compared with WT BMMNC. BMMNC differentiation into cells with endothelial phenotype was enhanced by PAI-1 deficiency. These effects were abrogated in PAI-1-/-:MMP9-/- and MMP9-/- BMMNC. In addition, using chimeric mice, we demonstrated that PAI-1 deficiency environment increased the BMMNC-GFP recruitment to the wound site, whereas this effect was abrogated when using PAI-1-/-:MMP9-/- BMMNC. PAI-1 deficiency, at least through MMP9 upregulation, enhanced wound healing and BMMNC therapeutic potential in irradiated and nonirradiated animals.
authors.affiliation: Institute of Radioprotection and Nuclear Safety (IRSN), DRPH/SRBE/LRTE, BP 17, Fontenay-aux-Roses Cedex, France.
authors.forename: Teni G
authors.initials: TG
authors.lastname: Ebrahimian
authors.forename: Claire
authors.initials: C
authors.lastname: Squiban
authors.forename: Telma
authors.initials: T
authors.lastname: Roque
authors.forename: Haydee
authors.initials: H
authors.lastname: Lugo-Martinez
authors.forename: Mohamad
authors.initials: M
authors.lastname: Hneino
authors.forename: Valerie
authors.initials: V
authors.lastname: Buard
authors.forename: Patrick
authors.initials: P
authors.lastname: Gourmelon
authors.forename: Marc
authors.initials: M
authors.lastname: Benderitter
authors.forename: Fabien
authors.initials: F
authors.lastname: Milliat
authors.forename: Radia
authors.initials: R
authors.lastname: Tamarat
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology* / Q000378:metabolism*; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism*; D014945:Wound Healing / Q000235:genetics / Q000502:physiology* / Q000528:radiation effects
chemical_list: D017395:Plasminogen Activator Inhibitor 1; D020780:Matrix Metalloproteinase 9