title: Combination of HIF-1α gene transfection and HIF-1-activated bone marrow-derived angiogenic cell infusion improves burn wound healing in aged mice.
abstract: Impaired burn wound healing in the elderly represents a major clinical problem. Hypoxia-inducible factor-1 (HIF-1) is a transcriptional activator that orchestrates the cellular response to hypoxia. Its actions in dermal wounds promote angiogenesis and improve healing. In a murine burn wound model, aged mice had impaired wound healing associated with reduced levels of HIF-1. When gene therapy with HIF-1 alone did not correct these deficits, we explored the potential benefit of HIF-1 gene therapy combined with the intravenous infusion of bone marrow-derived angiogenic cells (BMDACs) cultured with dimethyloxalylglycine (DMOG). DMOG is known to reduce oxidative degradation of HIF-1. The mice treated with a plasmid DNA construct expressing a stabilized mutant form of HIF-1α (CA5-HIF-1α)+BMDACs had more rapid wound closure. By day 17, there were more mice with completely closed wounds in the treated group (χ(2), P=0.05). The dermal blood flow measured by laser Doppler showed significantly increased wound perfusion on day 11. Homing of BMDACs to the burn wound was dramatically enhanced by CA5-HIF-1α gene therapy. HIF-1α mRNA expression in the burn wound was increased after transfection with CA5-HIF-1α plasmid. Our findings offer insight into the pathophysiology of burns in the elderly and point to potential targets for developing new therapeutic strategies.
authors.affiliation: 1] Department of General Surgery, First Hospital Affiliated to Medical School, Xi'an Jiaotong University, Xi'an, China [2] Hendrix Burn Laboratory, Section of Surgical Sciences, Department of Surgery, Johns Hopkins Bayview Medical Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: J
authors.initials: J
authors.lastname: Du
authors.forename: L
authors.initials: L
authors.lastname: Liu
authors.forename: F
authors.initials: F
authors.lastname: Lay
authors.forename: Q
authors.initials: Q
authors.lastname: Wang
authors.forename: C
authors.initials: C
authors.lastname: Dou
authors.forename: X
authors.initials: X
authors.lastname: Zhang
authors.forename: S M
authors.initials: SM
authors.lastname: Hosseini
authors.forename: A
authors.initials: A
authors.lastname: Simon
authors.forename: D J
authors.initials: DJ
authors.lastname: Rees
authors.forename: A K
authors.initials: AK
authors.lastname: Ahmed
authors.forename: R
authors.initials: R
authors.lastname: Sebastian
authors.forename: K
authors.initials: K
authors.lastname: Sarkar
authors.forename: S
authors.initials: S
authors.lastname: Milner
authors.forename: G P
authors.initials: GP
authors.lastname: Marti
authors.forename: G L
authors.initials: GL
authors.lastname: Semenza
authors.forename: J W
authors.initials: JW
authors.lastname: Harmon
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000375:Aging; D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism*; D016026:Bone Marrow Transplantation; D002056:Burns / Q000235:genetics / Q000503:physiopathology* / Q000628:therapy; D002478:Cells, Cultured; D003131:Combined Modality Therapy; D004195:Disease Models, Animal; D005260:Female; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018919:Neovascularization, Physiologic; D014162:Transfection; D014945:Wound Healing
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit