Combination of HIF-1α gene transfection and HIF-1-Activated bone marrow-derived angiogenic cell infusion improves burn wound healing in aged mice

J. Du, L. Liu, F. Lay, Q. Wang, C. Dou, X. Zhang, S. M. Hosseini, A. Simon, D. J. Rees, A. K. Ahmed, R. Sebastian, K. Sarkar, S. Milner, G. P. Marti, Gregg L Semenza, John Harmon

Research output: Contribution to journalArticle

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-1 (CA5-HIF-1)+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-1 gene therapy. HIF-1 mRNA expression in the burn wound was increased after transfection with CA5-HIF-1 plasmid. Our findings offer insight into the pathophysiology of burns in the elderly and point to potential targets for developing new therapeutic strategies. Copy; 2013 Macmillan Publishers Limited.

Original languageEnglish (US)
Pages (from-to)1070-1076
Number of pages7
JournalGene Therapy
Volume20
Issue number11
DOIs
StatePublished - Nov 2013

Fingerprint

Hypoxia-Inducible Factor 1
Wound Healing
Transfection
Bone Marrow
Genes
Wounds and Injuries
Genetic Therapy
Plasmids
Skin
Burns
Intravenous Infusions
Cultured Cells
Lasers
Perfusion

Keywords

  • angiogenesis
  • bone marrow-derived angiogenic cell (BMDAC)
  • burn wounds
  • dimethyloxalylglycine (DMOG)
  • hypoxia-inducible factor (HIF)
  • plasmid DNA transfection

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

Cite this

Combination of HIF-1α gene transfection and HIF-1-Activated bone marrow-derived angiogenic cell infusion improves burn wound healing in aged mice. / Du, J.; Liu, L.; Lay, F.; Wang, Q.; Dou, C.; Zhang, X.; Hosseini, S. M.; Simon, A.; Rees, D. J.; Ahmed, A. K.; Sebastian, R.; Sarkar, K.; Milner, S.; Marti, G. P.; Semenza, Gregg L; Harmon, John.

In: Gene Therapy, Vol. 20, No. 11, 11.2013, p. 1070-1076.

Research output: Contribution to journalArticle

Du, J, Liu, L, Lay, F, Wang, Q, Dou, C, Zhang, X, Hosseini, SM, Simon, A, Rees, DJ, Ahmed, AK, Sebastian, R, Sarkar, K, Milner, S, Marti, GP, Semenza, GL & Harmon, J 2013, 'Combination of HIF-1α gene transfection and HIF-1-Activated bone marrow-derived angiogenic cell infusion improves burn wound healing in aged mice', Gene Therapy, vol. 20, no. 11, pp. 1070-1076. https://doi.org/10.1038/gt.2013.32
Du, J. ; Liu, L. ; Lay, F. ; Wang, Q. ; Dou, C. ; Zhang, X. ; Hosseini, S. M. ; Simon, A. ; Rees, D. J. ; Ahmed, A. K. ; Sebastian, R. ; Sarkar, K. ; Milner, S. ; Marti, G. P. ; Semenza, Gregg L ; Harmon, John. / Combination of HIF-1α gene transfection and HIF-1-Activated bone marrow-derived angiogenic cell infusion improves burn wound healing in aged mice. In: Gene Therapy. 2013 ; Vol. 20, No. 11. pp. 1070-1076.
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