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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 volume 20, pages 1070–1076 (2013)Cite this article

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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 (χ2, 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.

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Acknowledgements

Funding for this work was provided by a subcontract to Johns Hopkins University from the NIH STTR of Canton Biotechnologies Inc., Baltimore, MD, R01 GM093023, as well as by funding from the Hendrix Burn Fund of Johns Hopkins University. This work was partly funded by the Science and Technology Project of Shaanxi Province, PR China.

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Author notes

  1. J Du and L Liu: These authors contributed equally to this project.

Authors and Affiliations

  1. Department of General Surgery, First Hospital Affiliated to Medical School, Xi’an Jiaotong University, Xi’an, China

    J Du

  2. Department of Surgery, Hendrix Burn Laboratory, Section of Surgical Sciences, Johns Hopkins Bayview Medical Center, Johns Hopkins University School of Medicine,

    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, S Milner, G P Marti & J W Harmon

  3. Baltimore, MD, USA

    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, S Milner, G P Marti & J W Harmon

  4. Departments of Medicine, Vascular Program, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    K Sarkar & G L Semenza

  5. Departments of Pediatrics, McKusick-Nathans Institute of Genetic Medicine, Medicine, Oncology, Radiation Oncology, Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    G L Semenza

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  1. J Du
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  2. L Liu
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  13. S Milner
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  14. G P Marti
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Corresponding author

Correspondence to J W Harmon.

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Competing interests

Drs John W Harmon and Guy P Marti report conflict of interest with equity in Canton Biotechnologies Inc., a startup biotech company formed to develop wound-healing technologies for clinical use. The remaining authors declare no conflict of interest.

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Du, J., Liu, L., Lay, F. et al. Combination of HIF-1α gene transfection and HIF-1-activated bone marrow-derived angiogenic cell infusion improves burn wound healing in aged mice. Gene Ther 20, 1070–1076 (2013). https://doi.org/10.1038/gt.2013.32

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