Insulin-like growth factor-1 gene therapy and cell transplantation in diabetic wounds

Tobias Hirsch, Malte Spielmann, Patrik Velander, Baraa Zuhaili, Oliver Bleiziffer, Magdalena Fossum, Lars Steinstraesser, Feng Yao, Elof Eriksson

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Impaired wound healing is a frequent phenomenon in diabetes mellitus. However, little is known of the fundamental cause of this pathology. The present study examined the effect of human insulin-like growth factor (hIGF)-1 overexpression in combination with autologous cell transplantation to diabetic wounds in a preclinical large-animal model. Methods: Diabetes was induced in Yorkshire pigs with streptozotocin. Keratinocytes were cultured and transfecteu with hIGF-1 or LacZ transgene. Plasmids were lipoplexed with either Upofectin or Lipofectamin 2000. Transgene expression was assessed by enzyme-linked immunosorbent assay or X-gal staining. For in vivo studies, full-thickness wounds were created and dressed with a sealed chamber. Transfected cells were transplanted into the wounds. Wound contraction was monitored and biopsies were obtained for measurement of re-epithelialization. Wound fluid was collected and analysed for IGF-1 concentrations. Results: Quantification showed up to 740 ng/ml IGF-1 in vitro and significantly higher concentrations over 14 days compared to controls for the Lipofectamin 2000 group. Lipofectin-mediated gene transfer showed peak expression on day 2 with 68.5 ng/ml. In vivo, transfected cells showed peak expression of 457 ng/ml at day 1, followed by subsequent decline to 5 ng/ml on day 12 with Lipofectamin 2000. For Lipofectin no significant IGF-1 expression could be detected. Gene therapy caused significantly faster wound closure (83%) than both controls (native-cell therapy = 57%; control wounds = 32%). Conclusions: The present study demonstrates that optimized nonviral gene transfer increased IGF-1 expression in diabetic wounds by up to 900-fold. This high IGF-1 concentration in combination with cell therapy improved diabetic wound healing significantly.

Original languageEnglish (US)
Pages (from-to)1247-1252
Number of pages6
JournalJournal of Gene Medicine
Volume10
Issue number11
DOIs
StatePublished - 2008
Externally publishedYes

Keywords

  • Cell transplantation
  • Diabetes
  • Gene therapy
  • IGF-1
  • Re-epithelialization
  • Wound healing

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Drug Discovery
  • Genetics(clinical)

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