HoxD3 accelerates wound healing in diabetic mice.
Poorly healing diabetic wounds are characterized by diminished collagen production and impaired angiogenesis. HoxD3, a homeobox transcription factor that promotes angiogenesis and collagen synthesis, is up-regulated during normal wound repair whereas its expression is diminished in poorly healing wounds of the genetically diabetic (db/db) mouse. To determine whether restoring expression of HoxD3 would accelerate diabetic wound healing, we devised a novel method of gene transfer, which incorporates HoxD3 plasmid DNA into a methylcellulose film that is placed on wounds created on db/db mice. The HoxD3 transgene was expressed in endothelial cells, fibroblasts, and keratinocytes of the wounds for up to 10 days. More importantly, a single application of HoxD3 to db/db mice resulted in a statistically significant acceleration of wound closure compared to control-treated wounds. Furthermore, we also observed that the HoxD3-mediated improvement in diabetic wound repair was accompanied by increases in mRNA expression of the HoxD3 target genes, Col1A1 and beta 3-integrin leading to enhanced angiogenesis and collagen deposition in the wounds. Although HoxD3-treated wounds also show improved re-epithelialization as compared to control db/db wounds, this effect was not due to direct stimulation of keratinocyte migration by HoxD3. Finally, we show that despite the dramatic increase in collagen synthesis and deposition in HoxD3-treated wounds, these wounds showed normal remodeling and we found no evidence of abnormal wound healing. These results indicate that HoxD3 may provide a means to directly improve collagen deposition, angiogenesis and closure in poorly healing diabetic wounds.
Hansen
Scott L
SL
Department of Surgery, University of California San Francisco, San Francisco, California 94143, USA.
Myers
Connie A
CA
Charboneau
Aubri
A
Young
David M
DM
Boudreau
Nancy
N
D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D003094:Collagen / Q000235:genetics; D004268:DNA-Binding Proteins; D003920:Diabetes Mellitus / Q000235:genetics / Q000503:physiopathology*; D018014:Gene Transfer Techniques; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D039661:Integrin beta3 / Q000235:genetics; D015603:Keratinocytes; D051379:Mice; D008810:Mice, Inbred C57BL; D018919:Neovascularization, Physiologic; D012333:RNA, Messenger / Q000378:metabolism; D012867:Skin / Q000098:blood supply / Q000293:injuries* / Q000473:pathology; D014157:Transcription Factors; D014945:Wound Healing / Q000187:drug effects; D014950:Wounds, Penetrating / Q000473:pathology / Q000503:physiopathology
D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; C484113:Hoxd3 protein, mouse; D039661:Integrin beta3; D012333:RNA, Messenger; D014157:Transcription Factors; C073547:HOXA4 protein, human; D003094:Collagen