Journal
AMERICAN JOURNAL OF PATHOLOGY
Volume 163, Issue 6, Pages 2421-2431Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/S0002-9440(10)63597-3
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Funding
- NCI NIH HHS [R01 CA094143] Funding Source: Medline
- NIGMS NIH HHS [P50 GM027345, P50GM27345, F32GM2084901, K08GM00674] Funding Source: Medline
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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 beta3-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 imigration 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.
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