HoxD3 accelerates wound healing in diabetic mice
HoxD3 accelerates wound healing in diabetic mice
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DOI：
10.1016/s0002-9440(10)63597-3
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发表时间：
2003-12-01
影响因子：
6
通讯作者：
Boudreau, N
中科院分区：
文献类型：
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作者：
Hansen, SL;Myers, CA;Boudreau, N
糖尿病创面愈合不良的特点是胶原生成减少，血管生成受损。Hoxd3是一种同源框转录因子，促进血管生成和胶原合成，在正常伤口修复过程中上调，而在遗传性糖尿病(db/db)小鼠愈合不良的伤口中表达减弱。为了确定恢复Hoxd3的表达是否会加速糖尿病伤口的愈合，我们设计了一种新的基因转移方法，将Hoxd3质粒DNA整合到甲基纤维素膜中，放置在db/db小鼠的伤口上。Hoxd3转基因在创面的内皮细胞、成纤维细胞和角质形成细胞中表达长达10天。更重要的是，与对照组相比，在db/db小鼠身上单独应用Hoxd3可以显著加速伤口愈合。此外，我们还观察到，Hoxd3介导的糖尿病创面修复的改善伴随着Hoxd3靶基因、Col1A1和Beta3-整合素的mRNA表达增加，导致创面血管生成和胶原沉积增加。尽管与对照db/db创面相比，Hoxd3处理的创面表现出更好的再上皮化，但这一效果并不是由于Hoxd3直接刺激角质形成细胞迁移所致。最后，我们发现，尽管Hoxd3处理的伤口中胶原合成和沉积显著增加，但这些伤口显示出正常的重塑，我们没有发现异常伤口愈合的证据。这些结果表明，Hoxd3可能提供了一种直接改善糖尿病愈合不良创面胶原沉积、血管生成和闭合的方法。
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.