Temporal Smad7 Transgene Induction in Mouse Epidermis Accelerates Skin Wound Healing
Temporal Smad7 Transgene Induction in Mouse Epidermis Accelerates Skin Wound Healing
复制标题
DOI：
10.1016/j.ajpath.2011.06.003
复制
发表时间：
2011-10-01
影响因子：
6
通讯作者：
Wang, Xiao-Jing
中科院分区：
文献类型：
--
作者：
Han, Gangwen;Li, Fulun;Wang, Xiao-Jing
肿瘤生长因子β（TGF β）拮抗剂Smad 7的表达在皮肤伤口愈合期间增加。为了评估这一意义，我们暂时诱导Smad 7转基因表达在受伤的皮肤基因开关Smad 7转基因（Smad 7 TG）小鼠。表皮角质形成细胞中Smad 7诱导引起角质形成细胞增殖增加，同时Smad 2活化减少，表明Smad 7消除了TGF β介导的生长抑制。此外，Smad 7 tg小鼠的受伤皮肤表现出加速的再上皮化，细胞外信号调节激酶（Erk）的活化增加，体外迁移试验表明，Erk活化有助于Smad 7介导的角质形成细胞迁移。值得注意的是，表皮特异性Smad 7转基因表达对伤口基质也有深远的影响，导致炎症减少，血管生成和I型胶原蛋白的产生。在Smad 7转基因（Smad 7 tg）小鼠的创伤基质中观察到Smad 2活化减少，这可能是由于与对照小鼠的伤口相比，浸润的TGF β产生白细胞较少。由于Smad 7不分泌，这些作用可能反映了Smad 7 tg角质形成细胞的功能变化。支持这一观点，NF-κ B，转录激活炎性细胞因子的非分泌蛋白复合物的激活，减少在受伤的表皮从Smad 7 tg小鼠相比，在受伤的野生型表皮。总之，表皮Smad 7过表达通过其对角质形成细胞增殖和迁移的直接作用以及通过对伤口基质的间接作用加速伤口愈合。(Am J Pathol 2011，179：1768-1779。DOI：10.1016/j.ajpath.2011.06.003）
The expression of Smad7, a tumor growth factor-beta (TGF beta) antagonist, is increased during cutaneous wound healing. To assess this significance, we temporally induced Smad7 transgene expression in wounded skin in gene-switch-Smad7 transgenic (Smad7 tg) mice. Smad7 induction in epidermal keratinocytes caused an increase in keratinocyte proliferation with reduced Smad2 activation, indicating that Smad7 abrogated TGF beta-mediated growth inhibition. Additionally, wounded skin from Smad7 tg mice exhibited accelerated re-epithelialization, with increased activation of extracellular signal-regulated kinase (Erk), and an in vitro migration assay revealed that Erk activation contributed to Smad7-mediated keratinocyte migration. Notably, epidermis-specific Smad7 transgene expression also has a profound effect on the wound stroma, resulting in reduced inflammation, angiogenesis, and production of type I collagen. Reduced Smad2 activation was observed in wounded stroma from Smad7 transgenic (Smad7 tg) mice, possibly owing to fewer infiltrated TGF beta-producing leukocytes compared to those in wounds from control mice. Because Smad7 is not secreted, these effects could reflect functional changes in Smad7 tg keratinocytes. Supporting this notion, the activation of NF-kappa B, a nonsecreted protein complex that transcriptionally activates inflammatory cytokines, was reduced in wounded epidermis from Smad7 tg mice compared to that in wounded wildtype epidermis. In sum, epidermal Smad7 overexpression accelerated wound healing through its direct effects on keratinocyte proliferation and migration, and through indirect effects 1768 on wound stroma. (Am J Pathol 2011, 179:1768-1779. DOI: 10.1016/j.ajpath.2011.06.003)