Deregulation of epidermal stem cell niche contributes to pathogenesis of nonhealing venous ulcers.
Deregulation of epidermal stem cell niche contributes to pathogenesis of nonhealing venous ulcers.
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DOI：
10.1111/wrr.12142
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发表时间：
2014-03
期刊：
影响因子：
--
通讯作者：
Tomic-Canic M
中科院分区：
文献类型：
--
作者：
Stojadinovic O;Pastar I;Nusbaum AG;Vukelic S;Krzyzanowska A;Tomic-Canic M
表皮由表皮干细胞（ESC）维持，所述表皮干细胞驻留在不同的小生境中并有助于稳态和伤口闭合。静脉性溃疡（VU）非愈合边缘的角质形成细胞不能愈合，过度增殖和非迁移，表明ESC失调。迄今为止，只在小鼠中研究了调控ESC小生境的基因。利用微阵列分析的VU非愈合边缘，我们确定了基因表达的变化，窝藏调节胚胎干细胞和他们的命运。在10个VU的前瞻性临床研究中，我们证实了骨形态发生蛋白受体和加塔结合蛋白3以及DNA结合蛋白2和4的抑制剂的抑制。我们还发现磷酸化糖原合成酶激酶3水平降低，β-连环蛋白的核存在及其转录靶点c-myc的过表达，表明Wnt途径的激活。此外，我们发现了亮氨酸丰富的重复序列和免疫球蛋白样结构域蛋白1的下调，这是一种对维持ESC处于静止状态很重要的基因，并且没有角蛋白15，这是基底干细胞室的标志物，表明ESC的局部耗竭。我们的研究表明，对调节ESC及其命运重要的基因的丢失以及VU中β-连环蛋白和c-myc的激活沿着，可能导致ESC剥夺和过度增殖、非迁移、不能愈合的伤口边缘。
The epidermis is maintained by epidermal stem cells (ESC) that reside in distinct niches and contribute to homeostasis and wound closure. Keratinocytes at the non-healing edges of venous ulcers (VUs) are healing-incompetent, hyper-proliferative and non-migratory suggesting deregulation of ESCs. To date genes which regulate ESC niches have been studied in mice only. Utilizing microarray analysis of VU non-healing edges, we identified changes in expression of genes harboring regulation of ESCs and their fate. In a prospective clinical study of ten VUs, we confirmed suppression of the bone morphogenetic protein receptor and GATA binding protein3 as well as inhibitors of DNA-binding proteins 2 and 4. We also found decreased levels of phosphorylated glycogen synthase kinase 3, nuclear presence of ß-catenin and overexpression of its transcriptional target, c-myc indicating activation of the Wnt pathway. Additionally, we found down-regulation of leucine-rich repeats and immunoglobulin-like domains protein 1, a gene important for maintaining ESCs in a quiescent state, and absence of keratin 15, a marker of the basal stem cell compartment suggesting local depletion of ESCs. Our study shows that loss of genes important for regulation of ESCs and their fate along with activation of ß-catenin and c-myc in the VU may contribute to ESC deprivation and a hyper-proliferative, non-migratory, healing incapable wound edge.
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