Stojadinovic Olivera, Pastar Irena, Nusbaum Aron G, Vukelic Sasa, Krzyzanowska Agata, Tomic-Canic Marjana
Wound Healing and Regenerative Medicine Research Program, Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL 33136.
Department of Medicine, Division of Cardiology, Emory University, Atlanta, GA 30322, USA.
Wound Repair Regen. 2014 Mar-Apr;22(2):220-227. doi: 10.1111/wrr.12142.
The epidermis is maintained by epidermal stem cells (ESCs) that reside in distinct niches and contribute to homeostasis and wound closure. Keratinocytes at the nonhealing edges of venous ulcers (VUs) are healing-incompetent, hyperproliferative, and nonmigratory, suggesting deregulation of ESCs. To date, genes which regulate ESC niches have been studied in mice only. Utilizing microarray analysis of VU nonhealing edges, we identified changes in expression of genes harboring regulation of ESCs and their fate. In a prospective clinical study of 10 VUs, we confirmed suppression of the bone morphogenetic protein receptor (BMPR) and GATA binding protein 3 (GATA3) as well as inhibitors of DNA-binding proteins 2 and 4 (ID2 and ID4). We also found decreased levels of phosphorylated glycogen synthase kinase 3 (GSK3), nuclear presence of β-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 (LRIG1), a gene important for maintaining ESCs in a quiescent state, and absence of keratin 15 (K15), 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 β-catenin and c-myc in the VU may contribute to ESC deprivation and a hyperproliferative, nonmigratory healing incapable wound edge.
表皮由位于不同微环境中的表皮干细胞（ESC）维持，这些干细胞有助于维持内环境稳定和伤口愈合。静脉溃疡（VU）不愈合边缘的角质形成细胞愈合能力差、增殖过度且不迁移，提示ESC失调。迄今为止，调控ESC微环境的基因仅在小鼠中进行过研究。通过对VU不愈合边缘进行微阵列分析，我们确定了与ESC调控及其命运相关的基因表达变化。在一项对10例VU的前瞻性临床研究中，我们证实骨形态发生蛋白受体（BMPR）和GATA结合蛋白3（GATA3）以及DNA结合蛋白2和4（ID2和ID4）的抑制剂受到抑制。我们还发现磷酸化糖原合酶激酶3（GSK3）水平降低、β-连环蛋白在细胞核中存在，以及其转录靶点c-myc过表达，表明Wnt信号通路被激活。此外，我们发现富含亮氨酸重复序列和免疫球蛋白样结构域蛋白1（LRIG1）下调，LRIG1是一个对维持ESC静止状态很重要的基因，同时未检测到角蛋白15（K15），K15是基底干细胞区室的标志物，提示局部ESC耗竭。我们的研究表明，VU中对ESC调控及其命运至关重要的基因缺失，以及β-连环蛋白和c-myc的激活，可能导致ESC缺失以及伤口边缘增殖过度、不迁移且无法愈合。
