Ghatak Subhadip, Chan Yuk Cheung, Khanna Savita, Banerjee Jaideep, Weist Jessica, Roy Sashwati, Sen Chandan K
Department of Surgery, Davis Heart and Lung Research Institute, Center for Regenerative Medicine and Cell-Based Therapies, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA.
Department of Surgery, Davis Heart and Lung Research Institute, Center for Regenerative Medicine and Cell-Based Therapies, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA.
Mol Ther. 2015 Jul;23(7):1201-1210. doi: 10.1038/mt.2015.65. Epub 2015 Apr 21.
Tissue injury transiently silences miRNA-dependent posttranscriptional gene silencing in its effort to unleash adult tissue repair. Once the wound is closed, miRNA biogenesis is induced averting neoplasia. In this work, we report that Dicer plays an important role in reestablishing the barrier function of the skin post-wounding via a miRNA-dependent mechanism. MicroRNA expression profiling of skin and wound-edge tissue revealed global upregulation of miRNAs following wound closure at day 14 post-wounding with significant induction of Dicer expression. Barrier function of the skin, as measured by trans-epidermal water loss, was compromised in keratinocyte-specific conditional (K14/Lox-Cre) Dicer-ablated mice because of malformed cornified epithelium lacking loricrin expression. Studies on human keratinocytes recognized that loricrin expression was inversely related to the expression of the cyclin-dependent kinase inhibitor p21(Waf1/Cip1). Compared to healthy epidermis, wound-edge keratinocytes from Dicer-ablated skin epidermis revealed elevated p21(Waf1/Cip1) expression. Adenoviral and pharmacological suppression of p21(Waf1/Cip1) in keratinocyte-specific conditional Dicer-ablated mice improved wound healing indicating a role of Dicer in the suppression of p21(Waf1/Cip1). This work upholds p21(Waf1/Cip1) as a druggable target to restore barrier function of skin suffering from loss of Dicer function as would be expected in diabetes and other forms of oxidant insult.
组织损伤会暂时抑制微小RNA（miRNA）依赖的转录后基因沉默，以促进成年组织修复。伤口闭合后，miRNA生物合成被诱导，从而避免肿瘤形成。在这项研究中，我们报告了Dicer通过一种miRNA依赖的机制在伤口愈合后重建皮肤屏障功能中发挥重要作用。对皮肤和伤口边缘组织的miRNA表达谱分析显示，在伤口愈合后第14天伤口闭合时，miRNA整体上调，同时Dicer表达显著诱导。通过经表皮水分流失测量的皮肤屏障功能，在角质形成细胞特异性条件性（K14/Lox-Cre）Dicer敲除小鼠中受损，这是因为缺乏兜甲蛋白表达的角化上皮畸形。对人类角质形成细胞的研究发现，兜甲蛋白的表达与细胞周期蛋白依赖性激酶抑制剂p21（Waf1/Cip1）的表达呈负相关。与健康表皮相比，来自Dicer敲除皮肤表皮的伤口边缘角质形成细胞显示p21（Waf1/Cip1）表达升高。在角质形成细胞特异性条件性Dicer敲除小鼠中，腺病毒介导的和药理学上对p21（Waf1/Cip1）的抑制改善了伤口愈合，表明Dicer在抑制p21（Waf1/Cip1）中发挥作用。这项研究支持将p21（Waf1/Cip1）作为一个可药物作用的靶点，以恢复因Dicer功能丧失而受损的皮肤屏障功能，糖尿病和其他形式的氧化应激损伤中可能会出现这种情况。
