title: Barrier Function of the Repaired Skin Is Disrupted Following Arrest of Dicer in Keratinocytes.
abstract: 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.
authors.affiliation: 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.
authors.forename: Subhadip
authors.initials: S
authors.lastname: Ghatak
authors.affiliation: 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.
authors.forename: Yuk Cheung
authors.initials: YC
authors.lastname: Chan
authors.affiliation: 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.
authors.forename: Savita
authors.initials: S
authors.lastname: Khanna
authors.affiliation: 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.
authors.forename: Jaideep
authors.initials: J
authors.lastname: Banerjee
authors.affiliation: 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.
authors.forename: Jessica
authors.initials: J
authors.lastname: Weist
authors.affiliation: 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.
authors.forename: Sashwati
authors.initials: S
authors.lastname: Roy
authors.affiliation: 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. Electronic address: chandan.sen@osumc.edu.
authors.forename: Chandan K
authors.initials: CK
authors.lastname: Sen
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002460:Cell Line; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis* / Q000235:genetics; D005786:Gene Expression Regulation; D006801:Humans; D015603:Keratinocytes / Q000473:pathology; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics; D043244:Ribonuclease III / Q000096:biosynthesis* / Q000235:genetics; D012867:Skin / Q000254:growth & development / Q000473:pathology; D014945:Wound Healing / Q000235:genetics*
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D008565:Membrane Proteins; D035683:MicroRNAs; C064554:loricrin; D043244:Ribonuclease III