title: Deregulation of epidermal stem cell niche contributes to pathogenesis of nonhealing venous ulcers.
abstract: 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.
authors.affiliation: Wound Healing and Regenerative Medicine Research Program, Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL 33136.
authors.forename: Olivera
authors.initials: O
authors.lastname: Stojadinovic
authors.affiliation: Wound Healing and Regenerative Medicine Research Program, Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL 33136.
authors.forename: Irena
authors.initials: I
authors.lastname: Pastar
authors.affiliation: Wound Healing and Regenerative Medicine Research Program, Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL 33136.
authors.forename: Aron G
authors.initials: AG
authors.lastname: Nusbaum
authors.affiliation: Department of Medicine, Division of Cardiology, Emory University, Atlanta, GA 30322, USA.
authors.forename: Sasa
authors.initials: S
authors.lastname: Vukelic
authors.affiliation: Tissue Engineering, Regeneration and Repair Program, Hospital for Special Surgery, New York, NY.
authors.forename: Agata
authors.initials: A
authors.lastname: Krzyzanowska
authors.affiliation: Wound Healing and Regenerative Medicine Research Program, Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL 33136.
authors.forename: Marjana
authors.initials: M
authors.lastname: Tomic-Canic
mesh_terms: D000818:Animals; D004268:DNA-Binding Proteins / Q000378:metabolism; D015536:Down-Regulation; D004817:Epidermis / Q000473:pathology*; D050990:GATA3 Transcription Factor / Q000378:metabolism; D020869:Gene Expression Profiling; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D011446:Prospective Studies; D040081:Protein Array Analysis; D055153:Stem Cell Niche; D014647:Varicose Ulcer / Q000276:immunology / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D060449:Wnt Signaling Pathway; D014945:Wound Healing; D051176:beta Catenin / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D050990:GATA3 Transcription Factor; C494749:GATA3 protein, human; C484445:LRIG1 protein, human; D008562:Membrane Glycoproteins; D051176:beta Catenin; D038362:Glycogen Synthase Kinase 3