Premium
Deregulation of epidermal stem cell niche contributes to pathogenesis of nonhealing venous ulcers
Author(s) -
Stojadinovic Olivera,
Pastar Irena,
Nusbaum Aron G.,
Vukelic Sasa,
Krzyzanowska Agata,
TomicCanic Marjana
Publication year - 2014
Publication title -
wound repair and regeneration
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.847
H-Index - 109
eISSN - 1524-475X
pISSN - 1067-1927
DOI - 10.1111/wrr.12142
Subject(s) - wnt signaling pathway , biology , stem cell , wound healing , epidermis (zoology) , microbiology and biotechnology , gsk 3 , gene , kinase , cancer research , signal transduction , immunology , genetics , anatomy
The epidermis is maintained by epidermal stem cells ( ESC s) that reside in distinct niches and contribute to homeostasis and wound closure. Keratinocytes at the nonhealing edges of venous ulcers ( VU s) are healing‐incompetent, hyperproliferative, and nonmigratory, suggesting deregulation of ESC s. 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 VU s, we confirmed suppression of the bone morphogenetic protein receptor ( BMPR ) and G ATA binding protein 3 ( GATA 3) as well as inhibitors of DNA ‐binding proteins 2 and 4 ( ID 2 and ID 4). We also found decreased levels of phosphorylated glycogen synthase kinase 3 ( GSK 3), 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 ( LRIG 1), a gene important for maintaining ESC s in a quiescent state, and absence of keratin 15 ( K 15), a marker of the basal stem cell compartment suggesting local depletion of ESC s. Our study shows that loss of genes important for regulation of ESC s 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.