Deregulation of epidermal stem cell niche contributes to pathogenesis of nonhealing venous ulcers

Abstract

The epidermis is maintained by epidermal stem cells (ESC) that reside in distinct niches and contribute to homeostasis and wound closure. Keratinocytes at the non-healing edges of venous ulcers (VUs) are healing-incompetent, hyper-proliferative and non-migratory suggesting deregulation of ESCs. To date genes which regulate ESC niches have been studied in mice only. Utilizing microarray analysis of VU non-healing edges, we identified changes in expression of genes harboring regulation of ESCs and their fate. In a prospective clinical study of ten VUs, we confirmed suppression of the bone morphogenetic protein receptor and GATA binding protein3 as well as inhibitors of DNA-binding proteins 2 and 4. We also found decreased levels of phosphorylated glycogen synthase kinase 3, nuclear presence of ß-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, a gene important for maintaining ESCs in a quiescent state, and absence of keratin 15, 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 ß-catenin and c-myc in the VU may contribute to ESC deprivation and a hyper-proliferative, non-migratory, healing incapable wound edge.

Wound repair and regeneration: Mechanisms, signaling, and translation

“…3), such as aging and diabetes (29, 45). Furthermore, frequent cycling of epidermal stem cells in patients with chronic wounds can lead to depletion of local stem cell populations (46). Compromised function of local and systemic stem cells and progenitors may play a considerable role in pathology of chronic wounds.…”

Pathogenesis of wound healing disorders in the elderly

“…Said effects are primarily attributed to mitochondrial dysfunction and increased oxidative stress [ 39 ] , epigenetic regulation [ 42 ] , or disturbances in the resident niche [ 43 ] . Sequelae may include local depletion of epidermal cells and escape from the quiescence phase, and thus explain the observation that epidermal skin cells at the wound margins of chronic venous ulcers are hyperproliferative, nonmigratory, and healing-incompetent [ 44 ] . In addition to epidermal stem cells, adipocyte [ 45 ] and melanocyte progenitors [ 46 ] , mesenchymal stem cells [ 47 ] , bone marrow as well as endothelial progenitors [ 48 ] also contribute to the wound healing process, and are regulated by various specifi c cytokines and chemokines that have likewise been shown to be affected by aging [ 49 ] .…”

“…Among others, markers downstream of the Wnt signaling pathway (e. g. elevated expression of nuclear β -catenin and c-myc [ 44 ] ), epidermal stem cell markers (e. g. decreased expression of leucine-rich repeats and immunoglobulin-like domain-containing protein 1 [LRIG 1] and keratin 15 [K15]), members of the TGF β superfamily (e. g. decreased expression of the bone morphogenetic protein receptor [BMPR] and TGF β I and II ligands), immunomodulatory proteins (e. g. decreased expression GATA-binding protein 3 (GATA3) and of inhibitors of DNA-binding proteins 2 and 4 (ID2 and ID4) [ 44,59 ] ), as well as antimicrobial peptides (e. g. decreased expression of cathelicidin [ 60 ] ) have been shown to be clinically associated with impaired healing in patients with chronic wounds. On the other hand, wound fl uid markers have also been identifi ed, including increased expression of metalloproteinases (e. g. MMP-1, 2, 3, 7, 8, 9, 10, 11, 13), decreased expression of their inhibitors (e. g. TIMP-1) [61][62][63] , increased IL-1 and IL-6 [ 64 ] levels, as well as decreased levels of albumin and total protein [ 65 ] .…”

Skin Wound Healing: An Update on the Current Knowledge and Concepts

“…In the context of epidermal regeneration, stem cells deriving from the hair follicle bulge and the interfollicular epidermis niche replace missing cells [34,35,36]. A deregulation of the epidermal stem cell niche is present in chronic wounds, i.e., nonhealing ulcers [37], where the cell pool is limited caused by continuous inflammation due to infection, hypoxia, ischemia and/or excessive exudates [38]. The use of stem cells, however, is propagated to overcome the problem of nonhealing wounds with extensive on-going research.…”