title: Fibroblast dysfunction is a key factor in the non-healing of chronic venous leg ulcers.
abstract: Chronic age-related degenerative disorders, including the formation of chronic leg wounds, may occur due to aging of the stromal tissues and ensuing dysfunctional cellular responses. This study investigated the impact of environmental-driven cellular aging on wound healing by conducting a comprehensive analysis of chronic wound fibroblast (CWF) behavior in comparison with patient-matched healthy skin normal fibroblasts (NF). The dysfunctional wound healing abilities of CWF correlated with a significantly reduced proliferative life span and early onset of senescence compared with NF. However, pair-wise comparisons of telomere dynamics between NF and CWF indicated that the induction of senescence in CWF was telomere-independent. Microarray and functional analysis suggested that CWFs have a decreased ability to withstand oxidative stress, which may explain why these cells prematurely senescence. Microarray analysis revealed lower expression levels of several CXC chemokine genes (CXCL-1, -2, -3, -5, -6, -12) in CWF compared with NF (confirmed by ELISA). Functionally, this was related to impaired neutrophil chemotaxis in response to CWF-conditioned medium. Although the persistence of non-healing wounds is, in part, due to prolonged chronic inflammation and bacterial infection, our investigations show that premature fibroblast aging and an inability to correctly express a stromal address code are also implicated in the disease chronicity.
authors.affiliation: Wound Biology Group, Cardiff Institute of Tissue Engineering and Repair, Cardiff University, Cardiff, UK.
authors.forename: Ivan B
authors.initials: IB
authors.lastname: Wall
authors.forename: Ryan
authors.initials: R
authors.lastname: Moseley
authors.forename: Duncan M
authors.initials: DM
authors.lastname: Baird
authors.forename: David
authors.initials: D
authors.lastname: Kipling
authors.forename: Peter
authors.initials: P
authors.lastname: Giles
authors.forename: Iraj
authors.initials: I
authors.lastname: Laffafian
authors.forename: Patricia E
authors.initials: PE
authors.lastname: Price
authors.forename: David W
authors.initials: DW
authors.lastname: Thomas
authors.forename: Phil
authors.initials: P
authors.lastname: Stephens
mesh_terms: D000368:Aged; D049109:Cell Proliferation; D002478:Cells, Cultured; D016922:Cellular Senescence; D019743:Chemokines, CXC / Q000235:genetics; D002634:Chemotaxis, Leukocyte; D002908:Chronic Disease; D005260:Female; D005347:Fibroblasts; D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D007871:Leg Ulcer / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D046228:Microarray Analysis; D009504:Neutrophils; D018384:Oxidative Stress; D013481:Superoxides / Q000378:metabolism; D016615:Telomere / Q000235:genetics; D014945:Wound Healing
chemical_list: D019743:Chemokines, CXC; D013481:Superoxides