1. ¹Wound Biology Group, Cardiff Institute of Tissue Engineering and Repair, Tissue Engineering and Reparative Dentistry Group, School of Dentistry, Cardiff University, Cardiff, UK
2. ²Department of Pathology, School of Medicine, Cardiff University, Cardiff, UK
3. ³Department of Surgery, School of Medicine, Cardiff University, Cardiff, UK
4. ⁴Wound Healing Research Unit, School of Medicine, Cardiff University, Cardiff, UK

Correspondence: Dr Phil Stephens, Wound Biology Group, Cardiff Institute of Tissue Engineering and Repair, Tissue Engineering and Reparative Dentistry Group, School of Dentistry, Cardiff University, Cardiff CF14 4XY, UK. E-mail: StephensP@cf.ac.uk

⁵Current address: Division of Cellular Therapy, Institute of Ophthalmology, University College London, 11-43 Bath Street, London EC1V 9EL, UK

Received 18 October 2007; Revised 22 January 2008; Accepted 20 February 2008; Published online 1 May 2008.

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.