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.

17β-estradiol ameliorates age-associated loss of fibroblast function by attenuating IFN-γ/STAT1-dependent miR-7 upregulation

“…In addition, telomerase‐independent senescence and fibroblast dysfunction are regarded as being central to failure of wound closure (Wall et al ., 2008). The persistence of inflammation and over‐activation of immune‐regulated pathways, such as IFN‐stimulated responses, may contribute to the senescence‐like state of chronic wound fibroblasts, through induction of miR‐7.…”

Can Venous Ulcer Size be Associated with the Healing Potential of Serum? Pilot Study

“…Also, the accumulation of degraded collagen in the ECM could inhibit type I procollagen synthesis [21,22,23]. Finally, fibroblast senescence is implicated in the wound chronicity [24,25,26,27]. Senescent fibroblasts exhibit an ECM degradative phenotype and down regulate the type I collagen [28].…”

Tropical ulcer plant treatments used by Papua New Guinea's Apsokok nomads

“…Another feature of the chronic wounds and infected wounds is fibroblasts that exhibit a premature senescence phenotype (Wall et al, 2008). As fibroblasts are essential for collagen deposition and growth factor secretion, plants metabolites that stimulate normal fibroblast growth in response to stress from bacterial bio-burden may help stimulate wound healing.…”

“…Another characteristic of stalled wound healing is a stress-induced premature senescence phenotype that may result from excessive inflammation and oxidative stress (Wall et al, 2008). As fibroblasts play a central role in wound repair through collagen synthesis and the production of cytokines, normal fibroblast activity is essential for normal wound healing (Tepole and Kuhl, 2013).…”