Growth factors secreted by fibroblasts: role in healing diabetic foot ulcers (original) (raw)
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Journal of Investigative Dermatology, 1999
Several pathophysiologic mechanisms have been proposed to explain slow-healing leg ulcers, but little is known about the growth behavior of cells in these wounds. Platelet-derived growth factor-BB applied topically to chronic wounds has shown beneficial effects, although the effects have been less pronounced than would have been expected based on studies on acute wounds. The objective of this study was to compare fibroblasts in culture obtained from chronic wounds (non-healing chronic venous leg ulcers), acute wounds and normal dermis regarding growth, mitogenic response to platelet-derived growth factor-BB and levels of platelet-derived growth factor α-receptor and β-receptor. Fibroblasts were obtained by an explant technique and expanded in vitro using fibroblast growth medium supplemented with 10% fetal bovine serum and used for the assays at their third passage. Growth of chronic wound fibroblasts (n ⍧ 8) was significantly (p < 0.05) decreased compared with those from acute wounds (n ⍧ 10) and normal dermis (n ⍧ 5). Fibroblasts from ulcers older than 3 y grew S everal pathophysiologic mechanisms have been proposed to explain slow/non-healing leg ulcers. Overproduction of reactive oxygen species, hypoxia, imbalances in levels of cytokines and proteolytic enzymes, excessive fibrin deposition, and failure of keratinocyte migration on the chronic wound bed have been presented as possible explanations for the defective healing of leg ulcers (Coleridge Smith, 1994; Falanga et al, 1994). Little is known, however, about growth and other biologic activities of cells in these wounds. Fibroblasts are one of the key cells in wound repair. Apart from producing the major extracellular components of collagen, elastin,
Journal of Investigative Dermatology, 1998
In diabetic patients, wound healing is impaired. We studied the pathogenesis behind this clinical observation by characterizing the pattern of deposition of extracellular matrix (ECM) molecules and the cellular infiltrate in chronic (>8 wk) diabetic wounds, compared with chronic venous ulcers and an acute wound healing model. Punch biopsies were obtained from the chronic ulcer margins and control samples were collected from upper leg skin 5, 19, 28 d and 12 and 18 mo postwounding (p.w.). T . Abundant staining was seen 3 mo p.w., returning to prewounding levels after 12-18 mo p.w. In the dermis of chronic diabetic and venous
The pro-inflammatory environment in recalcitrant diabetic foot wounds
International Wound Journal, 2008
Lower extremity ulceration is one of the serious and long-term diabetic complications rendering a significant social burden in terms of amputation and quality-of-life reduction. Diabetic patients experience a substantial wound-healing deficit. These lesions are featured by an exaggerated and prolonged inflammatory reaction with a significant impairment in local bacterial invasion control. Experimental and clinical evidences document the deleterious consequences of the wound’s pro-inflammatory phenotype for the repair process. From a biochemical standpoint, hyperinflammation favours wound matrix degradation, thus, amplifying a pre-existing granulation tissue productive cells’ invasiveness and recruitment deficit. Tumour necrosis factor perpetuates homing of inflammatory cells, triggers pro-apoptotic genes and impairs reepithelialisation. Advanced glycation end-products act in concert with inflammatory mediators and commit fibroblasts and vascular cells to apoptosis, contributing to granulation tissue demise. Therapeutic approaches aimed to downregulate hyperinflammation and/or attenuate glucolipotoxicity may assist in diabetic wound healing by dismantling downstream effectors. These medical interventions are demanded to reduce amputations in an expanding diabetic population.
Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society, 2016
Current chronic wound treatments often fail to promote healing of diabetic foot ulcers (DFU), leading to amputation and increased patient morbidity. A critical mediator of proper wound healing is the production, assembly, and remodeling of the extracellular matrix (ECM) by fibroblasts. However, little is known about how these processes are altered in fibroblasts within the DFU microenvironment. Thus, we investigated the capacity of multiple, primary DFU-derived fibroblast strains to express, produce, and assemble ECM proteins compared to diabetic patient-derived fibroblasts and healthy donor-derived fibroblasts. Gene expression microarray analysis demonstrated differential expression of ECM and ECM-regulatory genes by DFU-derived fibroblasts which translated to functional differences in a 3D in vitro ECM tissue model. DFU-derived fibroblasts produced thin, fibronectin-rich matrices and responded abnormally when challenged with transforming growth factor-beta (TGF-β), a key regulator...
Histological and Transcriptional Expression differences between Diabetic Foot and Pressure Ulcers
Journal of Diabetes & Metabolism, 2013
Decubitus and diabetic foot ulcers remain as important clinical challenges with significant socioeconomic impact. Both are individual forms of chronic wounds with diverse proximal ethiopathogenic triggers. This study aimed to characterize and compare the main histological features as the transcriptional expression profile of a set of wound-healing relevant genes of the ulcers' granulation tissue. Following patients' consent, biopsies were collected from sacrolumbar pressure ulcers (N=5, stage IV) and diabetic foot ulcers (N=9, both of neuropathic and ischemic origin) with clean, non-infected granulation tissue. Biopsies fragments were processed for histological analysis and for RNA extraction and subsequent transcriptional expression characterization via RT-PCR. The group of targeted genes included cell proliferation control, extracellular matrix, glucose metabolism, anabolismsurvival, as anti-hypoxia and anti-oxidant defense. Gene expression was determined, normalized with an internal housekeeping gene, and statistically compared. Each class of chronic ulcer granulation tissue: decubitus, and diabetics' ischemic and neuropathic proved to develop a particular histological pattern thus establishing individual differences. Moreover, diabetes appeared to significantly reduce the expression of numerous genes irrespective to their biological significance. Most importantly, we found that diabetic granulation tissue cells exhibit a sort of "genetic or epigenetic imprinting" for the expression of glucose-metabolism related genes which are deeply involved in type-2 diabetes pathophysiology. Our data indicate that in addition to a protracted inflammation and abnormal angiogenesis, diabetic granulation tissue cells are affected by gene expression failures that may lead to a negative pro-anabolic and energetic balance. J ou rna l o f D ia be tes & M e ta bolism
Fibroblasts cultured from venous ulcers display cellular characteristics of senescence
Journal of Vascular Surgery, 1998
Purpose: A well-recognized characteristic of venous ulcers is impaired healing. Fibroblasts cultured from venous ulcers (wound-fb) have been shown to have reduced growth rates and are larger than normal fibroblasts (normal-fb) from the ipsilateral limb. Reduced growth capacity and morphologic changes are 2 well-known traits of cellular senescence. Other molecular changes are overexpression of matrix proteins, such as cellular fibronectin (cFN), and enhanced activity of β-galactosidase at pH of 6.0 (senescence associated β-Gal, or SA-β-Gal). Senescence, an irreversible arrest of cell proliferation with maintenance of metabolic functions, may represent in vivo aging and thus may be related to impaired healing.
Wound healing and treatments for people with diabetic foot ulcers
Diabetes/Metabolism Research and Reviews, 2004
The factors that delay wound healing are multiple and relate both to diabetes and to the effect of its complications. Diabetic foot ulcers readily become chronic, and chronic ulcers have biological properties that differ substantially from acute ones. Much of the available information on the biology of wound healing relates to acute and experimental wounds and may not be directly relevant. It follows that there is limited evidence currently available to underpin protocols for the management of diabetic foot ulcers, or to guide choice of applications and dressings [1]. Nevertheless, it is possible to define certain principles.