Fibroblasts derived from chronic diabetic ulcers differ in their response to stimulation with EGF, IGF-I, bFGF and PDGF-AB compared to controls

Loot, Miriam A. M.; Kenter, Susan; Au, Fung L.; Galen, W. J. M. van; Middelkoop, Esther; Bos, Jan D.; Mekkes, Jan R.

doi:10.1078/0171-9335-00228

Cited by 196 publications

(114 citation statements)

References 26 publications

(15 reference statements)

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“…Evidence from studies of fibroblasts from diabetic ulcers have shown similar abnormalities (Loots et al, 1999;Loot et al, 2002). The microenvironment of the wound is likely to be another important determinant of cellular selection and phenotypic expression.…”

Section: Discussionmentioning

confidence: 98%

“…There is increasing evidence in support of this hypothesis, much of it developed in the context of diabetic and venous ulcers. Fibroblasts cultured from diabetic ulcers show decreased mitogenic potential and differential responses to certain cytokines, either along or in combination (Loots et al, 1999;Loot et al, 2002). It has been shown that dermal fibroblasts cultured from venous ulcers are senescent (Stanley and Osler, 2001), show decreased proliferative potential (Stanley et al, 1997), and are unresponsive to stimulation by such critical growth factors as transforming growth factor-b1 (TGF-b1) (Hasan et al, 1997) and platelet-derived growth factor BB (PDGF-BB) (Agren et al, 1999).…”

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confidence: 99%

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Fibroblasts from chronic wounds show altered TGF‐β‐signaling and decreased TGF‐β Type II Receptor expression

Kim

Park

et al. 2003

Journal Cellular Physiology

171

128

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Chronic wounds are characterized by failure to heal in a defined time frame. However, the pathogenic steps leading from the etiological factors to failure to heal are unknown. Recently, increasing evidence suggests that resident cells in chronic wounds display a number of critical abnormalities, including senescence and unresponsiveness to the stimulatory action of transforming growth factor-b1 (TGF-b1). In this study, we have determined some of the mechanisms that might be responsible for unresponsiveness to TGF-b1. Using Northern analysis and affinity labeling, we show that venous ulcer fibroblasts have decreased TGF-b Type II receptor expression. This finding is not the result of genetic mutation, as shown by experiments with Type II receptor satellite instability. Decreased Type II receptor expression was accompanied by failure of ulcer fibroblasts to phosphorylate Smad 2, Smad 3, and p42/44 mitogen activating protein kinase (MAPK), and was associated with a slower proliferative rate in response to TGF-b1. We conclude that venous ulcer fibroblasts show decreased Type II receptor expression and display abnormalities in the downstream signaling pathway involving MAPK and the early Smad pathway. These findings suggest ways to address and treat the abnormal cellular phenotype of cells in chronic wounds.

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Section: Discussionmentioning

confidence: 98%

mentioning

confidence: 99%

Fibroblasts from chronic wounds show altered TGF‐β‐signaling and decreased TGF‐β Type II Receptor expression

Kim

Park

et al. 2003

Journal Cellular Physiology

171

128

View full text Add to dashboard Cite

show abstract

“…The current increment in DFUs associated risk factors such as, ageing population, smoking and obesity can complicate and slow down the healing process (Loots, et al 2002). The etiology of DFU is related to the damage of blood vessels, nerves and immune system modulation, caused by the long-term hyperglycaemia suffered by diabetic patients (Cevc and Vierl 2010;Falanga 2004).…”

Section: Introductionmentioning

confidence: 99%

rhEGF-loaded PLGA-Alginate microspheres enhance the healing of full-thickness excisional wounds in diabetised Wistar rats

Gainza

Aguirre

Pedraz

et al. 2013

European Journal of Pharmaceutical Sciences

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Diabetic foot ulcers (DFUs) represent a major clinical challenge in the ageing population. To address this problem, rhEGF-loaded Poly-Lactic-co-Glycolic-Acid (PLGA)-Alginate microspheres (MS) were prepared by a modified w/o/w-doubleemulsion/solvent evaporation method. Different formulations were evaluated with the aim of optimising MSs properties by adding NaCl to the surfactant solution and/or the solvent removal phase and adding alginate as a second polymer. The characterization of the developed MS showed that alginate incorporation increased the encapsulation efficiency (EE) and NaCl besides increasing the EE also became the particle surface smooth and regular. Once the MS were optimised, the target loading of rhEGF was increased to 1% (PLGA-Alginate MS), and particles were sterilised by gamma radiation to provide the correct dosage for in vivo studies. In vitro cell culture assays demonstrated that neither the microencapsulation nor the sterilisation process affected rhEGF bioactivity or rhEGF wound contraction. Finally, the MS were evaluated in vivo for treatment of the full-thickness wound model in diabetised Wistar rats. rhEGF MS treated animals showed a statistically significant decrease of the wound area by days 7 and 11, a complete re-epithelisation by day 11 and an earlier resolution of the inflammatory process. Overall, these findings demonstrate the promising potential of rhEGF-loaded MS (PLGA-Alginate MS) to promote faster and more effective wound healing, and suggest its possible application in DFU treatment.

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“…Microangiopathy is particularly important as the thickened basement membrane surrounding the ulcer impairs inflammatory cell recruitment affecting the first and second stages of wound healing [10]. At the cellular level, fibroblasts in the diabetic ulcer show signs of senescence and have a decreased proliferative response to growth factors as compared to fibroblasts in non-diabetic wounds [11,12]. At the molecular level, biopsies taken from diabetic ulcers have lower levels of TGF-β and type 2 TGF-β receptors as compared to wounds from non-diabetic individuals [13,14].…”

Section: Introductionmentioning

confidence: 99%

A Pilot Study to Evaluate the Efficacy of IZN 6D4 for the Treatment of Diabetic Foot Ulcers

Oberbaum¹,

Rosenblum²

2017

J Diabetic Complications Med

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Diabetic foot ulcers (DFU), which can affect up to 15% of individuals with diabetes, remain a major unmet medical need. Left untreated, DFU seriously impact on quality of life and level of function. Conventional treatment is costly and often ineffective. In severe cases, patients with DFU may undergo painful amputations. IZN 6D4 is an impregnated hydrogel containing active pharmaceutical ingredients that have both wound-healing promoting and anti-inflammatory activities This is an observational human clinical trial study involving 15 patients treated with IZN 6D4. Subjects in the study had DFU which were categorized as being at stage 1A or greater using the University of Texas Health Science Center, San Antonio scale (UTHSC) grading system. Treatment lasted 21 days, and during the course of the study, patches were applied every 3-4 days. Response to therapy was measured by extent and depth of the lesion (wound grid and digital photography), qualitative assessment of wound healing (tissue granulation), and the rate of wound closure over the trial period. Results of the study showed that 40% of subjects had 75% closure of the wound and 27% had complete wound closure. Nearly all patients had evidence of active wound healing (e.g., presence of granulation tissue), and percent mean wound reduction for the entire study group was 67.7 ± 26.4%. Photo documentation of wound healing showed impressive differences between pre-and posttreatment appearances of diabetic ulcers in many of the patients studied. Based on the promising data from preclinical studies and the observational clinical trial provide strong justification for initiating a large-scale, longer duration clinical trial evaluating the efficacy of IZN 6D4 hydrogel in the treatment of patients with DFU.

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Fibroblasts derived from chronic diabetic ulcers differ in their response to stimulation with EGF, IGF-I, bFGF and PDGF-AB compared to controls

Cited by 196 publications

References 26 publications

Fibroblasts from chronic wounds show altered TGF‐β‐signaling and decreased TGF‐β Type II Receptor expression

Fibroblasts from chronic wounds show altered TGF‐β‐signaling and decreased TGF‐β Type II Receptor expression

rhEGF-loaded PLGA-Alginate microspheres enhance the healing of full-thickness excisional wounds in diabetised Wistar rats

A Pilot Study to Evaluate the Efficacy of IZN 6D4 for the Treatment of Diabetic Foot Ulcers

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