Wound healing revised: A novel reepithelialization mechanism revealed by in vitro and in silico models

Safferling, Kai; Sütterlin, Thomas; Westphal, Kathi; Ernst, Claudia; Breuhahn, Kai; James, Merlin; Jäger, Dirk; Halama, Niels; Grabe, Niels

doi:10.1083/jcb.201212020

Cited by 140 publications

(104 citation statements)

References 71 publications

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“…19,20 However, our model provides a more biologically relevant context to study epithelial migration as a sheet and enables us to examine the support of this process by DFU-derived fibroblasts. 29 We found that incorporation of DFU-derived fibroblasts into this model recapitulated the impaired wound closure of DFUs. As we have previously shown that fibroblast-keratinocyte cross-talk directs re-epithelialization in this model, 12,28 our results further substantiate that DFU-derived fibroblasts have altered communication with keratinocytes.…”

Section: D In Vitro Chronic Wound Modelsmentioning

confidence: 86%

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Three-Dimensional Human Tissue Models That Incorporate Diabetic Foot Ulcer-Derived Fibroblasts Mimic In Vivo Features of Chronic Wounds

Maione

Brudno

Stojadinović

et al. 2015

Tissue Engineering Part C: Methods

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Diabetic foot ulcers (DFU) are a major, debilitating complication of diabetes mellitus. Unfortunately, many DFUs are refractory to existing treatments and frequently lead to amputation. The development of more effective therapies has been hampered by the lack of predictive in vitro methods to investigate the mechanisms underlying impaired healing. To address this need for realistic wound-healing models, we established patientderived fibroblasts from DFUs and site-matched controls and used them to construct three-dimensional (3D) models of chronic wound healing. Incorporation of DFU-derived fibroblasts into these models accurately recapitulated the following key aspects of chronic ulcers: reduced stimulation of angiogenesis, increased keratinocyte proliferation, decreased re-epithelialization, and impaired extracellular matrix deposition. In addition to reflecting clinical attributes of DFUs, the wound-healing potential of DFU fibroblasts demonstrated in this suite of models correlated with in vivo wound closure in mice. Thus, the reported panel of 3D DFU models provides a more biologically relevant platform for elucidating the cell-cell and cell-matrix-related mechanisms responsible for chronic wound pathogenesis and may improve translation of in vitro findings into efficacious clinical applications.

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Section: D In Vitro Chronic Wound Modelsmentioning

confidence: 86%

“…*p < 0.05. To determine the ability of fibroblasts to support wound re-epithelialization Re-epithelialization NHKs, HFFs, DFUF/DFF/NFF 12,28,29 Self-assembled ECM Figure 5 To evaluate fibroblast capacity to synthesize and assemble ECM de novo…”

Section: Discussionmentioning

confidence: 99%

Three-Dimensional Human Tissue Models That Incorporate Diabetic Foot Ulcer-Derived Fibroblasts Mimic In Vivo Features of Chronic Wounds

Maione

Brudno

Stojadinović

et al. 2015

Tissue Engineering Part C: Methods

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“…In the proliferation phase of the wound healing process, angiogenesis, collagen deposition, granulation tissue formation, re-epithelialization and wound contraction occur (Midwood et al 2004;Safferling et al 2013). Re-epithelialization of the epithelium occurs by proliferation and migration of epithelial cells atop of the wound bed providing cover for the new tissue (Safferling et al 2013). In this study, the proliferation and migration of oral mucosal cells treated with Pluchea indica extract and NPs containing Pluchea indica leaf extract were assessed to investigate the in vitro wound healing properties.…”

Section: Discussionmentioning

confidence: 99%

Wound healing activity of Pluchea indica leaf extract in oral mucosal cell line and oral spray formulation containing nanoparticles of the extract

Buranasukhon

Athikomkulchai

Tadtong

et al. 2017

Pharmaceutical Biology

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Context: Pluchea indica (L.) Less (Asteraceae) is an herb used as a traditional medicine for wound healing. The chemical compounds found in Pluchea indica leaves are phenolic acids, flavonoids, anthocyanins and carotenoids.Objective: This study investigates the effect of Pluchea indica leaf ethanol extract and its nanoparticles (NPs) on cytotoxicity, cell survival and migration of human oral squamous carcinoma cell line. Materials and methods: Cell viability was measured using MTT assay to assess the effect of Pluchea indica leaf extract and NPs (1-500 lg/mL) on cytotoxicity and cell survival. The effect of Pluchea indica leaf extract and NPs on cell migration was determined by scratch assay. The % relative migration was calculated after 24, 48 and 72 h of treatment.Results: The sizes of Pluchea indica leaf extract NPs were in a range of nanometers. NPs possessed negative charge with the polydispersity index (PDI) smaller than 0.3. After the treatment for 24, 48 and 72 h, Pluchea indica leaf extract had IC 50 value of 443.2, 350.9 and 580.5 lg/mL, respectively, whereas the IC 50 value of NPs after the treatment for 24, 48 and 72 h were 177.4, 149.2 and 185.1 lg/mL, respectively. The % relative migration of cells was significantly increased when the cells were treated with 62.5 and 125 lg/mL of the extract and 62.5 lg/mL of NPs. Discussion and Conclusions: NPs increased cytotoxicity of the Pluchea indica leaf extract, increased the migration of cells at low concentration and increased colloidal stability of the extract in an oral spray formulation. ARTICLE HISTORY

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“…These cells alter their keratin expression profiles, increase their metabolic activities, and collectively form a thickened epithelial front that traverses a bed of provisional matrix beneath the scab. 3,4 Numerous paracrine interactions between keratinocytes, fibroblasts and immune cells promote re-epithelialization, while intercellular signals such as FGF, HGF, TGF-b and EGF family members likely play key modulatory roles. 5,6 After the wound has resolved, most of the suprabasal acanthotic layers of the regenerated epithelium are lost as the skin gradually reverts to a more normal, IFE-like phenotype.…”

Section: Introductionmentioning

confidence: 99%

Hair follicle and interfollicular epidermal stem cells make varying contributions to wound regeneration

2015

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Upon wounding, multiple stem cell populations in the hair follicle (HF) and interfollicular epidermis (IFE) converge at the site of injury. Although these cells can contribute permanently to the regenerating epithelium, it remains unclear whether these contributions vary among cells originating from diverse compartments in the skin. By comparing the fates of several keratinocyte lineages, we observed here an initial decrease in both HF-and IFE-derived cells within the transient acanthotic layers of the regenerating epithelium. At the same time, the relative abundance of early-arriving IFE-derived cells specifically in the wound basal layer declined as later-arriving HF-derived cells entered the site of injury. Although laggard bulge-derived cells were typically constrained at the regenerative periphery, these cells persisted in the wound basal layer. Finally, suppressing Notch enabled IFE-derived cells to out-compete HF-derived cells. Taken together, these findings indicate that IFE-, HF-and bulge-derived cells make distinct contributions to regeneration over time. Furthermore, we speculate that extrinsic, non-genetic factors such as spatial constraint, distance from the wound, and basal versus suprabasal position may largely determine whether a cell ultimately persists.

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Wound healing revised: A novel reepithelialization mechanism revealed by in vitro and in silico models

Abstract: Experimental analysis and computational modeling of epidermal wound closure in 3D suggests an important role for surrounding tissue in determining epithelial cell movement and fate.

Cited by 140 publications

References 71 publications

Three-Dimensional Human Tissue Models That Incorporate Diabetic Foot Ulcer-Derived Fibroblasts Mimic In Vivo Features of Chronic Wounds

Three-Dimensional Human Tissue Models That Incorporate Diabetic Foot Ulcer-Derived Fibroblasts Mimic In Vivo Features of Chronic Wounds

Wound healing activity of Pluchea indica leaf extract in oral mucosal cell line and oral spray formulation containing nanoparticles of the extract

Hair follicle and interfollicular epidermal stem cells make varying contributions to wound regeneration

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