Reconstitution of Human Keloids in Mouse Skin

Sunaga, Ataru; Kamochi, Hideaki; Sarukawa, Shunji; Uda, Hirokazu; Sugawara, Yasuhiko; Asahi, Rintaro; Chi, Daekwan; Nakagawa, Shiho; Kanayama, Koji

doi:10.1097/gox.0000000000001304

Cited by 11 publications

(12 citation statements)

References 17 publications

(15 reference statements)

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“…The percentage induction of keloid tumors in the murine xenograft model of the present study is consistent with that of other workers [21,[41][42][43][44][45][46]. Our results showed that AKCs administered with hydroxyapatite (HA) produced 100% of keloid tumors in SCID mice and HNA staining confirmed that the tumors were indeed those of human origin.…”

Section: Discussionsupporting

confidence: 92%

Inhibition of growth of Asian keloid cells with human umbilical cord Wharton’s jelly stem cell-conditioned medium

Subramanian

Shen²,

Choolani

et al. 2020

Stem Cell Res Ther

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Background: Keloid formation occurs in Caucasian, African, and Asian populations and is a severe psychosocial burden on patients. There is no permanent treatment for this problem as its pathogenesis is not properly understood. Furthermore, differences in keloid behavior between ethnic groups are not known. It has been hypothesized that keloids behave like benign tumors because of their uncontrolled growth. The present study evaluated the tumoricidal properties of human Wharton's jelly stem cell-conditioned medium (hWJSC-CM) on fresh Asian keloid cells (AKCs). Methods: Human Wharton's jelly stem cells (hWJSCs) and AKCs were isolated based on our previous methods. hWJSCs and human skin fibroblasts (HSF) (controls) were used to collect hWJSC-CM and HSF-conditioned medium (HSF-CM). AKCs were treated with hWJSC-CM and HSF-CM in vitro and in vivo in a human keloid xenograft SCID mouse model. The inhibitory effect of hWJSC-CM on AKCs was tested in vitro using various assays and in vivo for attenuation/abrogation of AKC tumors created in a xenograft mouse model. Results: qRT-PCR analysis showed that the genes FN1, MMP1, and VCAN were significantly upregulated in AKCs and ANXA1, ASPN, IGFBP7, LGALS1, and PTN downregulated. AKCs exposed to hWJSC-CM in vitro showed significant decreases in cell viability and proliferation, increases in Annexin V-FITC+ cell numbers, interruptions of the cell cycle at Sub-G1 and G2/M phases, altered CD marker expression, downregulated anti-apoptotic-related genes, and upregulated pro-apoptotic and autophagy-related genes compared to controls. When AKCs were administered together with hWJSC-CM into immunodeficient mice there were no keloid tumors formed in 7 mice (n = 10) compared to the untreated control mice. When hWJSC-CM was injected directly into keloid tumors created in mice there were significant reductions in keloid tumor volumes and weights in 30 days.Conclusions: hWJSC-CM inhibited the growth of AKCs in vitro and in xenograft mice, and it may be a potential novel treatment for keloids in the human. The specific molecule(s) in hWJSC-CM that induce the anti-keloid effect need to be identified, characterized, and tested separately in larger preclinical and clinical studies.

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Section: Discussionsupporting

confidence: 92%

Inhibition of growth of Asian keloid cells with human umbilical cord Wharton’s jelly stem cell-conditioned medium

Subramanian

Shen²,

Choolani

et al. 2020

Stem Cell Res Ther

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“…38 Furthermore, prolonged presence of increased levels of type III collagen is indicative of white or keloid scarring. 39 The similarity in color ratios in both treatment and normal areas, along with the evident thinner collagen fibers, indicate that neocollagenesis, as opposed to scarring, is occurring. Increased vascularity with inflammatory infiltrates suggests active neovascularization.…”

Section: Discussionmentioning

confidence: 99%

Electrochemical Therapy of In Vivo Rabbit Cutaneous Tissue

et al. 2021

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Objectives: To examine the acid-base and histological changes in in vivo rabbit cutaneous tissue after electrochemical therapy.Study Design: In vivo rabbit tissue study.Methods: The shaved skin on the backs of female Oryctolagus cuniculi were assigned to treatments with or without tumescence with normal saline. Two platinum-needle electrodes were inserted into each treatment area and connected to a direct current (DC) power supply. Voltage (3-5 V) was varied and applied for 5 minutes. The wound-healing process was monitored via digital photography and ultrasonography until euthanasia at day 29. Treatment areas were biopsied, and specimens were sectioned through a sagittal midline across both electrode insertion sites. Samples were then evaluated utilizing light microscopy (hematoxylin and eosin, Masson's Trichrome, and Picrosirius red).Results: Treatment sites developed mild inflammation that dissipated at lower voltages or became scabs at higher voltages. Ultrasonography demonstrated acoustic shadowing with spatial spread that increased with increasing voltage application. The 4-and 5-V sites treated with saline had localized areas of increased tissue density at day 29. Although specimens treated with 3 V did not look significantly different from control tissue, 4-and 5-V samples with and without saline tumescence had finer, less-organized collagen fibers and increased presence of fibrocytes and inflammatory infiltrates.Conclusions: Electrochemical therapy caused localized injury to in vivo rabbit cutaneous tissue, prompting regenerative wound repair. With future development, this technology may offer precise, low-cost rejuvenation to restore the functionality and appearance of dermal scars and keloids.

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“…4 Existing models have succeeded in inducing hypertrophic (but not keloid) scar in wild-type 5 and immune-deficient mice, 6 rabbits 7 and red duroc pigs, 8 but although similar in appearance to keloids, they don't grow beyond the wound boundary. Other models use implantation of human keloid scar 9,10 or tissue-engineered keloid cells [11][12][13][14] on immune-deficient mice. While these models have found success in replicating a 'keloid-like' wound that grows beyond the wound boundary, there are inherent issues.…”

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confidence: 99%

The epigenetics of keloids

Stevenson

Deng

Allahham

et al. 2021

Experimental Dermatology

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Keloid scarring is a fibroproliferative disorder of the skin of unknown pathophysiology, characterised by fibrotic tissue that extends beyond the boundaries of the original wound. 1 Keloids develop as a result of disturbance to skin architecture by any wound, and have a strong genetic component, appearing in ethnicities with darker skin pigmentation. 1 There are estimated to be over 11 million keloids in the developed world, with the global number unknown but expected to be higher. 2 Current dogma suggests keloid development follows a similar pathway to normal wound healing but with chronic progression, suggesting disturbance in the fine control of cellular functions that occur during wound healing. 3 Epigenetics, defined as non-base-pair sequence alterations to the DNA, is a key regulator of cell functions, and aberrant epigenetic modifications have been found to contribute to many pathologies, including keloid scars. Our knowledge of progressive fibrosis remains limited, and therapeutic options are few and commonly ineffective, with keloids commonly recurring even after surgery and adjunct treatments. There is an urgent need to gain critical knowledge that will allow us to design better therapeutic strategies and provide evidence to support clinical decisions. This review will explore the current knowledge of the contribution of epigenetic modifications such as DNA methylation, histone modification, microRNAs, long non-coding RNAs to keloid scar formation and progression, and potential treatments utilising modifiers of these processes.

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Reconstitution of Human Keloids in Mouse Skin

Abstract: Supplemental Digital Content is available in the text.

Cited by 11 publications

References 17 publications

Inhibition of growth of Asian keloid cells with human umbilical cord Wharton’s jelly stem cell-conditioned medium

Inhibition of growth of Asian keloid cells with human umbilical cord Wharton’s jelly stem cell-conditioned medium

Electrochemical Therapy of In Vivo Rabbit Cutaneous Tissue

The epigenetics of keloids

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