Aberrant Notch signalling contributes to hypertrophic scar formation by modulating the phenotype of keratinocytes

Li, Bing; Gao, Chao; Diao, Jian-Sheng; Wang, Da-Lei; Chu, Feifei; Li, Yang; Wang, Gang; Guo, Shuzhong; Xia, Wei

doi:10.1111/exd.12897

Cited by 20 publications

(14 citation statements)

References 26 publications

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“…Jagged1 upregulation in pulmonary capillary endothelial cells induces Notch signaling in lung fibroblasts, which results in fibrosis [ 11 ].Zhu et al showed that Notch signaling is elevated during PDF-induced peritoneal fibrosis [ 12 ]. In addition, the Notch pathway was hyperactivated in skin biopsy samples from patients with scleroderma [ 13 , 14 ].…”

Section: Discussionmentioning

confidence: 99%

Reversal effect of Jagged1 signaling inhibition on CCl4-induced hepatic fibrosis in rats

et al. 2017

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The role of the Notch ligand Jagged1 in hepatic fibrosis remains to be elucidated. In the current study, we investigated the role of Jagged1 in the activation of hepatic stellate cells (HSCs) and development of hepatic fibrosis in rats. In vitro, Jagged1 in HSCs was downregulated and upregulated by Jagged1 siRNA and pcDNA3.1 Jagged1, respectively. The levels of epithelial-mesenchymal transition (EMT) markers and HSC activation markers were assessed using western blot analysis. The proliferation and migration capacity of HSCs were assessed using 5-ethynyl-2′-deoxyuridine (EdU) incorporation and Transwell migration assays. In vivo, a recombinant adeno-associated virus type 1 (rAAV1) vector carrying Jagged1 shRNA (rAAV1-Jagged1-shRNA) was constructed and transferred to rat livers via the tail vein. Reversion of liver fibrosis and the effect of Jagged1 signaling on EMT were studied using pathological, immunohistochemical and immunofluorescence methods. Our findings revealed that downregulation and upregulation of Jagged1 inhibited and promoted, respectively, HSC activation. The migratory capacity of HSCs was markedly restrained by Jagged1 siRNA. Furthermore, downregulation of Jagged1 suppressed EMT in HSCs. rAAV1-Jagged1-shRNA was generated to treat CCl4-induced hepatic fibrosis in rats. Treatment with rAAV1-Jagged1-shRNA reversed hepatic fibrosis by decreasing EMT. The results of the present study suggest that inhibition of Jagged1 is a potential treatment to ameliorate liver fibrosis.

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Section: Discussionmentioning

confidence: 99%

Reversal effect of Jagged1 signaling inhibition on CCl4-induced hepatic fibrosis in rats

et al. 2017

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“…Since Notch and TGF-β signaling converges in HS formation regulation ( 8 , 27 ), we further evaluated the expression of key molecules in these signaling pathways in macrophages isolated from PVA exudates. The macrophages from emodin-treated rats had significantly decreased protein levels of Notch1, Notch4, and Hes1 compared with those from the Control group ( Figure 5A ; Notch1, P<0.01, Figure 5B ; Notch4, P<0.01, Figure 5C ; Hes1, P<0.05, Figure 5D ).…”

Section: Resultsmentioning

confidence: 99%

“…Collectively, these results suggested that TGF-b downregulation was involved in emodin-suppressed HS formation and fibrosis in rats. Emodin inhibited the Notch and TGF-b signaling pathways in macrophages from PVA sponge-induced wound in rats Since Notch and TGF-b signaling converges in HS formation regulation (8,27), we further evaluated the expression of key molecules in these signaling pathways in macrophages isolated from PVA exudates. The macrophages from emodin-treated rats had significantly decreased protein levels of Notch1, Notch4, and Hes1 compared with those from the Control group (Figure 5A; Notch1, Po0.01, Figure 5B; Notch4, Po0.01, Figure 5C; Hes1, Po0.05, Figure 5D).…”

Section: Emodin Downregulated Tgf-b Expression In Pva Exudatesmentioning

confidence: 99%

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Emodin alleviates hypertrophic scar formation by suppressing macrophage polarization and inhibiting the Notch and TGF-β pathways in macrophages

Xia

Wang

Yang

et al. 2021

Braz J Med Biol Res

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Hypertrophic scar (HS) formation is a common complication that develops after skin injury; however, there are few effective and specific therapeutic approaches for HS. Emodin has previously been reported to inhibit mechanical stress-induced HS inflammation. Here, we investigated the molecular mechanisms underlying the inhibitory effects of emodin on HS formation. First, we conducted in vitro assays that revealed that emodin inhibited M1 and M2 polarization in rat macrophages. We subsequently established a combined rat model of tail HS and dorsal subcutaneous polyvinyl alcohol (PVA) sponge-induced wounds. Rats were treated with emodin or vehicle (DMEM). Tail scar specimens were harvested at 14, 28, and 42 days postincision and subjected to H&E staining and Masson's trichrome staining. Histopathological analyses confirmed that emodin attenuated HS formation and fibrosis. Macrophages were separated from wound cells collected from the PVA sponge at 3 and 7 days after implantation. Flow cytometry analysis demonstrated that emodin suppressed in vivo macrophage recruitment and polarization at the wound site. Finally, we explored the molecular mechanisms of emodin in modulating macrophage polarization by evaluating the expression levels of selected effectors of the Notch and TGF-b pathways in macrophages isolated from PVA sponges. Western blot and qPCR assays showed that Notch1, Notch4, Hes1, TGF-b, and Smad3 were downregulated in response to emodin treatment. Taken together, our findings suggested that emodin attenuated HS formation and fibrosis by suppressing macrophage polarization, which is associated with the inhibition of the Notch and TGF-b pathways in macrophages.

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“…Abnormal keratinocyte differentiation and their abnormal cytokine secretion are two factors demonstrated to contribute to tissue fibrosis and contraction by activating fibroblasts 74-76. The epidermis maintained its original appearance in the PHCS group, and epidermal ulcers were soon covered with new, thin epidermis within 3 days in the HCS group; while the STSG group showed less recovery (Figure 5).…”

Section: Discussionmentioning

confidence: 99%

Pre-vascularization Enhances Therapeutic Effects of Human Mesenchymal Stem Cell Sheets in Full Thickness Skin Wound Repair

et al. 2017

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Split thickness skin graft (STSG) implantation is one of the standard therapies for full thickness wound repair when full thickness autologous skin grafts (FTG) or skin flap transplants are inapplicable. Combined transplantation of STSG with dermal substitute could enhance its therapeutic effects but the results remain unsatisfactory due to insufficient blood supply at early stages, which causes graft necrosis and fibrosis. Human mesenchymal stem cell (hMSC) sheets are capable of accelerating the wound healing process. We hypothesized that pre-vascularized hMSC sheets would further improve regeneration by providing more versatile angiogenic factors and pre-formed microvessels. In this work, in vitro cultured hMSC cell sheets (HCS) and pre-vascularized hMSC cell sheets (PHCS) were implanted in a rat full thickness skin wound model covered with an autologous STSG. Results demonstrated that the HCS and the PHCS implantations significantly reduced skin contraction and improved cosmetic appearance relative to the STSG control group. The PHCS group experienced the least hemorrhage and necrosis, and lowest inflammatory cell infiltration. It also induced the highest neovascularization in early stages, which established a robust blood micro-circulation to support grafts survival and tissue regeneration. Moreover, the PHCS grafts preserved the largest amount of skin appendages, including hair follicles and sebaceous glands, and developed the smallest epidermal thickness. The superior therapeutic effects seen in PHCS groups were attributed to the elevated presence of growth factors and cytokines in the pre-vascularized cell sheet, which exerted a beneficial paracrine signaling during wound repair. Hence, the strategy of combining STSG with PHCS implantation appears to be a promising approach in regenerative treatment of full thickness skin wounds.

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Aberrant Notch signalling contributes to hypertrophic scar formation by modulating the phenotype of keratinocytes

Cited by 20 publications

References 26 publications

Reversal effect of Jagged1 signaling inhibition on CCl4-induced hepatic fibrosis in rats

Reversal effect of Jagged1 signaling inhibition on CCl4-induced hepatic fibrosis in rats

Emodin alleviates hypertrophic scar formation by suppressing macrophage polarization and inhibiting the Notch and TGF-β pathways in macrophages

Pre-vascularization Enhances Therapeutic Effects of Human Mesenchymal Stem Cell Sheets in Full Thickness Skin Wound Repair

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