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1.
Mol Med Rep ; 21(3): 1224-1232, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31922245

RESUMO

The hysteresis of keratinocyte (KC) re­epithelialization is an important factor resulting in chronic wounds; however, the molecular mechanisms involved in this cellular response remain yet to be completely elucidated. The present study demonstrated the function of transcription factor Forkhead box O3a (FoxO3a) in KC growth and migration functional effects, resulting in restrained KC re­epithelialization during wound healing. In chronic wound tissue samples, the expression of FoxO3a was significantly increased when compared with the acute wound healing group (P<0.01). Overexpressing FoxO3a significantly inhibited, whereas silencing endogenous FoxO3a enhanced, the growth and migration of HaCaT cells in vitro. Further investigation revealed that FoxO3a negatively regulated matrix metalloproteinases 1 and 9, and increased the expression of tissue inhibitor of metalloproteinase 1. In addition, the upregulation of FoxO3a retarded, whereas the downregulation of FoxO3a accelerated, transforming growth factor­ß1­induced epithelial­mesenchymal transition in HaCaT cells. Mechanistically, the overexpression of FoxO3a inactivated ß­catenin signaling and markedly reduced the levels of nuclear ß­catenin. These results reveal a novel mechanism of FoxO3a in regulating KC re­epithelialization, and provide novel targets for the prevention and treatment of chronic wounds.

2.
Front Immunol ; 9: 240, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29483920

RESUMO

Dendritic epidermal T cells (DETCs) and dermal Vγ4 T cells engage in wound re-epithelialization and skin inflammation. However, it remains unknown whether a functional link between Vγ4 T cell pro-inflammation and DETC pro-healing exists to affect the outcome of skin wound closure. Here, we revealed that Vγ4 T cell-derived IL-17A inhibited IGF-1 production by DETCs to delay skin wound healing. Epidermal IL-1ß and IL-23 were required for Vγ4 T cells to suppress IGF-1 production by DETCs after skin injury. Moreover, we clarified that IL-1ß rather than IL-23 played a more important role in inhibiting IGF-1 production by DETCs in an NF-κB-dependent manner. Together, these findings suggested a mechanistic link between Vγ4 T cell-derived IL-17A, epidermal IL-1ß/IL-23, DETC-derived IGF-1, and wound-healing responses in the skin.


Assuntos
Interleucina-17/imunologia , Células de Langerhans/imunologia , Pele/lesões , Linfócitos T/imunologia , Cicatrização/imunologia , Animais , Células Cultivadas , Modelos Animais de Doenças , Regulação para Baixo/imunologia , Humanos , Fator de Crescimento Insulin-Like I/imunologia , Fator de Crescimento Insulin-Like I/metabolismo , Interferon gama/genética , Interferon gama/imunologia , Interferon gama/metabolismo , Interleucina-17/genética , Interleucina-17/metabolismo , Interleucina-1beta/imunologia , Interleucina-1beta/metabolismo , Queratinócitos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Cultura Primária de Células , Receptores de Antígenos de Linfócitos T gama-delta/genética , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Pele/citologia , Pele/imunologia , Linfócitos T/metabolismo
3.
J Tissue Eng Regen Med ; 12(2): e905-e917, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28097806

RESUMO

A porous structure is critically important for wound dressing or tissue engineering scaffolds. However, the influence of the pore sizes on cell proliferation, tissue regeneration and the underlying mechanism remains unclear. In this study, silicone rubber membranes with different pore sizes were prepared using certain constituents of liquid silicone rubber precursor/liquid paraffin/hexane based on our previous studies. It was found that pore size had a significant impact on cell proliferation and wound healing. The CCK8 analysis revealed that the membrane with a certain pore size (110.47 µm, middle pore membrane, MPM) was suitable for cell proliferation compared with the membranes with other pore sizes (218.03 µm, large pore membrane, LPM; 5.27 µm, small pore membrane, SPM; non-porous membrane, NPM). Further studies demonstrated that the MPM promoted cell proliferation via activating the Wnt/ß-catenin signalling pathway. More importantly, wound healing experiments showed that 7 days post-wounding, the rate of wound healing was 89.25% with the MPM, which was significantly higher than with LPM, SPM or NPM. The in vivo data indicated that wound healing was accelerated by treatment with a silicone rubber membrane with a pore size of 110.47 µm. Our results strongly suggest that different pore structures might affect cell proliferation and wound healing and that a silicone rubber membrane with a specific pore size could potentially be used as a promising wound dressing. Copyright © 2017 John Wiley & Sons, Ltd.


Assuntos
Membranas Artificiais , Regeneração/efeitos dos fármacos , Elastômeros de Silicone/farmacologia , Cicatrização/efeitos dos fármacos , Animais , Adesão Celular/efeitos dos fármacos , Adesão Celular/genética , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Camundongos Endogâmicos BALB C , Porosidade , Antígeno Nuclear de Célula em Proliferação/metabolismo , Reepitelização/efeitos dos fármacos , Reepitelização/genética , Via de Sinalização Wnt/efeitos dos fármacos , Via de Sinalização Wnt/genética , beta Catenina/metabolismo
4.
J Invest Dermatol ; 137(12): 2513-2522, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28733202

RESUMO

Activated γδ T cells have been shown to accelerate allograft rejection. However, the precise role of skin-resident γδ T cells and their subsets-Vγ5 (epidermis), Vγ1, and Vγ4 (dermis)-in skin graft rejection have not been identified. Here, using a male to female skin transplantation model, we demonstrated that Vγ4 T cells, rather than Vγ1 or Vγ5 T cells, accelerated skin graft rejection and that IL-17A was essential for Vγ4 T-cell-mediated skin graft rejection. Moreover, we found that Vγ4 T cells were required for early IL-17A production in the transplanted area, both in skin grafts and in the host epidermis around grafts. Additionally, the chemokine (C-C motif) ligand 20-chemokine receptor 6 pathway was essential for recruitment of Vγ4 T cells to the transplantation area, whereas both IL-1ß and IL-23 induced IL-17A production from infiltrating cells. Lastly, Vγ4 T-cell-derived IL-17A promoted the accumulation of mature dendritic cells in draining lymph nodes to subsequently regulate αß T-cell function after skin graft transplantation. Taken together, our data reveal that Vγ4 T cells accelerate skin graft rejection by providing an early source of IL-17A.


Assuntos
Rejeição de Enxerto/imunologia , Interleucina-17/metabolismo , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Transplante de Pele , Animais , Quimiocina CCL20/metabolismo , Quimiocinas/metabolismo , Feminino , Interleucina-23/metabolismo , Ligantes , Linfonodos/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Receptores CCR6/metabolismo , Pele/imunologia , Pele/metabolismo , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo
5.
Cell Physiol Biochem ; 42(5): 1755-1768, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28746918

RESUMO

Backgroud/Aims: The effects of rapamycin (RPM) on wound healing have been previously studied. However, reciprocal contradictory data have been reported, and the underlying mechanism remains unclear. This study aims to uncover differential role of RPM in regulation of wound healing and explore the possible mechanism. METHODS: C57BL/6J mice and epidermal cells were treated with different doses of RPM. The wound re-epithelialization was observed by hematoxylin and eosin (HE) staining. The expression of IL-15 and IGF-1 were detected by immunohistochemistry and quantitative real-time PCR. Epidermal cell survival was determined by CCK-8 assays. Moreover, the mTORC1 and mTORC2 pathway were examined by western blot analysis. RESULTS: This study showed that differential doses of RPM could lead to separate consequences in epidermis. Histological analyses showed that low-dose RPM promoted wound healing, and enhanced the expression of IL-15 and IGF-1. Furthermore, western blot analysis showed that the effect of low-dose RPM in epidermis were not through mTORC1 pathway. Instead, activation of the Akt/mTORC2 pathway was involved in low-dose RPM-induced IL-15 and IGF-1 production in epidermis, while high-dose RPM inhibited the expression of IL-15 and IGF-1 and the activity of mTORC1 and mTORC2 pathway. CONCLUSION: This study for the first time demonstrated that RPM-mediated wound healing was dose-dependent.


Assuntos
Fator de Crescimento Insulin-Like I/metabolismo , Interleucina-15/metabolismo , Alvo Mecanístico do Complexo 2 de Rapamicina/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sirolimo/farmacologia , Animais , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Células Epidérmicas , Epiderme/efeitos dos fármacos , Epiderme/metabolismo , Epiderme/patologia , Imuno-Histoquímica , Fator de Crescimento Insulin-Like I/genética , Interleucina-15/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação/efeitos dos fármacos , Reação em Cadeia da Polimerase em Tempo Real , Cicatrização/efeitos dos fármacos
6.
Sci Rep ; 6: 24596, 2016 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-27086569

RESUMO

A desirable microenvironment is essential for wound healing, in which an ideal moisture content is one of the most important factors. The fundamental function and requirement for wound dressings is to keep the wound at an optimal moisture. Here, we prepared serial polyurethane (PU) membrane dressings with graded water vapor transmission rates (WVTRs), and the optimal WVTR of the dressing for wound healing was identified by both in vitro and in vivo studies. It was found that the dressing with a WVTR of 2028.3 ± 237.8 g/m(2)·24 h was able to maintain an optimal moisture content for the proliferation and regular function of epidermal cells and fibroblasts in a three-dimensional culture model. Moreover, the dressing with this optimal WTVR was found to be able to promote wound healing in a mouse skin wound model. Our finds may be helpful in the design of wound dressing for wound regeneration in the future.


Assuntos
Bandagens/efeitos adversos , Reepitelização , Animais , Proliferação de Células , Células Cultivadas , Células Epiteliais/metabolismo , Células Epiteliais/fisiologia , Fibroblastos/metabolismo , Fibroblastos/fisiologia , Umidade , Masculino , Membranas Artificiais , Camundongos , Camundongos Endogâmicos BALB C , Poliuretanos/química , Porosidade , Volatilização
7.
Zhonghua Shao Shang Za Zhi ; 31(2): 125-9, 2015 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-26320318

RESUMO

OBJECTIVE: To explore the role of dentritic epidermal T lymphocytes ( DETCs) in immune rejection of skin allograft in mice and its related mechanism. Methods (1) Full-thickness skin was harvested from back of one male wild type (WT) C57BL/6 mouse. Epithelial cells were isolated for detection of the expression of DETCs and their phenotype with flow cytometer. Another male WT C57BL/6 mouse was used to harvest full-thickness skin from the back. Epidermis was isolated for observation of the morphological characteristics of DETCs with immunofluorescence technology. (2) Four male green fluorescence protein (GFP)-marked C57BL/6 mice, 7 female WT C57BL/6 mice (group WT), and 7 female ybT lymphocytes 8 gene knock-out (GK) C57BL/6 mice (group GK) were used. Full-thickness skin in the size of 1.4 cm x 1.4 cm on the back of mice in groups WT and GK were excised, and the wounds were transplanted with full-thickness skin in the size of 1.2 cm x 1.2 cm obtained from male GFP-marked C57BL/6 mice. The survival time of skin grafts was affirmed with small animal in vivo imager and naked eyes and recorded. (3) Two male WT C57BL/6 mice were used to isolate epithelial cells. Cells were inoculated into 48-well plate and divided into activation group (A) and control group (C) according to the random number table, with 4 wells in each group. Cells in group A were treated with 10 pL concanavalin A in the concentration of 2 microg/mL for 24 hours, while those in group C with PBS in the same volume as that in group A. The expression of interferon y in DETCs was detected with flow cytometer. (4) Four male GFP-marked C57BL/6 mice were used as donors. Fourteen female WT C57BL/6 mice were used as receptors and divided into interferon gamma neutralizing group (IN) and control group (C) according to the random number table, with 7 mice in each group. The skin transplantation model of C57BL/6 male to C57BL/6 female was established as in part (2). Before surgery and 72 hours after, mice in group IN were intraperitoneally injected with 200 pL interferon y neutralizing antibody in the concentration of 1 mg/mL, and those in group C with normal saline in the same volume as that in group IN. The survival time of skin grafts was observed and recorded using the methods in part (2), and the result of group IN was compared with that of group GK in part (2). The survival curve of skin grafts was processed with Log-rank ( Mantel-Cox) test. Results (1) The positive expression rate of DETCs in epithelial cells of skin in mouse was 7.27%, and they were all CD3 cells. DETCs were found to be scattered in the epidermis of skin in mouse with dendritic morphology. (2) The survival time of skin grafts of mice in group GK was 22-35 d, obviously longer than that in group WT (12-16 d, y2 = 14. 10 , P < 0.001). (3) Expression of interferon gamma was detected in 22. 70% DETCs in group A, which was obviously higher than that in group C (0.51%). (4) The survival time of skin grafts of mice in group IN was 19-24 d, which was obviously longer than that in group C (12-16 d, chi 2 = 13.60, P < 0.001) but close to that in group GK as in part (2) (chi2 = 0.06, P = 0.810). Conclusions DETCs are involved in promotion of immune rejection of skin allograft probably by secretinf interferon gamma.


Assuntos
Sobrevivência de Enxerto/fisiologia , Interferon gama/metabolismo , Transplante de Pele , Linfócitos T/imunologia , Aloenxertos , Animais , Epiderme , Feminino , Sobrevivência de Enxerto/imunologia , Interferon gama/imunologia , Linfócitos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pele
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