E2F1 Hinders Skin Wound Healing by Repressing Vascular Endothelial Growth Factor (VEGF) Expression, Neovascularization, and Macrophage Recruitment

Wang, Ningning; Wu, Yiping; Zeng, Ning; Wang, Haiping; Deng, Pei; Xu, Yi; Feng, Yun‐Zhi; Zeng, Hong; Yang, Hongxia; Hou, Kai; Wang, Andrew; Parthasarathy, Keshav; Goyal, Sunali; Qin, Gangjian; Wu, Min

doi:10.1371/journal.pone.0160411

Cited by 11 publications

(10 citation statements)

References 27 publications

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“…Wound healing process is mediated by multiple steps including cells proliferation, extracellular matrix deposition, angiogenesis, and remodeling (Eming, et al, 2014). Enhancement production of collagen and angiogenesis is one of the crucial factors contributing to the optimum wound healing (Falanga, 2005;Wang, et al, 2016). The transforming growth factor β (TGF-β) and platelet derived growth factor (PDGF) have a crucial role in activating fibroblast leading to enhancement collagen disposition.…”

Section: Introductionmentioning

confidence: 99%

The Role of Hypoxic Mesenchymal Stem Cells Conditioned Medium in Increasing Vascular Endothelial Growth Factors (VEGF) Levels and Collagen Synthesis to Accelerate Wound Healing

Sunarto

Trisnadi

Putra

et al. 2020

Indones J Cancer Chemoprevent

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Full-thickness wound are areas damage of skin associated with loss of epidermis and dermis. The wound healing mechanism consists proliferation, migration and remodeling. Hypoxic conditional medium of mesenchymal stem cells (HMSCs-CM) contains lots of soluble molecules, such as protein growth factor and cytokine anti-inflammation. The soluble molecule of HMSCs-CM plays a critical role in wound healing by upregulation of VEGF and collagen synthesis. The objective of this study was to evaluate the effect of HMSCs-CM on VEGF and collagen concentrations in rats with incised wounds. The methods of this study were an experimental animal study with post-test only control group design was performed involving 24 Wistar rats. The rats were randomized into four groups consisting of sham, control and two treatment groups (gel of HMSCs-CM at doses of 200 μL and 400 μL). The VEGF levels and collagen density were analyses using ELISA assay and Masson-trichome specific staining, respectively. One-way ANOVA and Post Hoc LSD were used to analyses the data. The results of this study showed that a VEGF levels was significant increased on day 6 with doses-dependent manner. Interestingly, the VEGF levels gradual decrease on day 9. In addition, the decreased of VEGF levels on day 9 in this study in line with our findings in which we found there was a trend in the decreased of collagen density, it indicated the completion of remodeling phase and there has been an acceleration in wound healing. This study demonstrated that HMSCs-CM were able to regulate VEGF levels and collagen synthesis in accelerate wound healing. The role of HMSCs-CM stimulate cutaneous wound healing should be clarified further.Keywords: hypoxic conditional medium of mesenchymal stem cells (HMSCs-CM), vascular endothelial growth factor, collagen synthesis, paracrine factors

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Section: Introductionmentioning

confidence: 99%

The Role of Hypoxic Mesenchymal Stem Cells Conditioned Medium in Increasing Vascular Endothelial Growth Factors (VEGF) Levels and Collagen Synthesis to Accelerate Wound Healing

Sunarto

Trisnadi

Putra

et al. 2020

Indones J Cancer Chemoprevent

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“…23,24 Recruitment of additional M2 macrophages can accelerate the wound healing process in the later phase via activation of fibroplasia and epidermal regeneration. 16 E2F1 is classically considered an active transcription factor because of its overexpression trans-activates target genes and leads to cell-cycle progression. 25 In our studies, we intend to investigate the effect of E2F1 on the phenotypic changes of macrophages during the wound healing process.…”

Section: Discussionmentioning

confidence: 99%

“…Skin wound healing model was induced in male E2F1 −/− mice and their WT littermates (6-8 weeks old) as we described previously, and creating the model with the method as before. 16 Briefly, The WT and E2F1 −/− mice were shaved on the dorsum, and a full-thickness dorsal skin defect was created on the dorsal midline by using a 10 mm diameter biopsy punch for the evaluation of wound healing. The percentage of wound closure was calculated by using the following equation:…”

Section: Surgical Induction Of Skin Wound Healing Modelmentioning

confidence: 99%

“…15 At the wound site, mice with deletion of the E2F1 gene showed increased expression of VEGF and enhanced macrophage recruitment, which was associated with accelerated wound healing. 16 However, whether E2F1 mediates the M1/M2 polarization during the wound healing processes is not known. This study was conducted to evaluate the effect of the E2F1 genotype on peroxisome proliferatoractivated receptor (PPAR-γ) with regard to the M1/M2 polarization.…”

Section: Introductionmentioning

confidence: 99%

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Knockout of E2F1 enhances the polarization of M2 phenotype macrophages to accelerate the wound healing process

Yang

et al. 2020

The Kaohsiung J of Med Scie

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Wound healing is a complex process, which is classically divided into inflammation, proliferation, and remodeling phases. Macrophages play a key role in wound healing, however, whether E2F1 mediates the M1/M2 polarization during the wound healing process is not known. Skin wounds were surgically induced in E2F1−/− mice and their WT littermates. At day 2 and day 7 post‐surgery, the wounded skin tissues including 2 to 3 mm normal skin were obtained. The wounded skin tissues were used for the analyses of immunofluorescence staining (CD68, iNOS, CD206), western blotting (CD68, iNOS, CD206, PPAR‐γ) and Co‐immunoprecipitation (E2F1‐PPAR‐γ interactions). E2F1−/− mice exhibited faster wound healing process. At day 2, the M2 macrophages were remarkably increased in the E2F1−/− mice. Surprisingly, in the border zone of the wound, E2F1−/− mice had also more M2 macrophages and fewer M1 macrophages at day 7 post‐surgery, suggesting a certain degree of polarization amongst the M1 and M2 phenotypes. Co‐IP revealed that E2F1 indeed interacted with PPAR‐γ, meanwhile western blotting and RT‐PCR showed higher expression of PPAR‐γ in the E2F1−/− mice as compared to that in the WT mice. Therefore, the findings suggest that wound healing process could be accelerated with enhanced M2 polarization through increased PPAR‐γ expression in E2F1 knockout mice.

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“…However, the mechanisms governing resolution of inflammation remains unclear in the process of wound healing. Various cells, such as neutrophils 13 , macrophages 14 , 15 has been reported to participated in the regulation of inflammation during wound healing. Recently, Aguirre 16 found that fibroblasts could also regulate inflammation by interacting with T cells in intestinal.…”

Section: Introductionmentioning

confidence: 99%

Fibroblast-like cells Promote Wound Healing via PD-L1-mediated Inflammation Resolution

Wang¹,

Guo²,

Qiu³

et al. 2022

Int. J. Biol. Sci.

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Chronic non-healing wounds fail to progress beyond the inflammatory phase, characterized by a disorder of inflammation resolution. PD-1/PD-L1, a major co-inhibitory checkpoint signaling, plays critical roles in tumor immune surveillance and the occurrence of inflammatory or autoimmune diseases, but its roles in wound healing remains unclear. Here, we described a novel function of PD-L1 in fibroblast-like cells as a positive regulator of wound healing. PD-L1 dynamically expressed on the fibroblast-like cells in the granulation tissue during wound healing to form a wound immunosuppressive microenvironment, modulate macrophages polarization from M1-type to M2-type, and initiates resolution of inflammation, finally accelerate wound healing. Loss of PD-L1 delayed wound healing, especially in mice with LPS-induced severe inflammation. Furthermore, the mainly regulatory mechanism is that combination of FGF-2 and TGF-β1 promotes PD-L1 translation in fibroblasts through enhancing the eIF4E availability regulated by both PI3K-AKT-mTOR-4EBP1 and p38-ERK-MNK signaling pathways. Our results reveal the positive role of PD-L1 in wound healing, and provide a new strategy for the treatment of chronic wounds.

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E2F1 Hinders Skin Wound Healing by Repressing Vascular Endothelial Growth Factor (VEGF) Expression, Neovascularization, and Macrophage Recruitment

Cited by 11 publications

References 27 publications

The Role of Hypoxic Mesenchymal Stem Cells Conditioned Medium in Increasing Vascular Endothelial Growth Factors (VEGF) Levels and Collagen Synthesis to Accelerate Wound Healing

The Role of Hypoxic Mesenchymal Stem Cells Conditioned Medium in Increasing Vascular Endothelial Growth Factors (VEGF) Levels and Collagen Synthesis to Accelerate Wound Healing

Knockout of E2F1 enhances the polarization of M2 phenotype macrophages to accelerate the wound healing process

Fibroblast-like cells Promote Wound Healing via PD-L1-mediated Inflammation Resolution

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