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Scarring is a major cause of many clinical problems. Scar tissue interferes with growth, impairs function and is aesthetically unpleasant. However, scarring does not appear to be a problem of embryonic life. Embryonic wounds heal with a lower inflammatory and angiogenic response and have a different growth factor profile compared to adult wounds. W...
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... 28 days post-wounding, there were no differences between the experimental and any of the control wounds in groups IV and V. Wounds treated with neutralising antibody to TGF-β in groups I, II and III showed an improvement in the dermal architecture as demonstrated by Picrosirius red and Masson's trichrome staining whilst there was scarring in the control, sham control and TGF-β 1-treated wounds in all groups ( Fig. 6 and Table 7). The collagen content of these wounds did not show any significant differences (Table 8). ...
Similar publications
Exogenous addition of neutralising antibody to transforming growth factor-beta 1,2 to cutaneous wounds in adult rodents reduces scarring. Three isoforms of transforming growth factor-beta (1, 2 and 3) have been identified in mammals. We investigated the isoform/isoforms of TGF-beta responsible for cutaneous scarring by: (i) reducing specific endoge...
Citations
... Fibroblasts play a crucial role in cutaneous wound repair. This also explains why trauma is associated with the formation of extracellular matrix component-rich scar tissues that lack HFs [43][44][45]. Sustained activation of the canonical Wnt pathway in the adult epidermis induces the growth of existing HFs (anagen), the formation of new HFs [46], the proliferation of fibroblasts, and the remodeling of the dermal extracellular matrix [47,48]. Since epidermal Wnt signaling promotes HF growth, the expansion of the lower dermis may explain why the skin adipocyte layer increases in thickness during aging. ...
Wool is produced and controlled by hair follicles (HFs). However, little is known about the mechanisms involved in HF development and regulation. Sheep dermal fibroblasts (SDFs) play a key role in the initial stage of HF development. Analyzing the molecular mechanism that regulates early HF development in superfine wool sheep is of great importance for better understanding the HF morphogenesis process and for the breeding of fine wool sheep. Here, we show that two microRNAs (miRNAs) affect the development of HFs by targeting two genes that are expressed by SDFs. Meanwhile, the overexpression and inhibition of oar-miR-23b and oar-miR-133 in SDFs cells and cell proliferation, apoptosis, and migration were further detected using a CCK-8 assay, an Annexin V-FITC assay, a Transwell assay, and flow cytometry. We found that oar-miR-23b, oar-miR-133, and their cotarget genes TGFβ2 and NOTCH1 were differentially expressed during the six stages of HF development in superfine wool sheep. Oar-miR-23b and oar-miR-133 inhibited the proliferation and migration of SDFs and promoted the apoptosis of SDFs through TGFβ2 and NOTCH1. oar-miR-23b and oar-miR-133 inhibited the proliferation and migration of SDFs by jointly targeting TGFβ2 and NOTCH1, thereby inhibiting the development of superfine wool HFs. Our research provides a molecular marker that can be used to guide the breeding of ultrafine wool sheep.
... TGF-β1 is incriminated in several phases of the wound healing process, including several proliferative, regulatory, and inductive processes (Bitzer et al. 1998). In the proliferative phase, TGF-β1 stimulated the process of angiogenesis (Sporn et al 1986) as well as controlling the extracellular matrix components in the maturation phase (Shah et al 1994) and could improve tissue repair function via stimulation immune response (Wahl 1992). Zn is a crucial TGF-β1/SMAD pathway cofactor that promotes granulation tissue production (Maywald et al 2017b). ...
The experiment was designed to examine the influence of employing three doses of ZnSO 4 on the wound healing process in partially scaled common carp. A total of 240 healthy common carp fish (52.3 ± 0.9 g) were randomly allocated into four equal groups in triplicate (20 each). The first group left without any zinc sulfate treatment and served as a control group, while the second group through the fourth group were immersed in a zinc sulfate bath at a dose of 2.09, 1.05, and 0.53 mg/L corresponding to 1/5, 1/10, and 1/20 of 96 h LC 50 of Zn, (Zn/5, Zn/10, and Zn/20, respectively). After wound induction, tissue specimens were collected within three different intervals (6 h, 24 h, 72 h, and 14 days). The results indicated that the Zn/5 fish group induced doubled folding increments in the expression of transforming growth factor (TGF)-β1 after 6 h compared to other groups, whereas collagen type I alpha 1 (COL1α1) and metallothionein (Met) genes exhibited a triple folding increment compared to Zn/10 and a fivefold increase compared to control after two days of wound induction. Moreover, vascular endothelial growth factor (VEGF)-A and fibroblast growth factor (FGF)-7 genes showed a dose-dependent manner of expression at all examined points after wound induction. Also, all estimated antioxidant biomarker (superoxide-dismutase, SOD; catalase, CAT; glutathione, GSH; and malonaldehyde, MDA) activities were boosted in the Zn/5 group till three days of wound induction compared to all groups. In addition, the reepithelization score and histological alteration results revealed clear improvement in the Zn/5 group, as most muscle fibers appeared regular, straight, and parallel arranged. In contrast, other groups exhibited a detectable limited area of disrupted muscle fibers. Finally, it could be concluded that the ZnSO 4 immersion bath at 1/5 of the calculated LC 50 effectively enhanced the healing process and skin reepithelization.
... Fibroblasts play a crucial role in cutaneous wound repair. This also explains why trauma is associated with the formation of extracellular matrix component-rich scar tissues that lack HFs [42][43][44]. Sustained activation of the canonical Wnt pathway in the adult epidermis induces the growth of existing HFs (anagen), the formation of new HFs [45], the proliferation of broblasts and the remodeling of the dermal extracellular matrix [46,47]. Since epidermal Wnt signaling promotes HF growth, the expansion of the lower dermis may explain why the skin adipocyte layer increases in thickness during aging. ...
Background
Wool, which is a pure natural textile fiber raw material, has high economic value and is increasingly favored by modern textile enterprises and consumers. The output of fine wool, especially high-quality superfine wool, in China is far from meeting the processing needs of the textile market. Therefore, improving the yield and quality of wool has always been a focus of research related to fine wool sheep breeding. Wool is produced and controlled by hair follicles (HFs). However, little is known about the mechanisms involved in HF development and regulation. The structure, function and morphogenesis of HFs are complex biological processes. Sheep dermal fibroblasts (SDFs) play a key role in the initial stage of HF development. Analyzing the molecular mechanism that regulates early HF development in superfine wool sheep is of great importance for better understanding the HF morphogenesis process and for the breeding of fine wool sheep. Here, we show that two microRNAs (miRNAs) affect the development of HFs by targeting two genes that are expressed by SDFs.
Results
On the basis of our previous research, we further found that oar-miR-23b and oar-miR-133 and their cotarget genes TGFβ2 and NOTCH1 were differentially expressed during the six stages of HF development in superfine wool sheep. Overexpression/inhibition of oar-miR-23b and oar-miR-133 in SDFs showed that oar-miR-23b and oar-miR-133 inhibited the proliferation and migration of SDFs and promoted the apoptosis of SDFs through TGFβ2 and NOTCH1. By analyzing genes that are upstream and downstream of the target genes, we found that oar-miR-23b and oar-miR-133 affected the expression of genes in the TGF-β, Hippo and WNT signaling pathways.
Conclusion
oar-miR-23b and oar-miR-133 inhibit the proliferation and migration of SDFs by jointly targeting TGFβ2 and NOTCH1, thereby inhibiting the development of super fine wool HFs. Our research provides a molecular marker that can be used to guide the breeding of ultrafine wool sheep.
... Furthermore, exogenous TGF-β1 expression within fetal wounds results in increased fibrosis (Fig. 2) [33]. Shah et al. conducted studies where they neutralized TGF-β1 in adult wounds, resulting in no scar formation at the wound site [45]. In addition to age-related differences in TGF-β1 responses in healing, sex-specific differences have also been noted. ...
Chronic non-healing wounds are a significant healthcare challenge. Various biomaterials have been developed to treat chronic wounds but there are still opportunities for improvement of biomaterial therapeutics. This review discusses how fetal wound healing could be used as inspiration to develop pro-healing materials. Compared to adults, fetuses have enhanced wound healing outcomes and healing without scarring. Scarless fetal wound healing is associated with various key differences in several growth factors, cytokines, extracellular matrix components, and coagulation parameters. Mimicking the fetal wound healing environment through bioinspired materials could create improved therapeutics to treat chronic wounds. This review addresses the key differences between adult and fetal wound healing that allow for enhanced scarless fetal healing and discusses how these differences can be used to develop pro-healing materials.
... TGFb prominently increases the accumulation of ECM in the myocardium by inhibiting MMP expression [45,46]. Downregulation of TGFb by antibodies could suppress ECM expression and deposition [47,48]. After cardiac infarction, TGFb suppresses the inflammation in cardiac healing processes, regulating fibroblast phenotypes, and stimulating ECM deposition at the infarcted zone by increasing collagen synthesis and inhibiting the degradation of the matrix via the induction of protease inhibitors [45]. ...
Cardiac fibrosis is closely associated with multiple heart diseases, which are a prominent health issue in the global world. Neurohormones and cytokines play indispensable roles in cardiac fibrosis. Many signaling pathways participate in cardiac fibrosis as well. Cardiac fibrosis is due to impaired degradation of collagen and impaired fibroblast activation, and collagen accumulation results in increasing heart stiffness and inharmonious activity, leading to structure alterations and finally cardiac function decline. Herbal plants have been applied in traditional medicines for thousands of years. Because of their naturality, they have attracted much attention for use in resisting cardiac fibrosis in recent years. This review sheds light on several extracts from herbal plants, which are promising therapeutics for reversing cardiac fibrosis.
... Increased fibroblast activity leads to elevated production of extracellular matrix, especially collagen I and collagen III, and abnormal scar tissue formation. Antibodies against TGF-β1 can reduce scar tissue formation [7][8][9][10][11][12][13]. Studies have shown that the activation of the phosphoinositide 3-kinase/RAC-α serine/threonine-protein kinase (PI3K/Akt/mTOR) pathway can enhance KF cell proliferation, migration and invasion and promote the expression of collagen I and III [14][15][16]. ...
Background:
Keloids are abnormal fibrous hyperplasias that are difficult to treat. Melatonin can be used to inhibit the development of certain fibrotic diseases but has never been used to treat keloids. We aimed to discover the effects and mechanisms of melatonin in keloid fibroblasts (KFs).
Methods:
Flow cytometry, CCK-8 assays, western blotting, wound-healing assays, transwell assays, collagen gel contraction assays and immunofluorescence assays were applied to demonstrate the effects and mechanisms of melatonin in fibroblasts derived from normal skin, hypertrophic scars and keloids. The therapeutic potential of the combination of melatonin and 5-fluorouracil (5-FU) was investigated in KFs.
Results:
Melatonin significantly promoted cell apoptosis and inhibited cell proliferation, migration and invasion, contractile capability and collagen production in KFs. Further mechanistic studies demonstrated that melatonin could inhibit the cAMP/PKA/Erk and Smad pathways through the membrane receptor MT2 to alter the biological characteristics of KFs. Moreover, the combination of melatonin and 5-FU remarkably promoted cell apoptosis and inhibited cell migration and invasion, contractile capability and collagen production in KFs. Furthermore, 5-FU suppressed the phosphorylation of Akt, mTOR, Smad3 and Erk, and melatonin in combination with 5-FU markedly suppressed the activation of the Akt, Erk and Smad pathways.
Conclusions:
Collectively, melatonin may inhibit the Erk and Smad pathways through the membrane receptor MT2 to alter the cell functions of KFs, while combination with 5-FU could exert even more inhibitory effects in KFs through simultaneous suppression of multiple signalling pathways.
... The role of transforming growth factor β in reducing scar formation has been described, 34 and it has been reported that BNP reduces myocardial scar formation by blocking transforming growth factor β. 35 An in vitro proof-of-principal study revealed the presence of BNP around collagen, epithelial cells, and endothelial cells in human burned skin; in contrast, no BNP was observed in unscarred skin samples, indicating that BNP may be involved in skin wound healing and scarring. 36 Further studies reported the responsiveness of fibroblasts to BNP 37 and the improvement in the gross appearance of scars but without any histologic difference compared with controls in a rat burn model. ...
In addition to being a pump, the heart also has an endocrine function. The peptides synthesized and secreted from the heart may exert endocrine, autocrine, and paracrine effects. The natriuretic peptides are a family of vasoactive hormones that play a dominant role in the regulation of cardiovascular and renal homeostasis. The 2 major hormones synthesized by the heart are the atrial and the brain natriuretic peptides, and elevated circulating levels of these substances have important prognostic and therapeutic implications. Although plasma natriuretic peptide measurements are helpful in excluding chronic heart failure in the ambulatory setting, many factors independent of heart failure may influence their levels. During the acute phase response of severe burn injuries, the severity of the cardiac stress can determine the postburn outcomes, and the pleiotropic effects exerted by the natriuretic peptide system play a key role in this process by activating compensatory mechanisms that promote systemic arterial dilatation, diuresis, natriuresis, and renin inhibition. Natriuretic peptides may also play a role in the wound healing process, which could be of clinical utility to reduce apparent scar formation in burn patients.
... The role of transforming growth factor β in reducing scar formation has been described, 34 and it has been reported that BNP reduces myocardial scar formation by blocking transforming growth factor β. 35 An in vitro proof-of-principal study revealed the presence of BNP around collagen, epithelial cells, and endothelial cells in human burned skin; in contrast, no BNP was observed in unscarred skin samples, indicating that BNP may be involved in skin wound healing and scarring. 36 Further studies reported the responsiveness of fibroblasts to BNP 37 and the improvement in the gross appearance of scars but without any histologic difference compared with controls in a rat burn model. ...
Several manifestations of inflammatory skin reactions have been described. Toxic epidermal necrolysis is an acute skin inflammatory reaction. It is generally triggered by upper respiratory tract infections or by medications such as nonsteroid anti-inflammatory drugs, antibiotics, and anticonvulsants. It is associated with a significant mortality of 30% to 50% and long-term sequelae. Here, we present 2 cases of toxic epidermal necrolysis who were treated by a multidisciplinary team involving burn professionals.
... Together with this canonical pathway, TGF-β binds other accessory receptors (e.g., ALK1, which stimulates Smad1/5/8 phosphorylation) to carry out diverse, essential, and variable functions in orchestrating wound healing throughout all its phases (e.g., the chemoattraction of leukocytes to the wound bed, neovascularization, the stimulation of ECM deposition, and ultimately the attenuation of ECM production) [2,7]. Numerous studies have demonstrated the in vitro and in vivo attenuation of fibrosis by targeting the TGF-β pathway with interventions such as other small-molecule inhibitors, neutralizing antibodies, and exon skipping [7][8][9][10][11][12]. For example, a small human trial employing interferon alpha 2 (which reduces the secretion of TGF-β, among other cytokines) for the attenuation of pathological scarring showed a modest benefit [13]. ...
Dermal fibroblasts in pathological scars secrete constitutively elevated levels of TGF-β, signaling the transcription of fibrotic genes via activin-like kinase 5 (ALK5). In the present study, we examine the antifibrotic effects of galunisertib, a small-molecule inhibitor of ALK5, on fibroproliferative dermal fibroblasts in an in vitro model of wound healing. We induced fibrosis in human dermal fibroblasts with exogenous TGF-β and performed cellular proliferation assays after treatment with varying concentrations of galunisertib. Dermal fibroblast proliferation was diminished to homeostatic levels without cytotoxicity at concentrations as high as 10 μM. An in vitro scratch assay revealed that galunisertib significantly enhanced cellular migration and in vitro wound closure beginning 24 h post-injury. A gene expression analysis demonstrated a significant attenuation of fibrotic gene expression, including collagen-1a, alpha-smooth muscle actin, fibronectin, and connective tissue growth factor, with increased expression of the antifibrotic genes MMP1 and decorin. Protein synthesis assays confirmed drug activity and corroborated the transcription findings. In summary, galunisertib simultaneously exerts antifibrotic effects on dermal fibroblasts while enhancing rates of in vitro wound closure. Galunisertib has already completed phase II clinical trials for cancer therapy with minimal adverse effects and is a promising candidate for the treatment and prevention of pathological cutaneous scars.
... Since the discovery of the importance of TGF-β in fibrotic diseases, drug research targeting the TGF-β signaling pathway has increased significantly [58,67,90]. Related drug types include antisense oligonucleotides (AON), neutralizing antibodies, cyclic RGD pentapeptides, TGF-β ligand traps, and small molecule kinase inhibitors (SKIs), etc. [80,[116][117][118]. In early anti-fibrosis drug research, researchers found that pan-TGF-β antibody drugs might cause cardiotoxicity [54,119]. ...
Tissue fibrosis is a key factor leading to disability and death worldwide; however, thus far, there are no approved treatments for fibrosis. Transforming growth factor (TGF)-β is a major pro-fibrotic cytokine, which is expected to become a target in the treatment of fibrosis; however, since TGF-β has a wide range of biological functions involving a variety of biological processes in the body, a slight change in TGF-β may have a systematic effect. Indiscriminate inhibition of TGF-β can lead to adverse reactions, which can affect the efficacy of treatment. Therefore, it has become very important to explore how both the TGF-β signaling pathway is inhibited and the safe and efficient TGF-β small molecule inhibitors or neutralizing antibodies are designed in the treatment of fibrotic diseases. In this review, we mainly discuss the key role of the TGF-β signaling pathway in fibrotic diseases, as well as the development of fibrotic drugs in recent years, and explore potential targets in the treatment of fibrotic diseases in order to guide subsequent drug development.
