Fig 7
Histopathological examination of full-thickness incisional wounds at days 14 and 21 after treatment. Histopathology of the a control group, b AdFibromodulin-treated group, and c Ad-Gal-treated group at 14 and 21 days after the operation (20× magnification). Tissue sections were stained with hematoxylin and eosin and examined for the granulation tissue by a pathologist blinded to the treatment. The width of the granulation tissue is narrower in the Ad-Fibromodulintreated group (b) than the control group (a) or the Ad-Gal treated group (c) at days 14 and 21 after surgery. In none of the groups do signs of inflammation could be detected. Arrows indicate granulation tissue
Source publication
Fibromodulin, a member of the small leucine-rich proteoglycan family, has been recently suggested as a biologically significant mediator of fetal scarless repair. To assess the role of fibromodulin in the tissue remodeling, we constructed an adenoviral vector expressing human fibromodulin cDNA. We evaluated the effect of adenovirus-mediated overexp...
Context in source publication
Context 1
... change to draw a conclusion for the Ad-Fibromodulin- Of note, at day 7 after surgery, the Ad-Gal-treated wounds showed an inflamma- tory response that included the panniculus. At days 4 and 21 after surgery, a larger amount of granulation tissue was observed in the Ad-Gal and non-treated wounds than in the Ad-Fibromodulin-treated wounds (Fig. 7). At day 80 after surgery ( Fig. 8), the width of the scar was much narrower or undetectable in Ad-Fibromodulin-treated wounds com- pared to Ad-Gal and non-treated wounds. Thus, the histopathological examination of the scars of the three different treatment groups after incision demonstrated less evidence of scar formation in ...
Citations
... FMOD-/-mice were migration inhibited by TGF-β3, and delayed dermal cell migration results in delayed wound closure and a significant increase in scar size [100]. Furthermore, Ad-FMOD induced decreased expression of TGF-β1 and TGF-β2 precursor proteins, but increased expression of TGF-β3 precursor protein and TGF-β type II receptor, which can promote wound healing, suggesting that FMOD may be a key mediator in reducing scar formation [101]. LUM promoted cutaneous wound healing by promoting the activation and contraction of wound fibroblasts via integrin α2, but not by promoting the proliferation and migration of keratinocytes [102]. ...
Review Small Leucine Rich Proteoglycan in Fibrotic Diseases: New Frenemies? Jiayu Guo 1,2, Yan Wang 1,2, Haihai Liang 1,2,3,*, and Baofeng Yang 1,2,3,* 1 Department of Pharmacology (National Key Laboratory of Frigid Zone Cardiovascular Diseases), College of Pharmacy, Harbin Medical University, Harbin 150081, China 2 Northern Translational Medicine Research and Cooperation Center, Heilongjiang Academy of Medical Sciences, Harbin Medical University, Harbin 150081, China 3 Research Unit of Noninfectious Chronic Diseases in Frigid Zone (2019RU070), Chinese Academy of Medical Sciences, Harbin 150081, China * Correspondence: lianghaihai@ems.hrbmu.edu.cn (H.H.L),; yangbf@ems.hrbmu.edu.cn (B.F.Y) Received: 27 April 2023 Accepted: 2 June 2023 Abstract: The human body is a complex organism with self-regulating ability and can cope with external pressures and challenges. To protect the body from damage during exercise or confrontations, beneath the human epidermal layer, the human body has evolved a coverall gown: the extracellular matrix (ECM). ECM provides a suitable space for the survival and activity of cells in the body, and affects the behavior of cells through signal transduction system. Proteoglycans, particularly the small leucine rich proteoglycan (SLRP) family, have been shown to be molecules that play important roles in matrix remodeling and organ fibrosis, such as by affecting ECM components or altering the intracellular environment. But in recent years reports of SLRP families, their manifestations in different organs have not been consistent. Recent studies suggest that proteoglycans entering the blood in a soluble form hold promise as diagnostic biomarkers of organ fibrosis and may provide novel therapeutic strategies for fibrotic diseases. Herein, we discuss and review studies of SLRPs in multi-organ fibrotic diseases.
... Lower fibromodulin levels have been reported in HTS from human subjects and animal models compared to normal tissue [150,151] , and mice lacking fibromodulin heal with more inflammation [152] and more scar formation [153,154] . Increasing fibromodulin levels via adenoviral overexpression or treating with recombinant fibromodulin has been shown to reduce scar formation in rabbit, mouse, and red Duroc pig wounds [153][154][155][156] . Based on these studies, a fibromodulin-based peptide has been developed and is currently being tested in clinical trials [157] . ...
Inflammation is a key phase in the cutaneous wound repair process. The activation of inflammatory cells is critical for preventing infection in contaminated wounds and results in the release of an array of mediators, some of which stimulate the activity of keratinocytes, endothelial cells, and fibroblasts to aid in the repair process. However, there is an abundance of data suggesting that the strength of the inflammatory response early in the healing process correlates directly with the amount of scar tissue that will eventually form. This review will summarize the literature related to inflammation and cutaneous scar formation, highlight recent discoveries, and discuss potential treatment modalities that target inflammation to minimize scarring.
... Meanwhile, the administration of FMOD alone was capable of restoring scarless healing in lategestation rat fetal wounds, which would naturally heal with scar (Zheng et al., 2016). In addition to restoring scarless wound healing in late-gestation fetal wounds, forcing FMOD elevation by adenovirus can also promote skin wound healing in adult rabbit full-thickness incisions (Stoff et al., 2007). Additionally, FMOD-deficient mice exhibit delayed wound closure and increased scar formation Zheng et al., 2014b). ...
Healing of cutaneous wounds is a complex and well-coordinated process requiring cooperation among multiple cells from different lineages and delicately orchestrated signaling transduction of a diversity of growth factors, cytokines, and extracellular matrix (ECM) at the wound site. Most skin wound healing in adults is imperfect, characterized by scar formation which results in significant functional and psychological sequelae. Thus, the reconstruction of the damaged skin to its original state is of concern to doctors and scientists. Beyond the traditional treatments such as corticosteroid injection and radiation therapy, several growth factors or cytokines-based anti-scarring products are being or have been tested in clinical trials to optimize skin wound healing. Unfortunately, all have been unsatisfactory to date. Currently, accumulating evidence suggests that the ECM not only functions as the structural component of the tissue but also actively modulates signal transduction and regulates cellular behaviors, and thus, ECM should be considered as an alternative target for wound management pharmacotherapy. Of particular interest are small leucine-rich proteoglycans (SLRPs), a group of the ECM, which exist in a wide range of connecting tissues, including the skin. This manuscript summarizes the most current knowledge of SLRPs regarding their spatial-temporal expression in the skin, as well as lessons learned from the genetically modified animal models simulating human skin pathologies. In this review, particular focus is given on the diverse roles of SLRP in skin wound healing, such as anti-inflammation, pro-angiogenesis, pro-migration, pro-contraction, and orchestrate transforming growth factor (TGF)β signal transduction, since cumulative investigations have indicated their therapeutic potential on reducing scar formation in cutaneous wounds. By conducting this review, we intend to gain insight into the potential application of SLRPs in cutaneous wound healing management which may pave the way for the development of a new generation of pharmaceuticals to benefit the patients suffering from skin wounds and their sequelae.
... Several studies have used gene therapy to initiate scarfree repair status in wounds. In all studies, application of viral vectors resulted in active transgene expression in vivo (Liu et al. 2003;Gu et al. 2005;Stoff et al. 2007;Gordon et al. 2008;Wang and Li 2008;Ha et al. 2010;Waddington et al. 2010;Wang et al. 2013). The study of Stoff et al. (2007) indicated that application of Ad-Fibromodulin led to increased expression of TGF-b3 precursor protein and TGF-b type II receptor. ...
... In all studies, application of viral vectors resulted in active transgene expression in vivo (Liu et al. 2003;Gu et al. 2005;Stoff et al. 2007;Gordon et al. 2008;Wang and Li 2008;Ha et al. 2010;Waddington et al. 2010;Wang et al. 2013). The study of Stoff et al. (2007) indicated that application of Ad-Fibromodulin led to increased expression of TGF-b3 precursor protein and TGF-b type II receptor. They suggested that fibromodulin may be a key mediator in reduced scarring (Stoff et al. 2007). ...
... The study of Stoff et al. (2007) indicated that application of Ad-Fibromodulin led to increased expression of TGF-b3 precursor protein and TGF-b type II receptor. They suggested that fibromodulin may be a key mediator in reduced scarring (Stoff et al. 2007). In another study, Waddington et al. (2010) also used a lentiviral vector expressing the mutTGFb3 for wound repair in a mouse model and showed a reduction in re-epithelialization density and fibroblast/myofibroblast transdifferentiation in the wound area which is an explanation in reduced scar tissue formation (Waddington et al. 2010). ...
Objective
Several studies have investigated the role of gene therapy in the healing process. The aim of this review is to explain the gene delivery systems in wound area.
Results
Ninety-two studies were included and comprehensively overviewed. We described the importance of viral vectors such as adenoviruses, adeno-associated viruses, and retroviruses, and conventional non-viral vectors such as naked DNA injections, liposomes, gene gun, electroporation, and nanoparticles in achieving high-level expression of genes. Application of viral transfection, liposomal vectors, and electroporation were the main gene delivery systems. Genes encoding for growth factors or cytokines have been shown to result in a better wound closure in comparison to application of the synthetic growth factors. In addition, a combination of stem cell and gene therapy has been found an effective approach in regeneration of cutaneous wounds.
Conclusions
This article gives an overview of the methods and investigations applied on gene therapy in wound healing. However, clinical investigations need to be undertaken to gain a better understanding of gene delivery technologies and their roles in stimulating wound repair.
... Cells can influence the other two parts by producing ECM and releasing growth factors [6]. The cells can also be genetically modified to overproduce specific ECM or growth factors [7]. ...
... The growth factor in a dose dependent manner affects the cells bioprocesses as well as the type and amount of growth factors and ECM they produce [1,6]. Also, as previously stated, both the biomaterial and the cells can serve as drug delivery systems [1,7,10]. ...
... Transforming growth factor-b (TGF-b) superfamily includes a large group of soluble extracellular proteins which regulate the development in both vertebrates and invertebrates (Krauss 2006;Soo et al. 2000). TGF-b family regulates the cell functions such as migration, apoptosis, proliferation and differentiation (Stoff et al. 2007;Soo et al. 2000;Spagnoli et al. 2007). ...
Cytokines are extremely potent biomolecules that regulate cellular functions and play multiple roles in initiation and inhibition of disease. These highly specialised macromolecules are actively involved in control of cellular proliferation, apoptosis, cell migration and adhesion. This work, investigates the effect of transforming growth factor-beta2 (TGF-β2) on the biological regulation of chondrocyte and the repair of a created model wound on a multilayer culture system. Also the effect of this cytokine on cell length, proliferation, and cell adhesion has been investigated. Chondrocytes isolated from knee joint of rats and cultured at 4 layers. Each layer consisted of 2 × 10⁵ cells/ml with and without TGF-β2. The expression of mRNA and protein levels of TGF-β receptors and Smad1, 3, 4, and 7 have been analysed by RT-PCR and western blot analysis. The effect of different supplementations in chondrocyte cell proliferation, cell length, adhesion, and wound repair was statistically analysed by One-way ANOVA test. Our results showed that the TGFβ2 regulates mRNA levels of its own receptors, and of Smad3 and Smad7. Also the TGF-β2 caused an increase in chondrocyte cell length, but decreased its proliferation rate and the wound healing process. TGF-β2 also decreased cell adhesion ability to the surface of the culture flask. Since, TGF-β2 increased the cell size, but showed negative effect on cell proliferation and adhesion of CHC, the effect of manipulated TGF-β2 with other growth factors and/or proteins needs to be investigated to finalize the utilization of this growth factor and design of scaffolding in treatment of different types of arthritis.
... Specific studies have shown MSC's role in reepithelialization [16,18,39], angiogenesis [16,32], ECM production [16,18], and overall healing [8,16,18,19,31,38,39]. TGF-β 3 was selected for its regenerative ability; shown as a main reason why fetal wounds heal mostly by regeneration [48][49][50][51][52][53][54]. TGF-β 3 has been shown to have a role in fibroblast migration, which allows for a more normal basketweave collagen organization; resulting in a reduction in scarring as well as improved healing [49]. ...
Pressure ulcers are one of the most common forms of skin injury, particularly in the spinal cord injured (SCI). Pressure ulcers are difficult to heal in this population requiring at least six months of bed rest. Surgical treatment (grafting) is the fastest recovery time, but it still requires six weeks of bed rest plus significant additional costs and a high recurrence rate. A significant clinical benefit would be obtained by speeding the healing rate of a non-surgical treatment to close to that of surgical treatment (approximately doubling of healing rate). Current non-surgical treatment is mostly inactive wound coverings. The goal of this project was to look at the feasibility of doubling the healing rate of a full-thickness defect using combinations of three treatments, for the first time, each shown to increase healing rate: application of transforming growth factor-β3 (TGF-β3), an albumin based scaffold, and mesenchymal stem cells (MSCs). At one week following surgery, the combined treatment showed the greatest increase in healing rate, particularly for the epithelialization rate. Although the target level of a 100% increase in healing rate over the control was not quite achieved, it is anticipated that the goal would be met with further optimization of the treatment.
... Understanding that AP-1 promotes TGFβ1 auto-induction, 38 while SMAD2 regulates MMP2 expression, 39 may explain the seemingly paradoxical coupling of decreased TGFβ1 expression while upregulating TGFβ1 downstream target MMP2 in earlier human dermal fibroblasts studies after adenovirus-mediated FMOD overexpression. 40 With respect to Smad3, FMOD alone slightly inhibited its expression in RDFs, while FMOD+TGFβ1 combination significantly prolonged Smad3 phosphorylation/activation without altering its gene or protein expression (Figure 5e). Using a luciferase-reporter system specific for SMAD3 signal transduction (that is, CAGA-box reporter), we confirmed that FMOD prolonged TGFβ1-induced Smad3 signaling in RDFs in vitro (Figure 5f). ...
Blocking transforming growth factor (TGF)β1 signal transduction has been a central strategy for scar reduction; however, this approach appears to be minimally effective. Here, we show that fibromodulin (FMOD), a 59-kD small leucine-rich proteoglycan critical for normal collagen fibrillogenesis, significantly reduces scar formation while simultaneously increasing scar strength in both adult rodent models and porcine wounds, which simulate human cutaneous scar repair. Mechanistically, FMOD uncouples pro-migration/contraction cellular signals from pro-fibrotic signaling by selectively enhancing SMAD3-mediated signal transduction, while reducing AP-1-mediated TGFβ1 auto-induction and fibrotic extracellular matrix accumulation. Consequently, FMOD accelerates TGFβ1-responsive adult fibroblast migration, myofibroblast conversion, and function. Furthermore, our findings strongly indicate that, by delicately orchestrating TGFβ1 activities rather than indiscriminately blocking TGFβ1, FMOD elicits fetal-like cellular and molecular phenotypes in adult dermal fibroblasts in vitro and adult cutaneous wounds in vivo, which is a unique response of living system undescribed previously. Taken together, this study illuminates the signal modulating activities of FMOD beyond its structural support functions, and highlights the potential for FMOD-based therapies to be used in cutaneous wound repair.
... 20,23 In addition, adenovirus-mediated FM overexpression decreased TGF-b1 expression in human dermal fibroblasts. 35 In this study, we observed an inverse correlation between FM and Tgf-b1 with its downstream fibrosis target, type I collagen, in fetal cutaneous wound models: High FM levels correlated with decreased Tgf-b1 expression and scarless repair, while low FM levels correlated with increased Tgf-b1 expression and scar formation. Therefore, our current finding strongly suggests that FM plays crucial regulatory roles in TGF-b signaling during cutaneous wound repair. ...
In contrast to adult and late-gestation fetal skin wounds, which heal with scar, early-gestation fetal skin wounds display a remarkable capacity to heal scarlessly. Although the underlying mechanism of this transition from fetal-type scarless healing to adult-type healing with scar has been actively investigated for decades, in utero restoration of scarless healing in late-gestation fetal wounds has not been reported. In this study, using loss- and gain-of-function rodent fetal wound models, we identified that fibromodulin (Fm) is essential for fetal-type scarless wound healing. In particular, we found that loss of Fm can eliminate the ability of early-gestation fetal rodents to heal without scar. Meanwhile, administration of Fm protein alone was capable of restoring scarless healing in late-gestation rat fetal wounds, which naturally heal with scar, as characterized by dermal appendage restoration and organized collagen architectures that were virtually indistinguishable from those in age-matched unwounded skin. High Fm levels correlated with decreased transforming growth factor (TGF)-?1 expression and scarless repair, while low Fm levels correlated with increased TGF-?1 expression and scar formation. This study represents the first successful in utero attempt to induce scarless repair in late-gestation fetal wounds by using a single protein, Fm, and highlights the crucial role that the FM-TGF-?1 nexus plays in fetal-type scarless skin repair.
... Examples include manipulation of transforming growth factor-b (TGFb), angiotensin peptides, and tissue inhibitors of metalloproteinases. [11][12][13][14] Despite this, therapies proven to ameliorate the fibrotic response to injury remain elusive. 11 In contrast, relatively little attention has been given to the influence of ECM characteristics on tissue repair. ...
... Indeed, reduced scarring was observed in rabbit incisional wounds after increasing fibromodulin expression using an adenoviral vector while the addition of hyaluronic acid to healing organ cultured limb explants of gestational day (d) 18 fetal mice promoted scarless repair. 12,15 Tissue engineered dermal skin substitutes (dSS) represent another method by which to artificially alter ECM components. These biomaterials fundamentally provide replacement ECM in the form of porous three-dimensional dermal templates to stimulate wound healing. ...
Skin substitutes are heterogeneous biomaterials designed to accelerate wound healing through provision of replacement extracellular matrix. Despite growing evidence for their use in chronic wounds, the role of skin substitutes in acute wound management and their influence upon fibrogenesis remains unclear. Skin substitute characteristics including biocompatibility, porosity and elasticity strongly influence cellular behaviour during wound healing. Thus, we hypothesise that structural and biomechanical variation between biomaterials may induce differential scar formation after cutaneous injury. The following human prospective cohort study was designed to investigate this premise. Four 5mm full-thickness punch biopsies were harvested from fifty volunteers. In all cases, site 1 healed by secondary intention, site 2 was treated with collagen-GAG scaffold (CG), Decellularised Dermis (DCD) was applied to site 3, whilst tissue extracted from site 4 was replaced (autograft). Healing tissue was assessed weekly with optical coherence tomography (OCT), before being excised on days 7, 14, 21 or 28 depending on study group allocation for later histological and immunohistochemical evaluation. Extracted RNA was utilised in microarray analysis and PCR of highlighted genes. Autograft treatment resulted in minimal fibrosis confirmed immunohistochemically and with OCT through significantly lower collagen I levels (p=0.047 and 0.03) and reduced mean greyscale values (p=0.038 and 0.015) respectively. DCD developed intermediate scar formation with partial rete ridge reformation and reduced fasiculo-nodular fibrosis. It was uniquely associated with late up-regulation of matrix metalloproteinases 1 and 3, oncostatin M and interleukin-10 (p=0.007, 0.04, 0.019, 0.019). Regenerated dermis was significantly thicker in DCD and autografts 28 days post-injury compared to control and CG samples (p=0.003 and <0.0001) which resulted in greatest fibrosis and poorest cosmesis. In conclusion, variable fibrotic outcomes were observed in skin substitute-treated wounds with reduced scarring in autograft and DCD samples compared to controls. OCT enabled concurrent assessment of wound morphology and quantification of dermal fibrosis. This article is protected by copyright. All rights reserved.
© 2015 by the Wound Healing Society.
