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Model of the role of myofibroblasts during the healing of an open wound.a | In normal tissues, fibroblasts experience a relatively low amount of tension owing to stress-shielding by the surrounding collagen matrix, such that the organization of a contractile cytoskeleton is not stimulated (light pink area of dermis). When a full-thickness dermal wound is filled by a fibrin clot, local growth factors stimulate fibroblasts from the adjacent intact dermis to invade this provisional matrix. These migrating fibroblasts, along with vessels, fill the wound, which results in the formation of granulation tissue. At this point, fibroblasts are already stimulated to produce ED-A fibronectin (ED-A FN). b | Migrating fibroblasts exert tractional forces on the collagen matrix, which results in its reorganization along lines of stress. The development of mechanical stress stimulates fibroblasts to develop stress fibres and to produce collagen, so they acquire the proto-myofibroblast phenotype. Tensional forces and growth factors stimulate proto-myofibroblasts to secrete transforming growth factor 1 (TGF-1) and increased levels of ED-A FN. c | In a feedback loop, proto-myofibroblasts become differentiated myofibroblasts by synthesizing -smooth muscle actin and generating increased contractile force. At the same time, differentiated myofibroblasts lay down collagen and other extracellular-matrix (ECM) components, and produce proteases. This complex process of remodelling results in shortening of the collagen matrix with corresponding wound closure. d | When a normal healing wound closes, myofibroblasts disappear by apoptosis and a scar is formed. e | However, in many pathological situations, such as hypertrophic scar formation, myofibroblasts persist and continue to remodel the ECM, which results in connective-tissue contracture. In conclusion, myofibroblasts, far from being a 'bad' cell type, are functionally essential cells. It is their dysregulation that is the cause of tissue dysfunction.
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During the past 20 years, it has become generally accepted that the modulation of fibroblastic cells towards the myofibroblastic phenotype, with acquisition of specialized contractile features, is essential for connective-tissue remodelling during normal and pathological wound healing. Yet the myofibroblast still remains one of the most enigmatic o...
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Inflammatory fibrosis is a wound-healing reaction of the immune system in mammals against aggression. After a signalling cascade, fibroblasts and potentially myofibroblasts make a stiff collagenous tissue inside the body that modifies the original healthy tissue. We focus here on the implantinduced fibrosis that aims to encapsulate the implant with...
Citations
... This result implies that fibroblasts near the site of injury can experience a dramatic change in their mechanical environment. As mechanical forces influence the wound healing process, the changes in tension upon injury can result in orchestrated responses of fibroblasts [37][38][39]. Tensegrity has been proposed to describe how mechanical forces regulate cellular biochemical systems [40][41][42]. To describe this orchestrated phenomenon, we can introduce the concept of hierarchical tensegrity (Fig. 3b). ...
... These findings suggest that a specific range of mechanical tension may function as a morphogenetic cue for local tissue pattern formation in vivo. In terms of fibroblast-to-myofibroblast differentiation, it has been established that mechanical stimuli play a crucial role in increasing ECM proteins and proteoglycan content [9, 37,57,59]. In addition, the effect of cyclic mechanical stimulation on fibroblast proliferation has been extensively investigated, revealing its ability to either enhance or inhibit proliferation [60][61][62][63][64]. ...
Background
Scar formation is a common end-point of the wound healing process, but its mechanisms, particularly in relation to abnormal scars such as hypertrophic scars and keloids, remain not fully understood. This study unveils a novel mechanistic insight into scar formation by examining the differential expression of Homeobox (HOX) genes in response to mechanical forces in fibroblasts derived from normal skin, hypertrophic scars, and keloids.
Methods
We isolated fibroblasts from different scar types and conducted RNA sequencing (RNA-Seq) to identify differential gene expression patterns among the fibroblasts. Computational modeling provided insight into tension alterations following injury, and these findings were complemented by in vitro experiments where fibroblasts were subjected to exogenous tensile stress to investigate the link between mechanical tension and cellular behavior.
Results
Our study revealed differential HOX gene expression among fibroblasts derived from normal skin, hypertrophic scars, and keloids. Computational simulations predicted injury-induced tension reduction in the skin, and in vitro experiments revealed a negative correlation between tension and fibroblast proliferation. Importantly, we discovered that applying mechanical tension to fibroblasts can modulate HOX gene expression, suggesting a pivotal role of mechanical cues in scar formation and wound healing.
Conclusion
This study proposes a model wherein successful wound healing and scar formation are critically dependent on maintaining tensional homeostasis in the skin, mediated by tension-sensitive HOX genes. Our findings highlight the potential of targeting mechanotransduction pathways and tension-sensitive HOX gene expression as therapeutic strategies for abnormal scar prevention and treatment, offering a new perspective on the complex process of scar formation.
... Typically, following wound healing, the ECM is efficiently degraded. 33,34 However, in cases of severe or persistent injury, there can be an over-accumulation of ECM, which leads to necrosis of parenchymal cells, proliferation of connective tissue, and ultimately fibrosis. 35 This complex pathological process involves not only the activation of fibroblasts but also the interplay of multiple signaling pathways. ...
Selenium (Se), a critically essential trace element, plays a crucial role in diverse physiological processes within the human body, such as oxidative stress response, inflammation regulation, apoptosis, and lipid metabolism. Organ fibrosis, a pathological condition caused by various factors, has become a significant global health issue. Numerous studies have demonstrated the substantial impact of Se on fibrotic diseases. This review delves into the latest research advancements in Se and Se-related biological agents for alleviating fibrosis in the heart, liver, lungs, and kidneys, detailing their mechanisms of action within fibrotic pathways. Additionally, the article summa-rizes some of the anti-fibrotic drugs currently in clinical trials for the aforementioned organ fibroses.
... In chronic fibroproliferative diseases, the sensitive balance between the synthesis and degradation of the ECM is disrupted, and continuously activated myofibroblasts produce surplus ECM, causing connective tissue to infiltrate parenchymal tissue [62,63]. Fibrosis is a common age-related disease characterized by excessive formation of fibrous connective tissue. ...
Organ fibrosis is gradually becoming a human health and safety problem, and various organs of the body are likely to develop fibrosis. The ultimate pathological feature of numerous chronic diseases is fibrosis, and few interventions are currently available to specifically target the pathogenesis of fibrosis. The medical detection of organ fibrosis has gradually matured. However, there is currently no effective treatment method for these diseases. Therefore, we need to strive for developing effective and reliable drugs or substances to treat and prevent fibrotic diseases. Lactoferrin (LF) is a multifunctional glycoprotein with many pathological and physiologically active effects, such as antioxidant, anti-inflammatory and antimicrobial effects, and it protects against pathological and physiological conditions in various disease models. This review summarizes the effects and underlying mechanisms of LF in preventing organ fibrosis. As a naturally active substance, LF can be used as a promising and effective drug for the prevention and remission of fibrotic diseases.
... The transition of fibroblast into myofibroblast is vastly activated by different signaling pathways, such as the transforming growth factor-β (TGF-β) pathway [8], the epithelial-mesenchymal transition [9], and the Notch signaling pathway [10]. By Scheme 1. Schematic illustration of (Au+IL-4)@MFM NPs promoting skin wound healing. ...
The fibroblast-myofibroblast transition marked by extracellular matrix (ECM) secretion and contraction of actomyosin-based stress fibers, plays central roles in the wound healing process. This work aims to utilize the cell membrane-based nanoplatform to improve the outcomes of dysregulated wound healing. The cell membranes of myofibroblasts isolated from mouse skin are used as the camouflage for gold nanoparticles loaded with IL-4 cytokine. The membrane-modified nanoparticles show effective in situ clearance of bacterial infection, and act as the activator in IL-4Rα signaling pathway to induce pro-inflammatory M1 macrophages into the anti-inflammatory M2 phenotype. Thus, the poor bacteria-clearance and non-stop inflammation in refractory wounds are improved and accelerated. Furthermore, the nanoplatform releases myofibroblast membranes to propel primitive fibroblasts toward the fibroblast-myofibroblast transition in an epigenetic manner. Matrix-production, vascularization, and epithelial regeneration are then initiated, leading to the satisfactory wound closure. Our study devises a new strategy for activating fibroblasts into myofibroblasts under prolonged and continuous exposure to the fibrotic environment, and develops a promising biomimetic nanoplatform for effective treatment of dysregulated chronic wound healing.
... The a-SMA is the most common molecular marker to refer to the myofibroblast [25][26][27] . However, no significant differences were evidenced between treatments at different times, but it was notable great the presence of myofibroblasts in C+AT (seven days, Table 3), providing an improvement in the healing process in this initial phase of inflammation followed by a decrease, providing an inhibitory effect of the corticosteroid, which corroborates the study by Seibold et al. 17 . ...
Purpose: The surgical glue is widely used in closing cutaneous surgical wounds. Corticosteroids are indicated for their anti-inflammatory and immunomodulatory properties. The present work evaluated the pharmacological effects of triamcinolone (AT) incorporated into surgical glue (C) on the initial phase of the wound healing process in Wistar rats.
Methods: Through in-vivo studies, the effects of the healing process, C or C+AT in the same rat were evaluated for seven and 14 days post-surgery.
Results: The C+AT association did not change the physicochemical properties of the polymer. This association in wound healing confirmed the anti-inflammatory and immunomodulatory effects of the corticosteroid, with less neovascularization and fibrosis, in addition to the remodeling of the extracellular matrix carried out by the balance of myofibroblasts and less dense collagen fibers, culminating in tissue regeneration and possible reduction of side effects.
Conclusion: This association is a powerful and innovative pharmacological tool, promising in translational medicine.
Key words Adhesives; Adrenal Cortex Hormones; Cyanoacrylates; Biocompatible Materials
... Hereby, fibrogenesis and certainly myofibroblast differentiation seem to play a crucial role. Although fibrotic disorders distinguish in etiological and clinical features, they are all based on an excessive production of growth factors, proteolytic enzymes, and angiogenic as well as fibrogenic factors and cytokines [1,2]. The interaction of all these factors leads to an increased differentiation of fibroblasts to myofibroblasts and thus to fibroproliferative processes that stimulate and remodel tissue architecture. ...
... Myofibroblasts have diverse origins; myofibroblasts may derive from local mesenchymal cells, may be transformed epithelial cells, or may derive from circulating mesenchymal stem cells originating in the bone marrow [3]. They are characterized by enhanced contractility mediated by an expression of stress fibers known as α-smooth muscle actin (α-SMA) [2,4]. Following activation, myofibroblasts coordinate the repair and remodeling of connective tissue. ...
Wound healing as a result of a skin injury involves a series of dynamic physiological processes, leading to wound closure, re-epithelialization, and the remodeling of the extracellular matrix (ECM). The primary scar formed by the new ECM never fully regains the original tissue’s strength or flexibility. Moreover, in some cases, due to dysregulated fibroblast activity, proliferation, and differentiation, the normal scarring can be replaced by pathological fibrotic tissue, leading to hypertrophic scars or keloids. These disorders can cause significant physical impairment and psychological stress and represent significant challenges in medical management in the wound-healing process. The present study aimed to investigate the therapeutic effects of exogenously applied carbon dioxide (CO2) on fibroblast behavior, focusing on viability, proliferation, migration, and differentiation to myofibroblasts. We found that CO2 exposure for up to 60 min did not significantly affect fibroblast viability, apoptosis rate, or proliferation and migration capacities. However, a notable finding was the significant reduction in α-smooth muscle actin (α-SMA) protein expression, indicative of myofibroblast differentiation inhibition, following CO2 exposure. This effect was specific to CO2 and concentration as well as time-dependent, with longer exposure durations leading to greater reductions in α-SMA expression. Furthermore, the inhibition of myofibroblast differentiation correlated with a statistically significantly reduced glycolytic and mitochondrial energy metabolism, and as a result, with a reduced ATP synthesis rate. This very noticeable decrease in cellular energy levels seemed to be specific to CO2 exposure and could not be observed in the control cultures using nitrogen (N2)-saturated solutions, indicating a unique and hypoxia-independent effect of CO2 on fibroblast metabolism. These findings suggest that exogenously applied CO2 may possess fibroblast differentiation-reducing properties by modulating fibroblast’s energy metabolism and could offer new therapeutic options in the prevention of scar and keloid development.
... A key factor in this process is transforming growth factor-beta (TGF-β), a cytokine that stimulates fibroblast proliferation, myofibroblast differentiation, and collagen production. Elevated levels of TGF-β have been observed in the affected tissues of patients, indicating its significant role in driving the fibroproliferative response [12][13][14]. Additionally, other cytokines, such as platelet-derived growth factor and basic fibroblast growth factor, also play a role in the disease by promoting fibrosis and tissue remodeling [12]. ...
Dupuytren's contracture is a chronic condition that affects the palmar fascia, leading to progressive flexion of the fingers, particularly the ring and little fingers. This article provides an in-depth review of the current understanding of the condition and its management. Commonly seen in older men of Northern European descent, Dupuytren's can significantly impair hand function as contractures develop. The underlying mechanisms involve complex cellular processes, particularly the role of transforming growth factor-beta in promoting fibroblast activity and collagen buildup. Treatment strategies depend on the severity of the condition; nonsurgical options like collagenase injections and needle aponeurotomy are effective for early stages but often have high recurrence rates. For more advanced cases, surgical options such as limited and radical fasciectomy are considered, aiming to restore finger extension while addressing potential complications. Challenges in management include high recurrence rates and variability in disease progression, emphasizing the need for standardized assessment protocols and innovative therapeutic approaches. This review underscores the importance of early diagnosis and intervention to preserve hand function and enhance quality of life. It calls for ongoing research into targeted therapies to reduce recurrence rates.
... In the WM, the overexpression of KGF and TGF-β1 has been quantified on day 3 ( Table 1). The role of fibroblasts-differentiated myofibroblasts, as the main actor of the ECM remodeling in tissue repair in an organotypic model, and the importance of FN expression during the repair is well known [59][60][61]. Myofibroblasts are associated with many phenomena, such as wound contraction, closure, granulation tissue formation, and new ECM [60,[62][63][64],while FN overexpression is associated with fibrosis and scarring [18,65,66]. The role of dermal fibroblasts in an open wound starting to proliferate from the wound margin one week after an injury has been widely reported. ...
... The role of fibroblasts-differentiated myofibroblasts, as the main actor of the ECM remodeling in tissue repair in an organotypic model, and the importance of FN expression during the repair is well known [59][60][61]. Myofibroblasts are associated with many phenomena, such as wound contraction, closure, granulation tissue formation, and new ECM [60,[62][63][64],while FN overexpression is associated with fibrosis and scarring [18,65,66]. The role of dermal fibroblasts in an open wound starting to proliferate from the wound margin one week after an injury has been widely reported. ...
Backgrounds/Objectives: Skin wound healing is a physiological process orchestrated by epithelial and mesenchymal cells able to restore tissue continuity by re-organizing themselves and the ECM. This research study aimed to develop an optimized in vitro experimental model of full-thickness skin, to address molecular and morphological modifications occurring in the re-epithelization and wound healing process. Methods: Wound healing starting events were investigated within an experimental window of 8 days at the molecular level by gene expression and immunofluorescence of key epidermal and dermal biomarkers. To mirror the behavior of infected wounds, the established wound healing model was then colonized with S. aureus, and the efficacy of a novel antibacterial agent, XZ.700, was investigated. Viable counts (CFU/tissue), IF, and ultrastructural analysis (SEM) were performed to evaluate S. aureus colonization inside and around the wound bed in an experimental window of 3 h of colonization and 24 h of treatment. Results: Endolysin showed an efficacy in counteracting bacterial growth and invasion within the wound bed, reducing the S. aureus load compared to its placebo, thanks to its selective antimicrobial activity interfering with biofilm formation. Conclusions: The preclinical in vitro infected wound model on FT-kin showed interesting applications to assess the repair efficacy of dermo-pharmaceutical and cosmetic formulations.
... TGF-β plays a pivotal role in fibrosis development by promoting EMT induction [28], and its activation is associated with mitochondrial dysfunction in the lung [29]. Intracellular ATP level and mitochondrial membrane potential (MtMP) were assessed with or without PN-101 in CCD8-Lu cells and HBECs to investigate the effect of TGF-β on mitochondrial function in lung fibroblasts and epithelial cells ( Figure 1C). ...
Idiopathic pulmonary fibrosis (IPF) is a pulmonary disease characterized by excessive extracellular matrix protein deposition in the lung interstitium, subsequently causing respiratory failure. IPF still has a high medical unmet requirement due to the lack of effective treatments to inhibit disease progression. The etiology of IPF remains unclear, but mitochondrial dysfunction is considered to be associated with IPF development. Therefore, targeting mitochondrial abnormalities would be a promising strategy for treating IPF. Recently, exogenous mitochondrial transplantation has been beneficial for treating mitochondrial dysfunction. The current study aimed to examine the therapeutic effect of mitochondrial transplantation on IPF in vitro and in vivo. Mitochondria were isolated from human umbilical cord mesenchymal stem cells, referred to as PN-101. Human lung fibroblasts and human bronchial epithelial cells were exposed to transforming growth factor-β, followed by PN-101 treatment to determine the in vitro efficacy of mitochondrial transplantation. An IPF mouse model established by a single intratracheal instillation of bleomycin was utilized to determine the in vivo efficacy of the intravenously treated mitochondria. PN-101 attenuated mitochondrial damage, inhibited EMC production, and suppressed epithelial-to-mesenchymal transition in vitro. Additionally, intravenous PN-101 administration alleviated bleomycin-induced fibrotic processes in the IPF mouse model with a therapeutic context. Our data indicate that PN-101 is a novel and potential therapeutic agent for IPF.
... disrupts normal kidney structure and can lead to organ failure. Some fibroblasts express contractile genes, such as Acta2 (encoding αSma), and are therefore called "myofibroblasts" 14 . Recent single-cell RNA-sequencing (scRNA-seq) analysis of human CKD demonstrated that activated fibroblasts exhibit highest ECM related gene expression scores, indicating their role as main ECM-producing cells in the chronically diseased kidney 15 . ...
Fibrosis is a common outcome of numerous pathologies, including chronic kidney disease (CKD), a progressive renal function deterioration. Current approaches to target activated fibroblasts, key effector contributors to fibrotic tissue remodeling, lack specificity. Here, we report Gucy1α1 as a specific kidney fibroblast marker. Gucy1α1 levels significantly increased over the course of two clinically relevant murine CKD models and directly correlated with established fibrosis markers. Immunofluorescent (IF) imaging showed that Gucy1α1 comprehensively labelled cortical and medullary quiescent and activated fibroblasts in the control kidney and throughout injury progression, respectively. Unlike traditionally used markers platelet derived growth factor receptor beta (Pdgfrβ) and vimentin (Vim), Gucy1α1 did not overlap with off-target populations such as podocytes. Notably, Gucy1α1 labelled kidney fibroblasts in both male and female mice. Furthermore, we observed elevated GUCY1α1 expression in the human fibrotic kidney and lung. Studies in the murine models of cardiac and liver fibrosis revealed Gucy1α1 elevation in activated Pdgfrβ-, Vim- and alpha smooth muscle actin (αSma)-expressing fibroblasts paralleling injury progression and resolution. Overall, we demonstrate Gucy1α1 as an exclusive fibroblast marker in both sexes. Due to its multiorgan translational potential, GUCY1α1 might provide a novel promising strategy to specifically target and mechanistically examine fibroblasts.