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Boris Hinz - One of the best experts on this subject based on the ideXlab platform.
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mir 127 3p is an epigenetic activator of myofibroblast senescence situated within the microrna enriched dlk1 dio3 imprinted domain on mouse chromosome 12
Journal of Investigative Dermatology, 2020Co-Authors: Markus Auler, Boris Hinz, Vera Bergmeier, Veronika S Georgieva, Lena Pitzler, Christian Frie, Julian Nuchel, Beate Eckes, Bent BrachvogelAbstract:During wound healing, fibroblasts differentiate into nonproliferative contractile Myofibroblasts, contribute to skin repair, and eventually undergo apoptosis or become senescent. MicroRNAs are post-transcriptional regulators of gene expression networks that control cell fate and survival and may also regulate senescence. In this study, we determined the regulated microRNAs in Myofibroblasts isolated from wounds and analyzed their role in senescent myofibroblast formation. Transcriptome profiling showed that a 200 kilobase pair region of the Dlk1-Dio3‒imprinted domain on mouse chromosome 12 encodes for most of the upregulated microRNAs in the entire genome of mouse Myofibroblasts. Among those, miR-127-3p induced a myofibroblast-like phenotype associated with a block in proliferation. Molecular analysis revealed that miR-127-3p induced a prolonged cell cycle arrest with unique molecular features of senescence, including the activation of the senescence-associated β-galactosidase, increase in p53 and p21 levels, inhibition of lamin B1, proliferation factors, and the production of senescence-associated inflammatory and extracellular matrix‒remodeling components. Hence, miR-127-3p emerges as an epigenetic activator regulating the transition from repair to remodeling during skin wound healing but may also induce age-related defects, pathological scarring, and fibrosis, all linked to myofibroblast senescence.
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Evasion of apoptosis by Myofibroblasts: a hallmark of fibrotic diseases
Nature Reviews Rheumatology, 2020Co-Authors: Boris Hinz, David LagaresAbstract:Myofibroblasts are important mediators of wound healing but can also perpetuate fibrosis in diseases such as systemic sclerosis by evading apoptosis. Therapeutic targeting of the survival mechanisms used by these cells in fibrotic disease holds promise for the reversal of fibrosis. Organ fibrosis is a lethal outcome of autoimmune rheumatic diseases such as systemic sclerosis (SSc). Myofibroblasts are scar-forming cells that are responsible for the excessive synthesis, deposition and remodelling of extracellular matrix proteins in SSc. Persistent myofibroblast activity leads to progressive tissue fibrosis and distortion of the normal tissue architecture, resulting in organ failure and, ultimately, in death. The termination of myofibroblast activity is suppressed in fibrotic disease by biomechanical and biochemical cues, which assist myofibroblast escape from apoptosis, thereby halting their elimination. Evasion of apoptosis results in persistent myofibroblast activation and/or the differentiation of Myofibroblasts into a pro-fibrotic or pro-inflammatory senescent phenotype, thereby preventing fibrosis resolution. Targeting myofibroblast apoptosis and reprogramming these cells to become scar-resolving cells are emerging as novel therapeutic strategies to reverse established fibrosis. Organ fibrosis is a lethal outcome of autoimmune rheumatic diseases such as systemic sclerosis. Myofibroblasts are scar-forming cells that are ultimately responsible for the excessive synthesis, deposition and remodelling of extracellular matrix proteins in fibrosis. Advances have been made in our understanding of the mechanisms that keep Myofibroblasts in an activated state and control myofibroblast functions. However, the mechanisms that help Myofibroblasts to persist in fibrotic tissues remain poorly understood. Myofibroblasts evade apoptosis by activating molecular mechanisms in response to pro-survival biomechanical and growth factor signals from the fibrotic microenvironment, which can ultimately lead to the acquisition of a senescent phenotype. Growing evidence suggests that Myofibroblasts and senescent Myofibroblasts, rather than being resistant to apoptosis, are actually primed for apoptosis owing to concomitant activation of cell death signalling pathways; these cells are poised to apoptose when survival pathways are inhibited. This knowledge of apoptotic priming has paved the way for new therapies that trigger apoptosis in Myofibroblasts by blocking pro-survival mechanisms, target senescent myofibroblast for apoptosis or promote the reprogramming of Myofibroblasts into scar-resolving cells. These novel strategies are not only poised to prevent progressive tissue scarring, but also have the potential to reverse established fibrosis and to regenerate chronically injured tissues.
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Evasion of apoptosis by Myofibroblasts: a hallmark of fibrotic diseases
Nature reviews. Rheumatology, 2019Co-Authors: Boris Hinz, David LagaresAbstract:Organ fibrosis is a lethal outcome of autoimmune rheumatic diseases such as systemic sclerosis. Myofibroblasts are scar-forming cells that are ultimately responsible for the excessive synthesis, deposition and remodelling of extracellular matrix proteins in fibrosis. Advances have been made in our understanding of the mechanisms that keep Myofibroblasts in an activated state and control myofibroblast functions. However, the mechanisms that help Myofibroblasts to persist in fibrotic tissues remain poorly understood. Myofibroblasts evade apoptosis by activating molecular mechanisms in response to pro-survival biomechanical and growth factor signals from the fibrotic microenvironment, which can ultimately lead to the acquisition of a senescent phenotype. Growing evidence suggests that Myofibroblasts and senescent Myofibroblasts, rather than being resistant to apoptosis, are actually primed for apoptosis owing to concomitant activation of cell death signalling pathways; these cells are poised to apoptose when survival pathways are inhibited. This knowledge of apoptotic priming has paved the way for new therapies that trigger apoptosis in Myofibroblasts by blocking pro-survival mechanisms, target senescent myofibroblast for apoptosis or promote the reprogramming of Myofibroblasts into scar-resolving cells. These novel strategies are not only poised to prevent progressive tissue scarring, but also have the potential to reverse established fibrosis and to regenerate chronically injured tissues.
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the myofibroblast in wound healing and fibrosis answered and unanswered questions
F1000Research, 2016Co-Authors: Marieluce Bochatonpiallat, Giulio Gabbiani, Boris HinzAbstract:The discovery of the myofibroblast has allowed definition of the cell responsible for wound contraction and for the development of fibrotic changes. This review summarizes the main features of the myofibroblast and the mechanisms of myofibroblast generation. Myofibroblasts originate from a variety of cells according to the organ and the type of lesion. The mechanisms of myofibroblast contraction, which appear clearly different to those of smooth muscle cell contraction, are described. Finally, we summarize the possible strategies in order to reduce myofibroblast activities and thus influence several pathologies, such as hypertrophic scars and organ fibrosis.
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YAP1 Is a Driver of Myofibroblast Differentiation in Normal and Diseased Fibroblasts
The American journal of pathology, 2015Co-Authors: Bram Piersma, Boris Hinz, Stellar Boo, Saskia De Rond, Paul M. N. Werker, Marike Van Beuge, Ruud A. BankAbstract:Dupuytren disease is a fibrotic disorder characterized by contraction of myofibroblast-rich cords and nodules in the hands. The Hippo member Yes-associated protein 1 (YAP1) is activated by tissue stiffness and the profibrotic transforming growth factor-β1, but its role in cell fibrogenesis is yet unclear. We hypothesized that YAP1 regulates the differentiation of dermal fibroblasts into highly contractile Myofibroblasts and that YAP1 governs the maintenance of a myofibroblast phenotype in primary Dupuytren cells. Knockdown of YAP1 in transforming growth factor-β1-stimulated dermal fibroblasts decreased the formation of contractile smooth muscle α-actin stress fibers and the deposition of collagen type I, which are hallmark features of Myofibroblasts. Translating our findings to a clinically relevant model, we found that YAP1 deficiency in Dupuytren disease Myofibroblasts resulted in decreased expression of ACTA2, COL1A1, and CCN2 mRNA, but this did not result in decreased protein levels. YAP1-deficient Dupuytren Myofibroblasts showed decreased contraction of a collagen hydrogel. Finally, we showed that YAP1 levels and nuclear localization were elevated in affected Dupuytren disease tissue compared with matched control tissue and partly co-localized with smooth muscle α-actin-positive cells. In conclusion, our data show that YAP1 is a regulator of myofibroblast differentiation and contributes to the maintenance of a synthetic and contractile phenotype, in both transforming growth factor-β1-induced myofibroblast differentiation and primary Dupuytren Myofibroblasts.
James J Tomasek - One of the best experts on this subject based on the ideXlab platform.
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whole animal knockout of smooth muscle alpha actin does not alter excisional wound healing or the fibroblast to myofibroblast transition
Wound Repair and Regeneration, 2013Co-Authors: James J Tomasek, Robert J Schwartz, Carol J Haaksma, Eric W HowardAbstract:The contractile phenotype and function of Myofibroblasts have been proposed to play a critical role in wound closure. It has been hypothesized smooth muscle alpha-actin expressed in Myofibroblasts is critical for their formation and function. We have used smooth muscle α-actin-null mice to test this hypothesis. Full-thickness excisional wounds closed at a similar rate in smooth muscle α-actin -null and wild type mice. In addition, fibroblasts in smooth muscle α-actin-null granulation tissue when immunostained with a monoclonal antibody that recognizes all muscle actin isoforms exhibited a myofibroblast-like distribution and a stress fiber-like pattern, demonstrating that these cells acquired the myofibroblast phenotype. Dermal fibroblasts from smooth muscle α-actin-null and wild type mice formed stress fibers and supermature focal adhesions, and generated similar amounts of contractile force in response to transforming growth factor-β1. Smooth muscle γ-actin and skeletal muscle alpha-actin were expressed in smooth muscle α-actin-null Myofibroblasts, as demonstrated by immunostaining, real-time PCR, and mass spectrometry. These results demonstrate that smooth muscle α-actin is not necessary for myofibroblast formation and function and for wound closure, and that smooth muscle γ-actin and skeletal muscle α-actin may be able to functionally compensate for the lack of smooth muscle α-actin in Myofibroblasts.
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whole animal knockout of smooth muscle alpha actin does not alter excisional wound healing or the fibroblast to myofibroblast transition
Wound Repair and Regeneration, 2013Co-Authors: James J Tomasek, Robert J Schwartz, Carol J Haaksma, Eric W HowardAbstract:The contractile phenotype and function of Myofibroblasts have been proposed to play a critical role in wound closure. It has been hypothesized that smooth muscle α-actin expressed in Myofibroblasts is critical for its formation and function. We have used smooth muscle α-actin-null mice to test this hypothesis. Full-thickness excisional wounds closed at a similar rate in smooth muscle α-actin-null and wild-type mice. In addition, fibroblasts in smooth muscle α-actin-null granulation tissue when immunostained with a monoclonal antibody that recognizes all muscle actin isoforms exhibited a myofibroblast-like distribution and a stress fiber-like pattern, showing that these cells acquired the myofibroblast phenotype. Dermal fibroblasts from smooth muscle α-actin-null and wild-type mice formed stress fibers and supermature focal adhesions, and generated similar amounts of contractile force in response to transforming growth factor-β1. Smooth muscle γ-actin and skeletal muscle α-actin were expressed in smooth muscle α-actin-null Myofibroblasts, as shown by immunostaining, real-time polymerase chain reaction, and mass spectrometry. These results show that smooth muscle α-actin is not necessary for myofibroblast formation and function and for wound closure, and that smooth muscle γ-actin and skeletal muscle α-actin may be able to functionally compensate for the lack of smooth muscle α-actin in Myofibroblasts.
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Myofibroblasts and mechano-regulation of connective tissue remodelling
Nature Reviews Molecular Cell Biology, 2002Co-Authors: James J Tomasek, Boris Hinz, Giulio Gabbiani, Christine Chaponnier, Robert A. BrownAbstract: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 of cells, not least owing to its transient appearance in association with connective-tissue injury and to the difficulties in establishing its role in the production of tissue contracture. It is clear that our understanding of the myofibroblast — its origins, functions and molecular regulation — will have a profound influence on the future effectiveness not only of tissue engineering but also of regenerative medicine generally. Myofibroblasts are the predominant cell type that are present in granulation tissue of contracting wounds and fibrocontractive diseases, and are also present in some developing or normal adult tissues. The putative function of Myofibroblasts is generating force and altering tissue tension. Myofibroblasts were initially characterized by the presence of microfilament bundles (stress fibres) that are not present in tissue fibroblasts. Two types of Myofibroblasts can be characterized: proto-Myofibroblasts, which contain stress fibres but lack α-smooth muscle (SM) actin, and differentiated Myofibroblasts, which contain both stress fibres and α-SM actin. The formation and maintenance of the proto-myofibroblast is dependent on isometric tension applied onto a non-compliant substratum. The expression of α-SM actin that is characteristic of the differentiated myofibroblast is dependent on interaction of ED-A fibronectin with the cell surface and transforming growth factor β1 (TGF-β1). Myofibroblasts in granulation tissue and in in vitro contraction assays generate contractile force in response to certain SM agonists (such as endothelin). Increased expression of α-SM actin is directly correlated with increased force generation by Myofibroblasts. We postulate a positive feedback loop in which tension facilitates TGF-β1 production and/or activation and α-SM actin expression. This, in turn, increases force production and tension development. Myofibroblast contraction is regulated by the level of myosin light chain phosphorylation and the key regulatory step seems to be activation of the Rho–Rho-kinase pathway, which results in the inhibition of myosin light chain phosphatase and increased myosin light chain phosphorylation and contraction. Tissue contraction (contracture) depends on collagen remodelling, a process that is dominated by extracellular-matrix reorganization under the mechanical control of myofibroblast contraction.
Eric W Howard - One of the best experts on this subject based on the ideXlab platform.
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whole animal knockout of smooth muscle alpha actin does not alter excisional wound healing or the fibroblast to myofibroblast transition
Wound Repair and Regeneration, 2013Co-Authors: James J Tomasek, Robert J Schwartz, Carol J Haaksma, Eric W HowardAbstract:The contractile phenotype and function of Myofibroblasts have been proposed to play a critical role in wound closure. It has been hypothesized smooth muscle alpha-actin expressed in Myofibroblasts is critical for their formation and function. We have used smooth muscle α-actin-null mice to test this hypothesis. Full-thickness excisional wounds closed at a similar rate in smooth muscle α-actin -null and wild type mice. In addition, fibroblasts in smooth muscle α-actin-null granulation tissue when immunostained with a monoclonal antibody that recognizes all muscle actin isoforms exhibited a myofibroblast-like distribution and a stress fiber-like pattern, demonstrating that these cells acquired the myofibroblast phenotype. Dermal fibroblasts from smooth muscle α-actin-null and wild type mice formed stress fibers and supermature focal adhesions, and generated similar amounts of contractile force in response to transforming growth factor-β1. Smooth muscle γ-actin and skeletal muscle alpha-actin were expressed in smooth muscle α-actin-null Myofibroblasts, as demonstrated by immunostaining, real-time PCR, and mass spectrometry. These results demonstrate that smooth muscle α-actin is not necessary for myofibroblast formation and function and for wound closure, and that smooth muscle γ-actin and skeletal muscle α-actin may be able to functionally compensate for the lack of smooth muscle α-actin in Myofibroblasts.
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whole animal knockout of smooth muscle alpha actin does not alter excisional wound healing or the fibroblast to myofibroblast transition
Wound Repair and Regeneration, 2013Co-Authors: James J Tomasek, Robert J Schwartz, Carol J Haaksma, Eric W HowardAbstract:The contractile phenotype and function of Myofibroblasts have been proposed to play a critical role in wound closure. It has been hypothesized that smooth muscle α-actin expressed in Myofibroblasts is critical for its formation and function. We have used smooth muscle α-actin-null mice to test this hypothesis. Full-thickness excisional wounds closed at a similar rate in smooth muscle α-actin-null and wild-type mice. In addition, fibroblasts in smooth muscle α-actin-null granulation tissue when immunostained with a monoclonal antibody that recognizes all muscle actin isoforms exhibited a myofibroblast-like distribution and a stress fiber-like pattern, showing that these cells acquired the myofibroblast phenotype. Dermal fibroblasts from smooth muscle α-actin-null and wild-type mice formed stress fibers and supermature focal adhesions, and generated similar amounts of contractile force in response to transforming growth factor-β1. Smooth muscle γ-actin and skeletal muscle α-actin were expressed in smooth muscle α-actin-null Myofibroblasts, as shown by immunostaining, real-time polymerase chain reaction, and mass spectrometry. These results show that smooth muscle α-actin is not necessary for myofibroblast formation and function and for wound closure, and that smooth muscle γ-actin and skeletal muscle α-actin may be able to functionally compensate for the lack of smooth muscle α-actin in Myofibroblasts.
Giulio Gabbiani - One of the best experts on this subject based on the ideXlab platform.
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the myofibroblast in wound healing and fibrosis answered and unanswered questions
F1000Research, 2016Co-Authors: Marieluce Bochatonpiallat, Giulio Gabbiani, Boris HinzAbstract:The discovery of the myofibroblast has allowed definition of the cell responsible for wound contraction and for the development of fibrotic changes. This review summarizes the main features of the myofibroblast and the mechanisms of myofibroblast generation. Myofibroblasts originate from a variety of cells according to the organ and the type of lesion. The mechanisms of myofibroblast contraction, which appear clearly different to those of smooth muscle cell contraction, are described. Finally, we summarize the possible strategies in order to reduce myofibroblast activities and thus influence several pathologies, such as hypertrophic scars and organ fibrosis.
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the myofibroblast one function multiple origins
American Journal of Pathology, 2007Co-Authors: Boris Hinz, Victor J Thannickal, Marieluce Bochatonpiallat, Sem H Phan, Andrea Galli, Giulio GabbianiAbstract:The crucial role played by the myofibroblast in wound healing and pathological organ remodeling is well established; the general mechanisms of extracellular matrix synthesis and of tension production by this cell have been amply clarified. This review discusses the pattern of myofibroblast accumulation and fibrosis evolution during lung and liver fibrosis as well as during atheromatous plaque formation. Special attention is paid to the specific features characterizing each of these processes, including the spectrum of different myofibroblast precursors and the distinct pathways involved in the formation of differentiated Myofibroblasts in each lesion. Thus, whereas in lung fibrosis it seems that most Myofibroblasts derive from resident fibroblasts, hepatic stellate cells are the main contributor for liver fibrosis and media smooth muscle cells are the main contributor for the atheromatous plaque. A better knowledge of the molecular mechanisms conducing to the appearance of differentiated Myofibroblasts in each pathological situation will be useful for the understanding of fibrosis development in different organs and for the planning of strategies aiming at their prevention and therapy.
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the stroma reaction myofibroblast a key player in the control of tumor cell behavior
The International Journal of Developmental Biology, 2004Co-Authors: Alexis Desmouliere, Christelle Guyot, Giulio GabbianiAbstract:The cooperation between epithelial and mesenchymal cells is essential for embryonic development and probably plays an important role in pathological phenomena such as wound healing and tumor progression. It is well known that many epithelial tumors are characterized by the local accumulation of connective tissue cells and extracellular material; this phenomenon has been called the stroma reaction. One of the cellular components of the stroma reaction is the myofibroblast, a modulated fibroblast which has acquired the capacity to neoexpress α-smooth muscle actin, the actin isoform typical of vascular smooth muscle cells, and to synthesize important amounts of collagen and other extracellular matrix components. It is now well accepted that the myofibroblast is a key cell for the connective tissue remodeling which takes place during wound healing and fibrosis development. Myofibrobasts are capable of remodeling connective tissue but also interact with epithelial cells and other connective tissue cells and may thus control such phenomena as tumor invasion and angiogenesis. In this review we discuss the mechanisms of myofibroblast evolution during fibrotic and malignant conditions and the interaction of Myofibroblasts with other cells in order to control tumor progression. On this basis we suggest that the myofibroblast may represent a new important target of antitumor therapy.
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Myofibroblasts and mechano-regulation of connective tissue remodelling
Nature Reviews Molecular Cell Biology, 2002Co-Authors: James J Tomasek, Boris Hinz, Giulio Gabbiani, Christine Chaponnier, Robert A. BrownAbstract: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 of cells, not least owing to its transient appearance in association with connective-tissue injury and to the difficulties in establishing its role in the production of tissue contracture. It is clear that our understanding of the myofibroblast — its origins, functions and molecular regulation — will have a profound influence on the future effectiveness not only of tissue engineering but also of regenerative medicine generally. Myofibroblasts are the predominant cell type that are present in granulation tissue of contracting wounds and fibrocontractive diseases, and are also present in some developing or normal adult tissues. The putative function of Myofibroblasts is generating force and altering tissue tension. Myofibroblasts were initially characterized by the presence of microfilament bundles (stress fibres) that are not present in tissue fibroblasts. Two types of Myofibroblasts can be characterized: proto-Myofibroblasts, which contain stress fibres but lack α-smooth muscle (SM) actin, and differentiated Myofibroblasts, which contain both stress fibres and α-SM actin. The formation and maintenance of the proto-myofibroblast is dependent on isometric tension applied onto a non-compliant substratum. The expression of α-SM actin that is characteristic of the differentiated myofibroblast is dependent on interaction of ED-A fibronectin with the cell surface and transforming growth factor β1 (TGF-β1). Myofibroblasts in granulation tissue and in in vitro contraction assays generate contractile force in response to certain SM agonists (such as endothelin). Increased expression of α-SM actin is directly correlated with increased force generation by Myofibroblasts. We postulate a positive feedback loop in which tension facilitates TGF-β1 production and/or activation and α-SM actin expression. This, in turn, increases force production and tension development. Myofibroblast contraction is regulated by the level of myosin light chain phosphorylation and the key regulatory step seems to be activation of the Rho–Rho-kinase pathway, which results in the inhibition of myosin light chain phosphatase and increased myosin light chain phosphorylation and contraction. Tissue contraction (contracture) depends on collagen remodelling, a process that is dominated by extracellular-matrix reorganization under the mechanical control of myofibroblast contraction.
A Jurjus - One of the best experts on this subject based on the ideXlab platform.
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modulation of wound contracture α smooth muscle actin and multispecific vitronectin receptor integrin αvβ3 in the rabbit s experimental model
International Wound Journal, 2009Co-Authors: Cynthia El G Kahi, Bishara S Atiyeh, Inaya Hajj Hussein, Rosalyne Jurjus, Saad A Dibo, A JurjusAbstract:The myofibroblast, a major component of granulation tissue, is a key cell during wound healing, tissue repair and connective tissue remodelling. Persistence of Myofibroblasts within a fibrotic lesion leads to excessive scarring impairing function and aesthetics. Various wound-healing cytokines can be modulated by topical application of active agents to promote optimal wound healing and improve scar quality. Thus, the myofibroblast may represent an important target for wound-healing modulation to improve the evolution of conditions such as hypertrophic scars. The purpose of this work is to study the modulation of Myofibroblasts and integrin αvβ3 in a full thickness wound performed on rabbits treated with different topical agents using: (1) saline, (2) Tegaderm occlusive dressing (3) silver sulfadiazine and (4) moist exposed burn ointment (MEBO). The reepithelialisation was 4 days faster in the MEBO group compared with the other therapies with less oedema formation, delayed contraction, less inflammatory cells and the lowest transepidermal water loss (TEWL) resulting in a soft scar. Although α-smooth muscle actin (α-SMA) was the highest around day 12 in the MEBO group, wound contraction and myofibroblast’s activity were the least for the same period probably because of a downregulation of the integrin αvβ3. It seems that the effect of MEBO could be more pronounced on force transmission rather then on force generation. Greater insight into the pathology of scars may translate into non surgical treatments in the future and further work in myofibroblast biology will eventually result in efficient pharmacological tools, improving the evolution of healing and scar formation.
