Normal skin and hypertrophic scar fibroblasts differentially regulate collagen and fibronectin expression as well as mitochondrial membrane potential in response to basic fibroblast growth factor.
01 Apr 2011-Brazilian Journal of Medical and Biological Research (Braz J Med Biol Res)-Vol. 44, Iss: 5, pp 402-410
TL;DR: BFGF has differential effects and mechanisms on fibroblasts of the normal skin and hypertrophic scars, indicating that bFGF may play a role in the early phase of skin wound healing and post-burn scar formation.
Abstract: Basic fibroblast growth factor (bFGF) regulates skin wound healing; however, the underlying mechanism remains to be defined. In the present study, we determined the effects of bFGF on the regulation of cell growth as well as collagen and fibronectin expression in fibroblasts from normal human skin and from hypertrophic scars. We then explored the involvement of mitochondria in mediating bFGF-induced effects on the fibroblasts. We isolated and cultivated normal and hypertrophic scar fibroblasts from tissue biopsies of patients who underwent plastic surgery for repairing hypertrophic scars. The fibroblasts were then treated with different concentrations of bFGF (ranging from 0.1 to 1000 ng/mL). The growth of hypertrophic scar fibroblasts became slower with selective inhibition of type I collagen production after exposure to bFGF. However, type III collagen expression was affected in both normal and hypertrophic scar fibroblasts. Moreover, fibronectin expression in the normal fibroblasts was up-regulated after bFGF treatment. bFGF (1000 ng/mL) also induced mitochondrial depolarization in hypertrophic scar fibroblasts (P < 0.01). The cellular ATP level decreased in hypertrophic scar fibroblasts (P < 0.05), while it increased in the normal fibroblasts following treatment with bFGF (P < 0.01). These data suggest that bFGF has differential effects and mechanisms on fibroblasts of the normal skin and hypertrophic scars, indicating that bFGF may play a role in the early phase of skin wound healing and post-burn scar formation.
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TL;DR: A basic science review of fibroblast heterogeneity in wound healing, cancer, organ fibrosis, and human dermal architecture is presented and it is hoped this information can spur readers to consider both what questions in plastic surgery can be studied from the lens of fiboblast heterogeneity, and how these preclinical insights can be translated to improving care of patients.
Abstract: Fibroblasts' integral role in tissue development, maintenance, and disease represents a fast-growing field of basic science research. Although fibroblasts were long thought to be a homogeneous cell population, recent research has illuminated the unforeseen complexity of these cells, giving rise to the rapidly expanding research field of "fibroblast heterogeneity." Fibroblasts play a critical role in states of tissue fibrosis such as skin scarring, which affects hundreds of millions of patients annually and causes severe aesthetic, developmental, and functional morbidity. Beyond scarring, major organ fibrosis is an enormous public health concern responsible for nearly half of all deaths in the United States. Because fibrosis is a conserved response to tissue damage in all organs, the study of fibroblasts throughout the body may help us to understand their role in the conditions most relevant to plastic and reconstructive surgery-for instance, skin scarring (eg, from burns, traumatic lacerations, or surgical incisions), "pathological" scarring (hypertrophic scars, keloids), and capsular contracture. Here, we present a basic science review of fibroblast heterogeneity in wound healing, cancer, organ fibrosis, and human dermal architecture. The field of fibroblast heterogeneity is young, and many of the insights discussed have yet to be translated clinically. However, plastic surgeons stand in a unique position to bridge these discoveries into clinical realities. We hope this information can spur readers to consider both what questions in plastic surgery can be studied from the lens of fibroblast heterogeneity, and how these preclinical insights can be translated to improving care of our patients.
10 citations
Journal Article•
TL;DR: ASMq reduces TGF-β1, increases Smad7 mRNA and protein expression through regulating TGFβ-1/Smad signaling pathway, inhibiting HSFs proliferation and reducing extracellular collagen deposition.
Abstract: Background: To study the effect of abnormal savda munziq (ASMq) on TGF-β1 and Smad7 expression in hypertrophic scar fibroblasts (HSFs) and to preliminarily assess the function of abnormal savda munziq in hypertrophic scar formation at the molecular biology level. Methods: HSFs were cultured in vitro. RT-PCR and Western-blot were used to investigate the influence of 48-h treatment with ASMq at different concentrations (0 mg/mL, 0.1 mg/mL, 0.4 mg/mL, and 0.7 mg/mL) on TGF-β1 and Smad7 mRNA and protein expression levels. Results: After 48-h treatment with ASMq, the expression of TGF-β1 mRNA and protein gradually decreased in HSFs as the concentration increased. In contrary, Smad7 mRNA and protein expression were positively correlated with ASMq concentration. Conclusions: ASMq reduces TGF-β1, increases Smad7 mRNA and protein expression through regulating TGFβ-1/Smad signaling pathway, inhibiting HSFs proliferation and reducing extracellular collagen deposition.
6 citations
Cites background from "Normal skin and hypertrophic scar f..."
...TGF-β1 is a cytokine that plays multiple biological roles affecting the entire wound healing process, including the inflammatory reaction and extracellular matrix deposition [4]....
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TL;DR: Histological analysis showed that highdose ASMq (1200 mg/kg) could enhance the softening of HTS of rabbit ears and increase the compliance as shown in general, and Ultrastructure analysis showed the fibroblasts, pro-collagen, collagen, endoplasmic reticulum and ribosomes were reduced gradually with increasedASMq dose.
Abstract: Objective
To investigate whether administrating Abnormal Savda Munziq (ASMq), a traditional Uighur herbal preparation used for the prevention or treatment of diseases, affects hypertrophic scar (HTS) formation by using an established rabbit ear model.
5 citations
Cites background from "Normal skin and hypertrophic scar f..."
...which compromise the appearance of healing skin and are commonly associated with contractures that limit movement and function of involved joints and facial features.((17)) HTS formation is a complex pathologic process of dermal fibrosis and remains a difficult problem to prevent and treat....
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TL;DR: 89 proteins present differently in the hypertrophic scar compared to normal skin by iTRAQ technology, which might indicate the pathologic process of hypertrophic Scar formation and guide us to propose new strategies against the hypertension scar.
Abstract: A hypertrophic scar is a unique fibrotic disease that only exists in humans. Despite advances in burn care and rehabilitation, as well as progress in the management during these decades, the hypertrophic scar remains hard to cure following surgical methods and drugs for treatment. In this study, we are looking forward to finding the multitude of possible traumatic mechanisms and the underlying molecular signal ways in the formation of the hypertrophic scar. We used isobaric tags for relative and absolute quantitation (iTRAQ) labeling technology, followed by high-throughput 2D LC-MS/MS, to determine relative quantitative differential proteins between the hypertrophic scar and normal skin tissue. A total of 3166 proteins were identified with a high confidence (≥95 % confidence). And, a total of 89 proteins were identified as the differential proteins between the hypertrophic scar and normal skin, among which 41 proteins were up-regulated and 48 proteins were down-regulated in the hypertrophic scar. GO-Analysis indicated the up-regulated proteins were involved in extracellular matrix, whereas the down-regulated proteins were involved in dynamic junction and structural molecule activity. In our study, we demonstrate 89 proteins present differently in the hypertrophic scar compared to normal skin by iTRAQ technology, which might indicate the pathologic process of hypertrophic scar formation and guide us to propose new strategies against the hypertrophic scar.
5 citations
TL;DR: In this paper, the authors created entirely biological tissue-engineered vascular grafts using sheets of cell-assembled extracellular matrix (CAM) produced by human fibroblasts in vitro.
Abstract: We have created entirely biological tissue-engineered vascular grafts (TEVGs) using sheets of cell-assembled extracellular matrix (CAM) produced by human fibroblasts in vitro. A large animal TEVG would allow long-term pre-clinical studies in a clinically relevant setting (graft size and allogeneic setting). Therefore, canine, porcine, ovine, and human skin fibroblasts were compared for their ability to form CAM sheets. Serum sourcing greatly influenced CAM production in a species-dependent manner. Ovine cells produced the most homogenous and strongest animal CAM sheets but remained ≈3-fold weaker than human sheets despite variations of serum, ascorbate, insulin, or growth factor supplementations. Key differences in cell growth dynamics, tissue development, and tissue architecture and composition were observed between human and ovine. This study demonstrates critical species-to-species differences in fibroblast behavior and how they pose a challenge when attempting to substitute animal cells for human cells during the development of tissue-engineered constructs that require long-term cultures.
4 citations
References
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TL;DR: The primary goals of the treatment of wounds are rapid wound closure and a functional and aesthetically satisfactory scar.
Abstract: The primary function of the skin is to serve as a protective barrier against the environment. Loss of the integrity of large portions of the skin as a result of injury or illness may lead to major disability or even death. Every year in the United States more than 1.25 million people have burns1 and 6.5 million have chronic skin ulcers caused by pressure, venous stasis, or diabetes mellitus.2 The primary goals of the treatment of wounds are rapid wound closure and a functional and aesthetically satisfactory scar. Recent advances in cellular and molecular biology have greatly expanded our understanding . . .
5,462 citations
"Normal skin and hypertrophic scar f..." refers background in this paper
...PR OV IS IO NA L myofibroblasts disappear from the scar (2)....
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TL;DR: Current understanding of the cellular and molecular mechanisms of fibrogenesis is explored and components of the renin–angiotensin–aldosterone system (ANG II) have been identified as important regulators of fibrosis and are being investigated as potential targets of antifibrotic drugs.
Abstract: Fibrosis is defined by the overgrowth, hardening, and/or scarring of various tissues and is attributed to excess deposition of extracellular matrix components including collagen. Fibrosis is the end result of chronic inflammatory reactions induced by a variety of stimuli including persistent infections, autoimmune reactions, allergic responses, chemical insults, radiation, and tissue injury. Although current treatments for fibrotic diseases such as idiopathic pulmonary fibrosis, liver cirrhosis, systemic sclerosis, progressive kidney disease, and cardiovascular fibrosis typically target the inflammatory response, there is accumulating evidence that the mechanisms driving fibrogenesis are distinct from those regulating inflammation. In fact, some studies have suggested that ongoing inflammation is needed to reverse established and progressive fibrosis. The key cellular mediator of fibrosis is the myofibroblast, which when activated serves as the primary collagen-producing cell. Myofibroblasts are generated from a variety of sources including resident mesenchymal cells, epithelial and endothelial cells in processes termed epithelial/endothelial-mesenchymal (EMT/EndMT) transition, as well as from circulating fibroblast-like cells called fibrocytes that are derived from bone-marrow stem cells. Myofibroblasts are activated by a variety of mechanisms, including paracrine signals derived from lymphocytes and macrophages, autocrine factors secreted by myofibroblasts, and pathogen-associated molecular patterns (PAMPS) produced by pathogenic organisms that interact with pattern recognition receptors (i.e. TLRs) on fibroblasts. Cytokines (IL-13, IL-21, TGF-beta1), chemokines (MCP-1, MIP-1beta), angiogenic factors (VEGF), growth factors (PDGF), peroxisome proliferator-activated receptors (PPARs), acute phase proteins (SAP), caspases, and components of the renin-angiotensin-aldosterone system (ANG II) have been identified as important regulators of fibrosis and are being investigated as potential targets of antifibrotic drugs. This review explores our current understanding of the cellular and molecular mechanisms of fibrogenesis.
3,390 citations
TL;DR: Once MMP has been induced, it causes the release of catabolic hydrolases and activators of such enzymes (including those of caspases) from mitochondria, meaning that mitochondria coordinate the late stage of cellular demise.
Abstract: Irrespective of the morphological features of end-stage cell death (that may be apoptotic, necrotic, autophagic, or mitotic), mitochondrial membrane permeabilization (MMP) is frequently the decisive event that delimits the frontier between survival and death. Thus mitochondrial membranes constitute the battleground on which opposing signals combat to seal the cell's fate. Local players that determine the propensity to MMP include the pro- and antiapoptotic members of the Bcl-2 family, proteins from the mitochondrialpermeability transition pore complex, as well as a plethora of interacting partners including mitochondrial lipids. Intermediate metabolites, redox processes, sphingolipids, ion gradients, transcription factors, as well as kinases and phosphatases link lethal and vital signals emanating from distinct subcellular compartments to mitochondria. Thus mitochondria integrate a variety of proapoptotic signals. Once MMP has been induced, it causes the release of catabolic hydrolases and activators of such enzymes (including those of caspases) from mitochondria. These catabolic enzymes as well as the cessation of the bioenergetic and redox functions of mitochondria finally lead to cell death, meaning that mitochondria coordinate the late stage of cellular demise. Pathological cell death induced by ischemia/reperfusion, intoxication with xenobiotics, neurodegenerative diseases, or viral infection also relies on MMP as a critical event. The inhibition of MMP constitutes an important strategy for the pharmaceutical prevention of unwarranted cell death. Conversely, induction of MMP in tumor cells constitutes the goal of anticancer chemotherapy.
3,340 citations
"Normal skin and hypertrophic scar f..." refers background in this paper
...It has been previously demonstrated that mitochondrial permeability transition causes ΔΨm dissipation, uncoupling of oxidative phosphorylation, ATP depletion, and equilibration of small solutes and ions between the cytosol and the mitochondrial matrix to control cell death or survival (31)....
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...Mitochondria are perceived to be necessary for controlling cell growth, differentiation, death, gene expression and other key cellular processes (31)....
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TL;DR: This review summarizes the results of expression studies that have been performed in rodents, pigs, and humans to localize growth factors and their receptors in skin wounds and reports on genetic studies addressing the functions of endogenous growth factors in the wound repair process.
Abstract: Werner, Sabine, and Richard Grose. Regulation of Wound Healing by Growth Factors and Cytokines. Physiol Rev 83: 835–870, 2003; 10.1152/physrev.00032.2002.—Cutaneous wound healing is a complex proce...
3,234 citations
"Normal skin and hypertrophic scar f..." refers background in this paper
...Fibroblasts play an important role in wound healing by producing a provisional wound healing matrix, including collagen and fibronectin (1)....
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Journal Article•
1,744 citations
"Normal skin and hypertrophic scar f..." refers background in this paper
..., transforming growth factor ß1 (TGF-ß1), insulin-like growth factor 1 (IGF-1), and interleukin-1] and exaggerated responses to these cytokines may also play a role in post-burn scars such as fibrosis and keloids (3)....
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...Excessive myofibroblast differentiation and extracellular matrix formation may be involved in hypertrophic scarring and formation of post-burn scars, such as fibrosis and keloids (3), resulting in hypertrophic scars, the management of which remains a challenge in clinical practice....
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...However, in pathological situations such as hypertrophic scar (HS), myofibroblasts persist in the tissue (3)....
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