scholarly journals The Effects of the Transforming Growth Factor-β1 (TGF-β1) Signaling Pathway on Cell Proliferation and Cell Migration are Mediated by Ubiquitin Specific Protease 4 (USP4) in Hypertrophic Scar Tissue and Primary Fibroblast Cultures

2020 ◽  
Vol 26 ◽  
Author(s):  
Yong Huang ◽  
Yuting Wang ◽  
Xueming Wang ◽  
Lixin Lin ◽  
Peng Wang ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Hypertrophic Scar ◽  
Transforming Growth Factor ◽  
Scar Tissue ◽  
Transforming Growth Factor Β1 ◽  
Primary Fibroblast ◽  
Specific Protease ◽  
Ubiquitin Specific Protease ◽  
Hypertrophic Scar Tissue ◽  
Tgf Β1

scholarly journals Inhibitory Effect of the LY2109761 on the Development of Human Keloid Fibroblasts

2021 ◽  
Vol 2021 ◽  
pp. 1-8
Author(s):  
Xiuxia Wang ◽  
Chuan Gu ◽  
Feng Shang ◽  
Rui Jin ◽  
Jia Zhou ◽  
...  
Keyword(s):  
Hypertrophic Scar ◽  
Transforming Growth Factor ◽  
Scar Tissue ◽  
Inhibitory Effect ◽  
Extracellular Matrix Components ◽  
Matrix Components ◽  
Hypertrophic Scar Tissue ◽  
Β Receptor ◽  
Tgf Β1 ◽  
Keloid Fibroblasts

Keloids are scars characterized by abnormal proliferation of fibroblasts and overproduction of extracellular matrix components including collagen. We previously showed that LY2109761, a transforming growth factor- (TGF-) β receptor inhibitor, suppressed the secretion of matrix components and slowed the proliferation of fibroblasts derived from human hypertrophic scar tissue. However, the exact mechanism underlying this effect remains unclear. Here, we replicated the above results in keloid-derived fibroblasts and show that LY2109761 promoted apoptosis, decreased the phosphorylation of Smad2 and Smad3, and suppressed TGF-β1. These results suggest that the development and pathogenesis of keloids are positively regulated by the Smad2/3 signaling pathway and the upregulation of TGF-β1 receptors. LY2109761 and other inhibitors of these processes may therefore serve as therapeutic targets to limit excessive scarring after injury.

Fibroblasts from Post-Burn Hypertrophic Scar Tissue Synthesize Less Decorin than Normal Dermal Fibroblasts

1998 ◽  
Vol 94 (5) ◽  
pp. 541-547 ◽  
Author(s):  
P. G. Scott ◽  
C. M. Dodd ◽  
A. Ghahary ◽  
Y.J. Shen ◽  
E. E. Tredget
Keyword(s):  
Growth Factor ◽  
Hypertrophic Scar ◽  
Transforming Growth Factor ◽  
Scar Tissue ◽  
Transforming Growth Factor Β1 ◽  
Dermal Fibroblasts ◽  
Northern Analysis ◽  
Cell Strains ◽  
Hypertrophic Scar Tissue ◽  
Small Proteoglycan

1. Fibroblast cultures were established from biopsies of hypertrophic scar and normal dermis taken from nine patients recovering from second- and third-degree burns. The capacity of these fibroblasts to synthesize the small proteoglycan decorin was assessed by quantitative Western blot analysis of conditioned medium collected from confluent cultures. Levels of mRNA for decorin were assessed by quantitative Northern analysis. Since transforming growth factor-β1 is implicated in various fibrotic conditions, including post-burn hypertrophic scar, its effect on decorin synthesis by these paired fibroblast cell strains was assessed. 2. Production of decorin was lower in all cell strains of hypertrophic scar fibroblasts tested, compared with normal dermal fibroblasts cultured from the same patients (mean 49 ± 23%; P < 0.001, n = 9). Levels of mRNA for decorin were also lower (mean 59 ± 28%; P < 0.02, n = 7) but those for biglycan and versican were not significantly different. Four pairs of cell strains were examined at more than one passage and the differences in decorin protein were found to be phenotypically persistent. Treatment of confluent cultures with transforming growth factor-β1 for 3 days caused a reduction in both decorin protein and mRNA in all six strains of hypertrophic scar fibroblasts tested and in five of six strains of normal dermal fibroblasts. An increase in the length of the dermatan sulphate chain on decorin, a previously reported characteristic of this glycosaminoglycan in hypertrophic scar, was seen in all but two of the strains treated with transforming growth factor-β1. The depression of decorin synthesis by transforming growth factor-β1 was reversed on removal of the agent and passaging the fibroblasts. 3. The reduced capacity of fibroblasts in hypertrophic scar tissue to synthesize decorin may have implications for the development of the condition since this small proteoglycan is involved in tissue organization and may also play a role in modulating the activity in vivo of fibrogenic cytokines such as transforming growth factor-β1.

scholarly journals Loureirin B Inhibits Hypertrophic Scar Formation via Inhibition of the TGF-β1-ERK/JNK Pathway

2015 ◽  
Vol 37 (2) ◽  
pp. 666-676 ◽  
Author(s):  
Ting He ◽  
Xiaozhi Bai ◽  
Longlong Yang ◽  
Lei Fan ◽  
Yan Li ◽  
...  
Keyword(s):  
Hypertrophic Scar ◽  
Ex Vivo ◽  
Scar Tissue ◽  
Scar Formation ◽  
Jnk Pathway ◽  
Protein Levels ◽  
Mapk Inhibitors ◽  
Hypertrophic Scar Tissue ◽  
Loureirin B ◽  
Tgf Β1

Background/Aims: Our previous study confirmed that Loureirin B (LB) can inhibit hypertrophic scar formation. However, the mechanism of LB-mediated inhibition of scar formation is still unknown. Methods: Immunohistochemistry was used to detect expression of Col1, FN and TGF-β1 in skin and scar tissue. Fibroblasts were stimulated with TGF-β1 to mimic scar formation. LB or MAPK inhibitors were used to study the pathways involved in the process. Western blotting was used to evaluate the expression of p-JNK, p-ERK, p-p38, Col1 and FN. The contractile capacity of fibroblasts was evaluated using a gel contraction assay. Tissues were cultured ex vivo with LB to further investigate the participation of ERK and JNK in the LB-mediated inhibition of scar formation. Results: FN and Col1 were up regulated in hypertrophic scars. LB down regulated p-ERK and p-JNK in TGF-β1-stimulated fibroblasts, while levels of phosphorylated p38 did not change. The down regulation of p-ERK and p-JNK was associated with a reduction of Col1 and FN. Similarly, inhibition of ERK and JNK down regulated the expression of Col1 and FN in TGF-β1-stimulated fibroblasts. LB down regulated protein levels of p-ERK and p-JNK in cultured hypertrophic scar tissue ex vivo. Conclusions: This study suggests that LB can inhibit scar formation through the ERK/JNK pathway.

Transforming growth factor β1 mediates cell-cycle arrest of primitive hematopoietic cells independent of p21Cip1/Waf1or p27Kip1

Blood ◽  
2001 ◽  
Vol 98 (13) ◽  
pp. 3643-3649 ◽  
Author(s):  
Tao Cheng ◽  
Hongmei Shen ◽  
Neil Rodrigues ◽  
Sebastian Stier ◽  
David T. Scadden
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Stem Cell ◽  
Progenitor Cell ◽  
Transforming Growth Factor ◽  
Hematopoietic Cells ◽  
Transforming Growth Factor Β1 ◽  
Primitive Cell ◽  
Hematopoietic Stem ◽  
Tgf Β1

Abstract The regulation of stem cell proliferation is a poorly understood process balancing rapid, massive blood cell production in times of stress with maintenance of a multipotent stem cell pool over decades of life. Transforming growth factor β1 (TGF-β1) has pleiotropic effects on hematopoietic cells, including the inhibition of primitive cell proliferation. It was recently demonstrated that the cyclin-dependent kinase inhibitors, p21Cip1/Waf1 (p21) and p27Kip1 (p27), can inhibit the proliferation of hematopoietic stem cells and progenitor cells, respectively. The relation of TGF-β1 stimulation to p21 and p27 was examined using a fine-mapping approach to gene expression in individual cells. Abundant TGF-β1 expression and p21 expression were documented in quiescent, cytokine-resistant hematopoietic stem cells and in terminally differentiated mature blood cells, but not in proliferating progenitor cell populations. TGF-β1 receptor (TβR II) was expressed ubiquitously without apparent modulation. Cell- cycle–synchronized 32D cells exposed to TGF-β1 demonstrated a marked antiproliferative effect of TGF-β1, yet neither the level of p21 mRNA nor the protein level of either p21 or p27 was altered. To corroborate these observations in primary cells, bone marrow mononuclear cells derived from mice engineered to be deficient in p21 or p27 were assessed. Progenitor and primitive cell function was inhibited by TGF-β1 equivalently in −/− and +/+ littermate controls. These data indicate that TGF-β1 exerts its inhibition on cell cycling independent of p21 and p27 in hematopoietic cells. TGF-β1 and p21 or p27 participate in independent pathways of stem cell regulation, suggesting that targeting each may provide complementary strategies for enhancing stem or progenitor cell expansion and gene transduction.

scholarly journals Ac-SDKP inhibits transforming growth factor-β1-induced differentiation of human cardiac fibroblasts into myofibroblasts

2010 ◽  
Vol 298 (5) ◽  
pp. H1357-H1364 ◽  
Author(s):  
Hongmei Peng ◽  
Oscar A. Carretero ◽  
Edward L. Peterson ◽  
Nour-Eddine Rhaleb
Keyword(s):  
Cell Proliferation ◽  
Smooth Muscle ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Cardiac Fibroblasts ◽  
Transforming Growth Factor Β1 ◽  
Collagen Production ◽  
Smad7 Expression ◽  
Human Cardiac Fibroblasts ◽  
Tgf Β1

N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) inhibits collagen production and cell proliferation in cultured rat cardiac fibroblasts, but its effect on differentiation of fibroblasts into myofibroblasts is not known. High amounts of transforming growth factor-β1 (TGF-β1) have been found in fibrotic cardiac tissue. TGF-β1 converts fibroblasts into myofibroblasts, which produce more extracellular matrix proteins than fibroblasts. We hypothesized that 1) Ac-SDKP inhibits TGF-β1-induced differentiation of fibroblasts into myofibroblasts; and 2) this effect is mediated in part by blocking phosphorylation of small-mothers-against-decapentaplegic (Smad) 2 and extracellular signal-regulated kinase (ERK) 1/2. For this study, we used human fetal cardiac fibroblasts (HCFs), which do not spontaneously become myofibroblasts when cultured at low passages. We investigated the effect of Ac-SDKP on TGF-β1-induced HCF transformation into myofibroblasts, Smad2 and ERK1/2 phosphorylation, Smad7 expression, cell proliferation, and collagen production. We also investigated TGF-β1 production by HCFs stimulated with endothelin-1 (ET-1). As expected, HCFs treated with TGF-β1 transformed into myofibroblasts as indicated by increased expression of α-smooth muscle actin and a higher proportion of the embryonic isoform of smooth muscle myosin compared with untreated cells. TGF-β1 also increased Smad2 and ERK1/2 phosphorylation but did not affect Smad7 expression. In addition, TGF-β1 stimulated HCF proliferation as indicated by an increase in mitochondrial dehydrogenase activity and collagen production (hydroxyproline assay). Ac-SDKP significantly inhibited all of the effects of TGF-β1. It also inhibited ET-1-stimulated TGF-β1 production. We concluded that Ac-SDKP markedly suppresses differentiation of human cardiac fibroblasts into myofibroblasts, probably by inhibiting the TGF-β/Smad/ERK1/2 signaling pathway, and thus mediating its anti-fibrotic effects.

Influence of exogenous growth factors on the synthesis and secretion of collagen types I and III by explants of normal and healing rabbit ligaments

1994 ◽  
Vol 72 (9-10) ◽  
pp. 403-409 ◽  
Author(s):  
Patricia G. Murphy ◽  
Barbara J. Loitz ◽  
Cyril B. Frank ◽  
David A. Hart
Keyword(s):  
Growth Factors ◽  
Growth Factor ◽  
Collagen Synthesis ◽  
Transforming Growth Factor ◽  
Scar Tissue ◽  
Transforming Growth Factor Β1 ◽  
Type I ◽  
Collagen Types ◽  
Collagen Secretion ◽  
Tgf Β1

In this investigation it has been demonstrated that specific growth factors are able to modify collagen secretion in explants from healing rabbit medial collateral ligaments. The addition of 2.5 ng transforming growth factor β1 (TGF-β1)/mL to 3-week-old scar explants resulted in an increase in the total amount of collagen secreted. Analysis of collagen types I and III individually revealed that the increase mediated by TGF-β1 was due primarily to an increase in collagen type I secretion. This led to a ratio of type I : type III that is closer to that found in normal ligament tissue. The addition of 100 ng insulin-like growth factor 2 (IGF-2) to explant cultures of 3-week-old scar tissue also led to an increase in the quantity of collagen secreted, but the increase was in both type I and III collagens. These effects were observed to a lesser degree in 6-week-old scar tissue, and by 12 weeks postinjury, minimal effects of the growth factors on collagen synthesis was detected. Neither growth factor influenced collagen secretion by normal ligament or synovium. In contrast, IGF-1 (100 ng/mL) or basic fibroblast growth factor (bFGF) (10 ng/mL) did not exert a detectable effect on collagen secretion by any of the normal or healing tissues. These results indicate that TGF-β1 and IGF-2 can modify the metabolic activity of cells in explants of healing ligaments early after injury and may enhance the repair process leading to improved function.Key words: ligament healing, transforming growth factor β1, insulin-like growth factors 1 and 2, basic fibroblast growth factor, collagen synthesis.

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