Increased periostin expression affects the proliferation, collagen synthesis, migration and invasion of keloid fibroblasts under hypoxic conditions

Zhang, Zhe; Nie, Fangfei; Kang, Chunfu; Chen, Bin; Qin, Zelian; Ma, Jianxun; Ma, Yussanne; Zhao, Xia

doi:10.3892/ijmm.2014.1760

Cited by 67 publications

(59 citation statements)

References 35 publications

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“…The presence of collagen fibres in mast cells of keloids has also been reported by Ehrlich et al (1994) and these authors hypothesised that this was related to an immunological dysfunction [35]. In contrast we believe, supported by recent scientific literature [32,33,50], that keloid formation is primary due to a defect in collagen synthesis and increased mast cell accumulation is a consequence of collagen overproduction or content in the dermis. As a consequence, in an endeavour to reduce the amount of collagen by phagocytosis, growth factors and mediators are released that further stimulate fibroblasts to produce more collagen.…”

supporting

confidence: 82%

Premature Collagen Fibril Formation, Fibroblast-Mast Cell Interactions and Mast Cell-Mediated Phagocytosis of Collagen in Keloids

Arbi

Eksteen

Oberholzer

et al. 2015

Ultrastructural Pathology

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Keloids are benign hyper-proliferative growths of fibrous tissue, where increased fibroblast activity results in abnormal collagen deposition. Excessive inflammation is a characteristic feature of keloids but little is known about the underlying ultrastructural features of keloids related to collagen processing, fibril and fibre formation, the interaction between fibroblasts and associated collagen fibres and mast cells. In this study, the ultrastructure of the dermis of keloid patients was evaluated using light and transmission electron microscopy techniques. Abnormal intracellular premature collagen fibril formation was observed. Phagocytosis of collagen fibrils by mast cells was a common ultrastructural feature of keloid tissue as was a close or direct 2 association between fibroblasts and mast cells. Based on these findings and recent advances in knowledge related to collagen synthesis, fibril formation and processing we hypothesise that keloid formation is primary due to abnormal collagen synthesis where the consequent accumulation of collagen fibres causes increased mast cell recruitment and collagen phagocytosis. Subsequent release of mast cell derived mediators then promotes further collagen synthesis. The observation of early formation in keloid tissue of premature insoluble collagen fibrils supports previous studies that enzymes such as procollagen C-proteinase are important early therapeutic targets.

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supporting

confidence: 82%

Premature Collagen Fibril Formation, Fibroblast-Mast Cell Interactions and Mast Cell-Mediated Phagocytosis of Collagen in Keloids

Arbi

Eksteen

Oberholzer

et al. 2015

Ultrastructural Pathology

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“…Hypoxia has been found to increase the expression of vascular endothelial growth factor (VEGF) in keloid fibroblasts (14). The level of HIF-1α is consistently higher in freshly biopsied keloid tissues than in their associated normal skin borders, which provides direct evidence of a local hypoxic state in keloids (9). However, whether hypoxia drives the differentiation of human dermal fibroblasts into myofibroblasts has not yet been reported, and the way this can influence human scarring is not clear.…”

Section: Introductionmentioning

confidence: 92%

“…Hypoxia inducible factors (HIFs) are a group of transcription factors rapidly activated in hypoxic cells (9). Once activated, these transcription factors regulate the expression of genes that allow cells to adapt to a hypoxic environment.…”

Section: Introductionmentioning

confidence: 99%

Hypoxia drives the transition of human dermal fibroblasts to a myofibroblast-like phenotype via the TGF-β1/Smad3 pathway

Zhao

Guan

Liu

et al. 2016

International Journal of Molecular Medicine

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Keloids, partially considered as benign tumors, are characterized by the overgrowth of fibrosis beyond the boundaries of the wound and are regulated mainly by transforming growth factor (TGF)-β1, which induces the transition of fibroblasts to myofibroblasts. Hypoxia is an important driving force in the development of lung and liver fibrosis by activating hypoxia inducible factor-1α and stimulating epithelial-mesenchymal transition. However, it is unknown whether and hypoxia can influence human dermal scarring. The aim of this study was to investigate whether hypoxia drives the transition of dermal fibroblasts to myofibroblasts and to clarify the potential transduction mechanisms involved. First, we observed that keloids are a relatively hypoxic tissue. Second, we found that hypoxia drives the transition of normal dermal fibroblasts to a myofibroblast-like phenotype [high expression of α-smooth muscle actin (α-SMA) and collagen I and III]. Finally, hypoxia effectively facilitated the nuclear import of the Smad2 and Smad3 complex, while blockade with the Smad3 inhibitor, SIS3, significantly impaired the expression of hypoxia-induced fibrosis-related molecules. Taken together, to the best of our knowledge, this study demonstrates for the first time that hypoxia facilitates the transition of dermal fibroblasts to myofibroblasts through the activation of the TGF-β1/Smad3 signaling pathway and our findings may provide a potential target for the treatment of keloids.

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“…TUBB3 is associated with aggressive tumorigenesis in hypoxic environments [162], where it has been linked with chemoresistance, particularly taxanes [163–165]. This may be relevant to KD where there is evidence of a similarly hypoxic environment [63, 166, 167]. …”

Section: Resultsmentioning

confidence: 99%

Site-specific gene expression profiling as a novel strategy for unravelling keloid disease pathobiology

et al. 2017

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Keloid disease (KD) is a fibroproliferative cutaneous tumour characterised by heterogeneity, excess collagen deposition and aggressive local invasion. Lack of a validated animal model and resistance to a multitude of current therapies has resulted in unsatisfactory clinical outcomes of KD management. In order to address KD from a new perspective, we applied for the first time a site-specific in situ microdissection and gene expression profiling approach, through combined laser capture microdissection and transcriptomic array. The aim here was to analyse the utility of this approach compared with established methods of investigation, including whole tissue biopsy and monolayer cell culture techniques. This study was designed to approach KD from a hypothesis-free and compartment-specific angle, using state-of-the-art microdissection and gene expression profiling technology. We sought to characterise expression differences between specific keloid lesional sites and elucidate potential contributions of significantly dysregulated genes to mechanisms underlying keloid pathobiology, thus informing future explorative research into KD. Here, we highlight the advantages of our in situ microdissection strategy in generating expression data with improved sensitivity and accuracy over traditional methods. This methodological approach supports an active role for the epidermis in the pathogenesis of KD through identification of genes and upstream regulators implicated in epithelial-mesenchymal transition, inflammation and immune modulation. We describe dermal expression patterns crucial to collagen deposition that are associated with TGFβ-mediated signalling, which have not previously been examined in KD. Additionally, this study supports the previously proposed presence of a cancer-like stem cell population in KD and explores the possible contribution of gene dysregulation to the resistance of KD to conventional therapy. Through this innovative in situ microdissection gene profiling approach, we provide better-defined gene signatures of distinct KD regions, thereby addressing KD heterogeneity, facilitating differential diagnosis with other cutaneous fibroses via transcriptional fingerprinting, and highlighting key areas for future KD research.

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Increased periostin expression affects the proliferation, collagen synthesis, migration and invasion of keloid fibroblasts under hypoxic conditions

Cited by 67 publications

References 35 publications

Premature Collagen Fibril Formation, Fibroblast-Mast Cell Interactions and Mast Cell-Mediated Phagocytosis of Collagen in Keloids

Premature Collagen Fibril Formation, Fibroblast-Mast Cell Interactions and Mast Cell-Mediated Phagocytosis of Collagen in Keloids

Hypoxia drives the transition of human dermal fibroblasts to a myofibroblast-like phenotype via the TGF-β1/Smad3 pathway

Site-specific gene expression profiling as a novel strategy for unravelling keloid disease pathobiology

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