TGF-beta1 increases cell rigidity by enhancing expression of smooth muscle actin: Keloid-derived fibroblasts as a model for cellular mechanics

Lee, Chih Hung; Hong, Chien Hui; Chen, Ying Ting; Chen, Yu Chien; Shen, Meng‐Ru

doi:10.1016/j.jdermsci.2012.06.004

Cited by 22 publications

(16 citation statements)

References 39 publications

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“…We demonstrated reinforcement of TGFβ1 overexpression in rhNRG1-treated keloid fibroblasts. TGFβ1, a pleiotropic growth factor already known to be upregulated in keloid disease (1,36), has been postulated to facilitate scar expansion through pro-inflammatory and pro-migratory effects (49,50). Interestingly, our finding of NRG1 and ErbB2 co-localisation in keloid dermis was frequently observed within previously described areas of keloid inflammatory infiltrate (51).…”

Section: Discussionsupporting

confidence: 71%

A Role for Neuregulin-1 in Promoting Keloid Fibroblast Migration via ErbB2-mediated Signaling

Jumper¹,

Hodgkinson²,

Paus³

2017

Acta Derm Venerol

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Keloid disease is a fibroproliferative tumour characterised by aggressive local invasion, evident from a clinically and histologically active migrating margin. During combined laser capture microdissection and microarray analysis-based in situ gene expression profiling, we identified upregulation of the polypeptide growth factor neuregulin-1 (NRG1) and ErbB2 oncogene in keloid margin dermis, leading to the hypothesis that NRG1 contributed to keloid margin migration through ErbB2-mediated signalling. The aim of this study was to probe this hypothesis through functional in vitro studies. Exogenous NRG1 addition to keloid and normal skin fibroblasts altered cytokine expression profiles, significantly increased in vitro migration and keloid fibroblast Src and protein tyrosine kinase 2 (PTK2/FAK) gene expression. ErbB2 siRNA knockdown attenuated both keloid fibroblast migration and Src/PTK2 expression, which were not recovered following NRG1 administration, suggesting the NRG1/ErbB2/Src/PTK2 signaling pathway may be a novel regulator of keloid fibroblast migration, and representing a potential new therapeutic target.

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Section: Discussionsupporting

confidence: 71%

A Role for Neuregulin-1 in Promoting Keloid Fibroblast Migration via ErbB2-mediated Signaling

Jumper¹,

Hodgkinson²,

Paus³

2017

Acta Derm Venerol

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“…Secondly, the results presented here demonstrate that mesenspheres treated with scrambled siRNA had a higher μ, E 0 and E ∞ than untreated cells at day 7, and lower at day 14. However, previous work using a scrambled siRNA on fibroblasts demonstrated a lower Young’s modulus than control cells (Lee et al, 2012). In the work presented here mesenspheres treated with N-cadherin or OB-cadherin siRNA were compared to those treated with scrambled siRNA, rather than untreated cells, so as to account for any change in μ, E 0 and E ∞ resulting from siRNA treatment alone.…”

Section: Discussionmentioning

confidence: 81%

The role of adhesion junctions in the biomechanical behaviour and osteogenic differentiation of 3D mesenchymal stem cell spheroids

Griffin

Schiavi

McDevitt

et al. 2017

Journal of Biomechanics

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Osteogenesis of mesenchymal stem cells (MSC) can be regulated by the mechanical environment. MSCs grown in 3D spheroids (mesenspheres) have preserved multi-lineage potential, improved differentiation efficiency, and exhibit enhanced osteogenic gene expression and matrix composition in comparison to MSCs grown in 2D culture. Within 3D mesenspheres, mechanical cues are primarily in the form of cell-cell contraction, mediated by adhesion junctions, and as such adhesion junctions are likely to play an important role in the osteogenic differentiation of mesenspheres. However the precise role of N- and OB-cadherin on the biomechanical behaviour of mesenspheres remains unknown. Here we have mechanically tested mesenspheres cultured in suspension using parallel plate compression to assess the influence of N-cadherin and OB-cadherin adhesion junctions on the viscoelastic properties of the mesenspheres during osteogenesis. Our results demonstrate that N-cadherin and OB-cadherin have different effects on mesensphere viscoelastic behaviour and osteogenesis. When OB-cadherin was silenced, the viscosity, initial and long term Young's moduli and actin stress fibre formation of the mesenspheres increased in comparison to N-cadherin silenced mesenspheres and mesenspheres treated with a scrambled siRNA (Scram) at day 2. Additionally, the increased viscoelastic material properties correlate with evidence of calcification at an earlier time point (day 7) of OB-cadherin silenced mesenspheres but not Scram. Interestingly, both N-cadherin and OB-cadherin silenced mesenspheres had higher BSP2 expression than Scram at day 14. Taken together, these results indicate that N-cadherin and OB-cadherin both influence mesensphere biomechanics and osteogenesis, but play different roles.

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“…The key role that the TGF-β signaling pathway serves in the formation of keloids has been reported in numerous studies ( 37 , 38 ). The TGF-β family is involved in numerous physiological activities, including cell proliferation, migration, differentiation, deposition and ECM remodeling, as well as the modulation of other signaling pathways.…”

Section: Discussionmentioning

confidence: 90%

Ginsenoside Rg3 inhibits keloid fibroblast proliferation, angiogenesis and collagen synthesis in vitro via the TGF‑β/Smad and ERK signaling pathways

et al. 2018

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A wide range of therapeutic options exists for the treatment of keloids, all of which have their own strengths; however, a high risk of side-effects and frequent recurrence remains. Therefore, the present study aimed to identify improved therapeutic approaches or drugs for the treatment of keloids. Ginsenoside Rg3 (Rg3) has been reported to exert numerous antitumor effects, thus indicating that Rg3 may be a potential therapeutic agent that targets keloids. The present study determined the effects of Rg3 on human keloid fibroblasts (KFs) in vitro, and further explored the associated molecular and cellular mechanisms. Keloid scar specimens were obtained from patients, aged between 22 and 35 years, without systemic diseases and primary cells were isolated from keloid tissues. In each assay, KFs were divided into three groups and were cultured in medium with or without various concentrations of Rg3 (50 or 100 μg/ml). Cell viability assay, flow cytometry, quantitative polymerase chain reaction, cell migration assay, immunofluorescence staining, western blot analysis, Transwell cell invasion assay and immunohistochemical analysis were used to analyze the KFs and keloid explant cultures. The results of the present study demonstrated that Rg3 was able to exert an inhibitory effect on the transforming growth factor-β/Smad and extracellular signal-regulated kinase signaling pathways in KFs. The proliferation, migration, invasion, angiogenesis and collagen synthesis of KFs were markedly suppressed following treatment with Rg3. Furthermore, the results of an ex vivo assay indicated that Rg3 inhibited angiogenesis and reduced collagen accumulation in keloids. Significant statistical differences existed between the control and Rg3-treated groups (P<0.05). All of these experimental results suggested that Rg3 may serve as a reliable drug for the treatment of patients with keloids.

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TGF-beta1 increases cell rigidity by enhancing expression of smooth muscle actin: Keloid-derived fibroblasts as a model for cellular mechanics

Cited by 22 publications

References 39 publications

A Role for Neuregulin-1 in Promoting Keloid Fibroblast Migration via ErbB2-mediated Signaling

A Role for Neuregulin-1 in Promoting Keloid Fibroblast Migration via ErbB2-mediated Signaling

The role of adhesion junctions in the biomechanical behaviour and osteogenic differentiation of 3D mesenchymal stem cell spheroids

Ginsenoside Rg3 inhibits keloid fibroblast proliferation, angiogenesis and collagen synthesis in vitro via the TGF‑β/Smad and ERK signaling pathways

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