TGF-β1-induced miR-424 promotes pulmonary myofibroblast differentiation by targeting Slit2 protein expression

Huang, Yapei; Xie, Yan; Abel, Peter W.; Wei, Peng; Plowman, Jocelyn; Toews, Myron L.; Strah, Heather; Siddique, Aleem; Bailey, Kristina L.; Tu, Yaping

doi:10.1016/j.bcp.2020.114172

Cited by 35 publications

(21 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In IPF, pro-fibrotic mediators secreted by activated fibroblasts continue to act on fibroblasts to form a positive feedback, which leads to production of ECM and myofibroblast differentiation ( Wipff et al, 2007 ). TGF-β is considered to be the primary factor that promotes fibroblast differentiation into myofibroblasts ( Huang et al, 2020 ). Myofibroblasts secrete more ECM than fibroblasts.…”

Section: Cells and Regulatorsmentioning

confidence: 99%

Idiopathic Pulmonary Fibrosis: An Update on Pathogenesis

et al. 2022

View full text Add to dashboard Cite

Idiopathic pulmonary fibrosis (IPF) is a progressive, lethal fibrotic lung disease that occurs primarily in middle-aged and elderly adults. It is a major cause of morbidity and mortality. With an increase in life expectancy, the economic burden of IPF is expected to continuously rise in the near future. Although the exact pathophysiological mechanisms underlying IPF remain not known. Significant progress has been made in our understanding of the pathogenesis of this devastating disease in last decade. The current paradigm assumes that IPF results from sustained or repetitive lung epithelial injury and subsequent activation of fibroblasts and myofibroblast differentiation. Persistent myofibroblast phenotype contributes to excessive deposition of the extracellular matrix (ECM) and aberrant lung repair, leading to tissue scar formation, distortion of the alveolar structure, and irreversible loss of lung function. Treatments of patients with IPF by pirfenidone and nintedanib have shown significant reduction of lung function decline and slowing of disease progression in patients with IPF. However, these drugs do not cure the disease. In this review, we discuss recent advances on the pathogenesis of IPF and highlight the development of novel therapeutic strategies against the disease.

show abstract

Section: Cells and Regulatorsmentioning

confidence: 99%

Idiopathic Pulmonary Fibrosis: An Update on Pathogenesis

et al. 2022

View full text Add to dashboard Cite

show abstract

“…TGF-β1 induced upregulation of miR-424 through the Smad3-denpendent signaling pathway, which inhibited the expression of Slit2, an inhibitory protein on TGF-β1 profibrogenic signaling. As a result, miR-424 acts as a positive feedback regulator of the TGF-β1 signaling pathway, promoting the myofibroblast differentiation of HLF ( 26 ). Interestingly, with the treatment of miR-424 inhibitor, Smad3 phosphorylation by TGF-β1 was reduced in HLFs, indicating miR-424 as a positive feedback regulator of TGF-β1/Smad3 synergistically ( 26 ).…”

Section: Tgf-β1-involved Pathway In Ipfmentioning

confidence: 99%

“…As a result, miR-424 acts as a positive feedback regulator of the TGF-β1 signaling pathway, promoting the myofibroblast differentiation of HLF ( 26 ). Interestingly, with the treatment of miR-424 inhibitor, Smad3 phosphorylation by TGF-β1 was reduced in HLFs, indicating miR-424 as a positive feedback regulator of TGF-β1/Smad3 synergistically ( 26 ). Previous findings demonstrated TGF-β1/Smad3-induced NADPH oxidase 4 (NOX4) mediated the production of H 2 O 2 , which was necessary for myofibroblast differentiation of lung mesenchymal cells, providing novel insight into the therapeutic targeting in IPF ( 27 , 28 ).…”

Section: Tgf-β1-involved Pathway In Ipfmentioning

confidence: 99%

TGF‑β1: Gentlemanly orchestrator in idiopathic pulmonary fibrosis (Review)

2021

Int J Mol Med

108

View full text Add to dashboard Cite

Idiopathic pulmonary fibrosis (IPF) is a worldwide disease characterized by the chronic and irreversible decline of lung function. Currently, there is no drug to successfully treat the disease except for lung transplantation. Numerous studies have been devoted to the study of the fibrotic process of IPF and findings showed that transforming growth factor-β1 (TGF-β1) plays a central role in the development of IPF. TGF-β1 promotes the fibrotic process of IPF through various signaling pathways, including the Smad, MAPK, and ERK signaling pathways. There are intersections between these signaling pathways, which provide new targets for researchers to study new drugs. In addition, TGF-β1 can affect the fibrosis process of IPF by affecting oxidative stress, epigenetics and other aspects. Most of the processes involved in TGF-β1 promote IPF, but TGF-β1 can also inhibit it. This review discusses the role of TGF-β1 in IPF. Contents1. Introduction 2. TGF-β1-involved pathway in IPF 3. Discussion 4. Conclusion

show abstract

“…miRNAs are small non-coding RNA molecules that regulate target gene expression and modulate various biological processes [ 7 ]. Dysregulation of miRNA expression has been implicated in myofibroblast transdifferentiation and the CAF phenotype [ 3 , 8 – 10 ]. Shen et al [ 11 ] reported the upregulation of miR-7 in CAFs of oral cancer compared with their paired normal fibroblasts, and inhibition of miR-7 induces a functional change of CAFs into normal fibroblasts.…”

Section: Introductionmentioning

confidence: 99%

Myofibroblast transdifferentiation is associated with changes in cellular and extracellular vesicle miRNA abundance

et al. 2021

View full text Add to dashboard Cite

Transforming growth factor-beta 1 (TGF-β1), a pro-fibrotic tumour-derived factor promotes fibroblast differentiation in the tumour microenvironment and is thought to contribute to the development of pro-tumourigenic cancer-associated fibroblasts (CAFs) by promoting myofibroblast differentiation. miRNA dysregulation has been demonstrated in myofibroblast transdifferentiation and CAF activation, however, their expression varies among cell types and with the method of fibroblast induction. Here, the expression profile of miRNA in human primary oral fibroblasts treated with TGF-β1, to derive a myofibroblastic, CAF-like phenotype, was determined compared to untreated fibroblasts. Myofibroblast transdifferentiation was determined by the expression of alpha-smooth muscle actin (α-SMA) and fibronectin-1 extra domain A (FN-EDA1) using quantitative real-time PCR (qRT-PCR) and western blot. The formation of stress fibres was assessed by fluorescence microscopy, and associated changes in contractility were assessed using collagen contraction assays. Extracellular vesicles (EVs) were purified by using size exclusion chromatography and ultracentrifugation and their size and concentration were determined by nanoparticle tracking analysis. miRNA expression profiling in oral fibroblasts treated with TGF-β1 and their extracellular vesicles was carried out using tiling low-density array cards. The Database for Annotation, Visualization, and Integrated Discovery (DAVID) was used to perform functional and pathway enrichment analysis of target genes. In this study, TGF-β1 induced a myofibroblastic phenotype in normal oral fibroblasts as assessed by expression of molecular markers, the formation of stress fibres and increased contractility. TaqMan Low-Density Array (TLDA) analysis demonstrated that miR-503 and miR-708 were significantly upregulated, while miR-1276 was significantly downregulated in TGF-β1-treated oral fibroblasts (henceforth termed experimentally-derived CAF, eCAF). The gene functional enrichment analysis showed that the candidate miRNAs have the potential to modulate various pathways; including the Ras associated protein 1 (Rap1), PI3K-Akt, and tumour necrosis factor (TNF) signalling pathways. In addition, altered levels of several miRNAs were detected in eCAF EV, including miR-142 and miR-222. No differences in size or abundance of EV were detected between eCAF and normal oral fibroblast (NOF). Little overlap was observed between changes in cellular and EV miRNA profiles, suggesting the possibility of selective loading of EV miRNA. The study reveals miRNA expression signature could be involved in myofibroblast transdifferentiation and the miRNA cargo of their EV, providing novel insight into the involvement of miRNA in CAF development and function.

show abstract

TGF-β1-induced miR-424 promotes pulmonary myofibroblast differentiation by targeting Slit2 protein expression

Cited by 35 publications

References 52 publications

Idiopathic Pulmonary Fibrosis: An Update on Pathogenesis

Idiopathic Pulmonary Fibrosis: An Update on Pathogenesis

TGF‑β1: Gentlemanly orchestrator in idiopathic pulmonary fibrosis (Review)

Myofibroblast transdifferentiation is associated with changes in cellular and extracellular vesicle miRNA abundance

Contact Info

Product

Resources

About