Pref-1 induced lung fibroblast differentiation by hypoxia through integrin α5β1/ERK/AP-1 cascade

Cheng, Wun Hao; Lee, Kang Yun; Yu, Ming Chih; Chen, Jing Yun; Lin, Chien Huang; Chen, Bing Chang

doi:10.1016/j.ejphar.2021.174385

Cited by 14 publications

(8 citation statements)

References 35 publications

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“…This is also in agreement with previous studies in skin, placenta, lung, and adipose tissue showing that Dlk1 marks fibroblast and/or fibroblast‐like precursors during development 39,45,46 . In EPDCs, Dlk1 seems to affect EMT at least partly through regulation of Itgb8 expression (Figure 7).…”

Section: Discussionsupporting

confidence: 92%

“…Others have shown that after liver injury DLK1 is expressed by some hepatocytes and, through paracrine signalling, activates hepatic stellate cells to undergo myofibroblast conversion with excessive ECM production 47 . Likewise, DLK1 is expressed at increased levels in airway fibrosis in chronic obstructive asthma, where it facilitates collagen accumulation through integrin α5β1 signalling 46 . A similar scenario may occur in the heart following MI.…”

Section: Discussionmentioning

confidence: 94%

“…This is also in agreement with previous studies in skin, placenta, lung, and adipose tissue showing that Dlk1 marks fibroblast and/or fibroblast-like precursors during development. 39,45,46 In EPDCs, Dlk1 seems to affect EMT at least partly through regulation of Itgb8 expression (Figure 7). This may link Dlk1 to TGFβ signalling and fibrosis, where ITGB8 is a recently identified activator of TGFβ, 40 a key mediator of EMT, as well as heart fibrosis after injury.…”

Section: Discussionmentioning

confidence: 99%

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Pericardial delta like non‐canonical NOTCH ligand 1 (Dlk1) augments fibrosis in the heart through epithelial to mesenchymal transition

Jensen,

Johnsen,

Eskildsen

et al. 2024

Clinical & Translational Med

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BackgroundHeart failure due to myocardial infarction (MI) involves fibrosis driven by epicardium‐derived cells (EPDCs) and cardiac fibroblasts, but strategies to inhibit and provide cardio‐protection remains poor. The imprinted gene, non‐canonical NOTCH ligand 1 (Dlk1), has previously been shown to mediate fibrosis in the skin, lung and liver, but very little is known on its effect in the heart.MethodsHerein, human pericardial fluid/plasma and tissue biopsies were assessed for DLK1, whereas the spatiotemporal expression of Dlk1 was determined in mouse hearts. The Dlk1 heart phenotype in normal and MI hearts was assessed in transgenic mice either lacking or overexpressing Dlk1. Finally, in/ex vivo cell studies provided knowledge on the molecular mechanism.ResultsDlk1 was demonstrated in non‐myocytes of the developing human myocardium but exhibited a restricted pericardial expression in adulthood. Soluble DLK1 was twofold higher in pericardial fluid (median 45.7 [34.7 (IQR)) μg/L] from cardiovascular patients (n = 127) than in plasma (median 26.1 μg/L [11.1 (IQR)]. The spatial and temporal expression pattern of Dlk1 was recapitulated in mouse and rat hearts. Similar to humans lacking Dlk1, adult Dlk1−/− mice exhibited a relatively mild developmental, although consistent cardiac phenotype with some abnormalities in heart size, shape, thorax orientation and non‐myocyte number, but were functionally normal. However, after MI, scar size was substantially reduced in Dlk1−/− hearts as compared with Dlk1+/+ littermates. In line, high levels of Dlk1 in transgenic mice Dlk1fl/flxWT1GFPCre and Dlk1fl/flxαMHCCre/+Tam increased scar size following MI. Further mechanistic and cellular insight demonstrated that pericardial Dlk1 mediates cardiac fibrosis through epithelial to mesenchymal transition (EMT) of the EPDC lineage by maintaining Integrin β8 (Itgb8), a major activator of transforming growth factor β and EMT.ConclusionsOur results suggest that pericardial Dlk1 embraces a, so far, unnoticed role in the heart augmenting cardiac fibrosis through EMT. Monitoring DLK1 levels as well as targeting pericardial DLK1 may thus offer new venues for cardio‐protection.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

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Pericardial delta like non‐canonical NOTCH ligand 1 (Dlk1) augments fibrosis in the heart through epithelial to mesenchymal transition

Jensen,

Johnsen,

Eskildsen

et al. 2024

Clinical & Translational Med

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“…To clarify whether the Eap-enhanced uptake of S. carnosus was integrin-mediated, the uptake of these bacteria was examined in the presence of the α 5 β 1 -integrin antagonist ATN161 ( 59 ). This inhibitor significantly diminished Eap-enhanced uptake (Fig.…”

Section: Resultsmentioning

confidence: 99%

Protein Disulfide Isomerase and Extracellular Adherence Protein Cooperatively Potentiate Staphylococcal Invasion into Endothelial Cells

et al. 2023

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“…Further, previous studies have shown that AP-1 intersects many signaling pathways as an ERK downstream target [38]. Since c-Jun is a major component of the AP-1 transactivator complex, it has been con rmed that hypoxia-induced release of preadipocyte factor-1 (Pref-1)-mediated CTGF expression via the α5β1 integrin receptor/ERK/c-Jun pathway in human lung broblasts may play a role in airway brosis in chronic obstructive asthma [39]. Besides, a study illustrated that resveratrol (Res) treatment blocked the activation of ERK/AP-1 pathways and suppressed miR-21 expression, which inhibited Smad7, subsequently leading to an alleviation of BLM-induced pulmonary brosis [40].…”

Section: Discussionmentioning

confidence: 99%

IL33-regulated NPM1 promotes fibroblast-to-myofibroblast transition via ERK/AP-1 signaling in silica-induced pulmonary fibrosis

Wang

Cheng

Sun

et al. 2022

Preprint

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Background Silicosis is a global occupational lung disease caused by the accumulation of silica dust. There is a lack of effective clinical drugs, and the pathogenic mechanisms remain obscure. Interleukin 33 (IL33), a pleiotropic cytokine, could promote wound healing and tissue repair via the receptor ST2. However, the mechanisms by which IL33 involves in silicosis progression need further exploration. Results Here, we demonstrated that the IL33 levels in the lung sections were significantly overexpressed after bleomycin (BLM) and silica treatment. ChIP assay, knockdown and reverse experiments were performed in lung fibroblasts to prove gene interaction following exogenous IL33 treatment or co-cultured with silica-treated lung epithelial cells. Mechanistically, we illustrated that silica-stimulated lung epithelial cells secreted IL33 and further promoted the activation, proliferation, and migration of pulmonary fibroblasts by activating the ERK/AP-1/NPM1 signaling pathway in vitro. Also, Treatment with NPM1 siRNA-loaded liposomes markedly protected mice from silica-induced pulmonary fibrosis in vivo. Conclusions In this study, we identified that NPM1 could involve in the progression of silicosis, which was regulated by IL33/ERK/AP-1 signaling. And treatment methods targeting this pathway may provide new anti-fibrotic clues in pulmonary fibrosis.

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Pref-1 induced lung fibroblast differentiation by hypoxia through integrin α5β1/ERK/AP-1 cascade

Cited by 14 publications

References 35 publications

Pericardial delta like non‐canonical NOTCH ligand 1 (Dlk1) augments fibrosis in the heart through epithelial to mesenchymal transition

Pericardial delta like non‐canonical NOTCH ligand 1 (Dlk1) augments fibrosis in the heart through epithelial to mesenchymal transition

Protein Disulfide Isomerase and Extracellular Adherence Protein Cooperatively Potentiate Staphylococcal Invasion into Endothelial Cells

IL33-regulated NPM1 promotes fibroblast-to-myofibroblast transition via ERK/AP-1 signaling in silica-induced pulmonary fibrosis

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