Tumor necrosis factor-inducible gene 6 protein ameliorates chronic liver damage by promoting autophagy formation in mice

Wang, Sihyung; Lee, Chanbin; Kim, Jieun; Hyun, Jeongeun; Lim, M.-K.; Cha, Hyuk‐Jin; Oh, Seh–Hoon; Choi, Yung Hyun; Jung, Youngmi

doi:10.1038/emm.2017.140

Cited by 16 publications

(10 citation statements)

References 53 publications

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“…Post-translational modification of histone proteins can markedly affect DNA accessibility to transcriptional regulators. For instance, trimethylation of different lysine residues at the N-terminus may induce either active or repressed chromatin composition [ 24 ]. To assess the importance of histone modifications in the maintenance of EC identity, we conducted Chromatin Immunoprecipitation Sequencing (ChIP-Seq) profiling of the H3K4me3 and H3K27me3 histone marks, which are enriched in active or repressed chromatin regions, respectively [ 25 , 26 ].…”

Section: Resultsmentioning

confidence: 99%

Epigenetic regulation of the lineage specificity of primary human dermal lymphatic and blood vascular endothelial cells

Tacconi

Ducoli

et al. 2020

Angiogenesis

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Lymphatic and blood vascular endothelial cells (ECs) share several molecular and developmental features. However, these two cell types possess distinct phenotypic signatures, reflecting their different biological functions. Despite significant advances in elucidating how the specification of lymphatic and blood vascular ECs is regulated at the transcriptional level during development, the key molecular mechanisms governing their lineage identity under physiological or pathological conditions remain poorly understood. To explore the epigenomic signatures in the maintenance of EC lineage specificity, we compared the transcriptomic landscapes, histone composition (H3K4me3 and H3K27me3) and DNA methylomes of cultured matched human primary dermal lymphatic and blood vascular ECs. Our findings reveal that blood vascular lineage genes manifest a more ‘repressed’ histone composition in lymphatic ECs, whereas DNA methylation at promoters is less linked to the differential transcriptomes of lymphatic versus blood vascular ECs. Meta-analyses identified two transcriptional regulators, BCL6 and MEF2C, which potentially govern endothelial lineage specificity. Notably, the blood vascular endothelial lineage markers CD34, ESAM and FLT1 and the lymphatic endothelial lineage markers PROX1, PDPN and FLT4 exhibited highly differential epigenetic profiles and responded in distinct manners to epigenetic drug treatments. The perturbation of histone and DNA methylation selectively promoted the expression of blood vascular endothelial markers in lymphatic endothelial cells, but not vice versa. Overall, our study reveals that the fine regulation of lymphatic and blood vascular endothelial transcriptomes is maintained via several epigenetic mechanisms, which are crucial to the maintenance of endothelial cell identity.

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Section: Resultsmentioning

confidence: 99%

Epigenetic regulation of the lineage specificity of primary human dermal lymphatic and blood vascular endothelial cells

Tacconi

Ducoli

et al. 2020

Angiogenesis

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“…The effects of TSG-6 are broad ranging (see Table 3) where these include the suppression of inflammation, the reduction of tissue injury and disease indices, and the enhancement of healing and repair processes. For instance, TSG-6 enhanced autophagy and reduced apoptosis of hepatocytes in a model of chronic liver damage [151] and had anti-fibrotic activities in acute liver injury [145], cutaneous wound healing [133] and following vein graft surgery where it limited restenosis [141]. Moreover, TSG-6 inhibited collagen expression and hypertrophic scaring in a rabbit ear model [142], but, conversely increased the production of collagens in atherosclerotic plaques of ApoE null mice [140], where it has been suggested to lead to plaque stabilization, e.g.…”

Section: The Immunomodulatory and Tissue Protective Activities Of Tsg-6mentioning

confidence: 99%

TSG-6: A multifunctional protein with anti-inflammatory and tissue-protective properties

2019

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Tumor necrosis factor- (TNF) stimulated gene-6 (TSG-6) is an inflammation-associated secreted protein that has been implicated as having important and diverse tissue protective and anti-inflammatory properties, e.g. mediating many of the immunomodulatory and beneficial activities of mesenchymal stem/stromal cells. TSG-6 is constitutively expressed in some tissues, which are either highly metabolically active or subject to challenges from the environment, perhaps providing protection in these contexts. The diversity of its functions are dependent on the binding of TSG-6 to numerous ligands, including matrix molecules such as glycosaminoglycans, as well as immune regulators and growth factors that themselves interact with these linear polysaccharides. It is becoming apparent that TSG-6 can directly affect matrix structure and modulate the way extracellular signalling molecules interact with matrix. In this review, we focus mainly on the literature for TSG-6 over the last 10 years, summarizing its expression, structure, ligand-binding properties, biological functions and highlighting TSG-6's potential as a therapeutic for a broad range of disease indications.

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“…Recent investigations have confirmed that autophagy plays a pivotal role in the progression of chronic liver disease (Wang et al 2017 ; Liu et al 2018 ). However, few studies have focused on the relationship between autophagy and the physical function of CK19-positive HPCs.…”

Section: Discussionmentioning

confidence: 91%

Autophagy promotes hepatic differentiation of hepatic progenitor cells by regulating the Wnt/β-catenin signaling pathway

Chen

et al. 2019

J Mol Hist

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Hepatic progenitor cells (HPCs) can be activated when the liver suffers persistent and severe damage and can differentiate into hepatocytes to maintain liver regeneration and homeostasis. However, the molecular mechanism underlying the hepatic differentiation of HPCs is unclear. Therefore, in this study, we aimed to investigate the roles of autophagy and the Wnt/β-catenin signaling pathway during hepatic differentiation of HPCs in vivo and in vitro. First, immunohistochemistry, immunofluorescence and electron microscopy showed that Atg5 and β-catenin were highly expressed in human fibrotic liver and mouse liver injury induced by feeding a 50% choline-deficient diet plus 0.15% ethionine solution in drinking water (CDE diet) for 21 days; in addition, these factors were expressed in CK19-positive HPCs. Second, Western blotting and immunofluorescence confirmed that CK19-positive HPCs incubated in differentiation medium for 7 days can differentiate into hepatocytes and that differentiated HPCs were able to take up ICG and secrete albumin and urea. Further investigation via Western blotting, immunofluorescence and electron microscopy revealed autophagy and the Wnt/β-catenin pathway to be activated during hepatic differentiation of HPCs. Next, we found that inhibiting autophagy by downregulating Atg5 gene expression impaired hepatic differentiation of HPCs and inhibited activation of the Wnt/β-catenin pathway, which was rescued by overexpression of the β-catenin gene. Moreover, downregulating β-catenin gene expression without inhibiting autophagy still impeded the differentiation of HPCs. Finally, coimmunoprecipitation demonstrated that P62 forms a complex with phosphorylated glycogen synthase kinase 3 beta (pGSK3β). Third, in mouse CDE-induced liver injury, immunohistochemistry and immunofluorescence confirmed that downregulating Atg5 gene expression inhibited autophagy, thus impeding hepatic differentiation of HPCs and inhibiting activation of the Wnt/β-catenin pathway. As observed in vitro, overexpression of β-catenin rescued this phenomenon caused by autophagy inhibition, though decreasing β-catenin levels without autophagy inhibition still impeded HPC differentiation. We also found that HPCs differentiated into hepatocytes in human fibrotic liver tissue. Collectively, these results demonstrate that autophagy promotes HPC differentiation by regulating Wnt/β-catenin signaling. Our results are the first to identify a role for autophagy in promoting the hepatic differentiation of HPCs.

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Tumor necrosis factor-inducible gene 6 protein ameliorates chronic liver damage by promoting autophagy formation in mice

Cited by 16 publications

References 53 publications

Epigenetic regulation of the lineage specificity of primary human dermal lymphatic and blood vascular endothelial cells

Epigenetic regulation of the lineage specificity of primary human dermal lymphatic and blood vascular endothelial cells

TSG-6: A multifunctional protein with anti-inflammatory and tissue-protective properties

Autophagy promotes hepatic differentiation of hepatic progenitor cells by regulating the Wnt/β-catenin signaling pathway

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