Hepatic stellate cell autophagy inhibits extracellular vesicle release to attenuate liver fibrosis

Gao, Jinhang; Wei, Bo; Assuncao, Thiago M. de; Liu, Zhikui; Hu, Xiao; Ibrahim, Samar H.; Cooper, Shawna A.; Cao, Sheng; Shah, Vijay H.; Kostallari, Enis

doi:10.1016/j.jhep.2020.04.044

Cited by 206 publications

(169 citation statements)

References 55 publications

Supporting

Mentioning

158

Contrasting

Order By: Relevance

“…A recent study demonstrated that in liver fibrosis, fibrogenic extracellular vesicles (EVs), including exosomes, induced HSC migration in an autocrine manner. Unlike TGF-β stimulation, PDGF and its downstream molecule Src homology 2-containing protein tyrosine phosphatase 2 (SHP2) exerted a pro-fibrotic effect in HSCs by enhancing the release of fibrogenic EVs via autophagic inhibition and activation of the mTOR pathway 53 .…”

Section: Liver Fibrosis and Autophagymentioning

confidence: 99%

“…In addition, the exact role of autophagy in fibrogenesis is dependent on specific cell types and different stimuli. Gao et al indicated that autophagy was inhibited in PDGF- but not TGF-β-stimulated HSCs, leading to enhanced release of fibrogenic EVs 53 . Consistent with these results, Allaire et al confirmed that the role of autophagy in fibrosis is more complicated than originally thought and probably depends on specific cell types 5 .…”

Section: Conclusion and Future Prospectionmentioning

confidence: 99%

See 1 more Smart Citation

Self-eating: friend or foe? The emerging role of autophagy in fibrotic diseases

Liu¹,

Wu²,

Li³

2020

Theranostics

View full text Add to dashboard Cite

Fibrosis occurs in most human organs including the liver, lung, heart and kidney, and is crucial for the progression of most chronic diseases. As an indispensable catabolic process for intracellular quality control and homeostasis, autophagy occurs in most mammalian cells and is implicated in many biological processes including fibrogenesis. Although advances have been made in understanding autophagy process, the potential role of autophagy in fibrotic diseases remains controversial and has recently attracted a great deal of attention. In the current review, we summarize the commonalities of autophagy affecting different types of fibrosis in different organs, including the liver, lung, heart, and kidney as well as in cystic fibrosis, systematically outline the contradictory results and highlight the distinct role of autophagy during the various stages of fibrosis. In summary, the exact role autophagy plays in fibrogenesis depends on specific cell types and different stimuli, and identifying and evaluating the pathogenic contribution of autophagy in fibrogenesis will promote the discovery of novel therapeutic strategies for the clinical management of these fibrotic diseases.

show abstract

Section: Liver Fibrosis and Autophagymentioning

confidence: 99%

Section: Conclusion and Future Prospectionmentioning

confidence: 99%

Self-eating: friend or foe? The emerging role of autophagy in fibrotic diseases

Liu¹,

Wu²,

Li³

2020

Theranostics

View full text Add to dashboard Cite

show abstract

“…Qu et al [ 53 ] suggested that exosomes released from adipose-derived mesenchymal stem cells carry miR-181-5p and transfer miR-181-5p into damaged liver cells to exert an antifibrotic effect. A recent report revealed that multivesicular body- (MVB-) derived exosomes created by autophagy promote fibrosis in HSCs via the mTOR signaling pathway [ 54 ]. Exosomes from HSCs can carry proteins such as histones and keratins, which contribute to HSC functions in vivo [ 55 ].…”

Section: Discussionmentioning

confidence: 99%

ASK1 Enhances Angiotensin II-Induced Liver Fibrosis In Vitro by Mediating Endoplasmic Reticulum Stress-Dependent Exosomes

Fang

Pan

Lin

et al. 2020

Mediators of Inflammation

View full text Add to dashboard Cite

Background. Apoptosis signal-regulating kinase 1 (ASK1) has been reported to induce fibrotic signaling in the setting of oxidative stress. However, the role of ASK1 and its mechanism of action in angiotensin II- (Ang II-) induced liver fibrosis remain largely unknown. Methods. Human hepatic LX-2 stellate cells were treated with Ang II alone or cotreated with Ang II plus an ASK1 inhibitor (GS-4997) or siRNA-targeting ASK1. Immunofluorescent staining, real-time PCR, and western blotting were used to determine the expressionof α-SMA, Col I, and Col III expression. Cell viability was assessed by the CCK-8 assay. The concentrations of IL-1β, IL-18, and TNF-α in conditioned medium were determined by ELISA. The levels of intracellular ROS in LX-2 cells were analyzed using a ROS assay kit. Exosome size was determined by electron microscopy. Results. Ang II markedly increased the expression of extracellular matrix (ECM) proteins (α-SMA, Col I, and Col III) and proinflammatory cytokines (IL-1β, IL-18, and TNF-α). Ang II also increased the expression of endoplasmic reticulum stress (ERS) markers (GRP78, p-PERK, and CHOP) and p-ASK1. Results also showed that pretreatment with GS-4997 or siRNA could abolish all the abovementioned effects on LX-2 cells. Furthermore, we found that exosome release caused by ASK1-mediated ERS was involved in the activation of LX-2 cells by Ang II. The activation of LX-2 cells could be blocked by treating the exosomes with annexin. Conclusions. In summary, we found that ASK1 mediates Ang II-activated ERS in HSCs and the subsequent activation of HSCs, suggesting a promising strategy for treating liver fibrosis.

show abstract

“…Although the molecular mechanisms underlying the role of mTOR in modulating the release of protein-enriched exosomes still remains largely unexplored. A very recent paper reported that activation of mTOR signaling induced the release of MVB-derived exosomes and microvesicles (MVs) through the activation of Rho-associated protein kinase (ROCK) signaling [93] (Figure 1). Remarkably, Rho GTPase and the associated protein ROCK are important regulators of actin dynamics and are required for membrane budding and vesicle biogenesis.…”

Section: The Role Of Mtor In Exosome-based Cell-to-cell Communicationmentioning

confidence: 99%

mTOR Modulates Intercellular Signals for Enlargement and Infiltration in Glioblastoma Multiforme

Ryskalin

Biagioni

Lenzi

et al. 2020

Cancers

View full text Add to dashboard Cite

Recently, exosomal release has been related to the acquisition of a malignant phenotype in glioblastoma cancer stem cells (GSCs). Remarkably, intriguing reports demonstrate that GSC-derived extracellular vesicles (EVs) contribute to glioblastoma multiforme (GBM) tumorigenesis via multiple pathways by regulating tumor growth, infiltration, and immune invasion. In fact, GSCs release tumor-promoting macrovesicles that can disseminate as paracrine factors to induce phenotypic alterations in glioma-associated parenchymal cells. In this way, GBM can actively recruit different stromal cells, which, in turn, may participate in tumor microenvironment (TME) remodeling and, thus, alter tumor progression. Vice versa, parenchymal cells can transfer their protein and genetic contents to GSCs by EVs; thus, promoting GSCs tumorigenicity. Moreover, GBM was shown to hijack EV-mediated cell-to-cell communication for self-maintenance. The present review examines the role of the mammalian Target of Rapamycin (mTOR) pathway in altering EVs/exosome-based cell-to-cell communication, thus modulating GBM infiltration and volume growth. In fact, exosomes have been implicated in GSC niche maintenance trough the modulation of GSCs stem cell-like properties, thus, affecting GBM infiltration and relapse. The present manuscript will focus on how EVs, and mostly exosomes, may act on GSCs and neighbor non tumorigenic stromal cells to modify their expression and translational profile, while making the TME surrounding the GSC niche more favorable for GBM growth and infiltration. Novel insights into the mTOR-dependent mechanisms regulating EV-mediated intercellular communication within GBM TME hold promising directions for future therapeutic applications.

show abstract

Hepatic stellate cell autophagy inhibits extracellular vesicle release to attenuate liver fibrosis

Cited by 206 publications

References 55 publications

Self-eating: friend or foe? The emerging role of autophagy in fibrotic diseases

Self-eating: friend or foe? The emerging role of autophagy in fibrotic diseases

ASK1 Enhances Angiotensin II-Induced Liver Fibrosis In Vitro by Mediating Endoplasmic Reticulum Stress-Dependent Exosomes

mTOR Modulates Intercellular Signals for Enlargement and Infiltration in Glioblastoma Multiforme

Contact Info

Product

Resources

About