HucMSC-derived exosomes delivered BECN1 induces ferroptosis of hepatic stellate cells via regulating the xCT/GPX4 axis

Tan, Youwen; Huang, Yuandong; Mei, Rong; Mao, Fei; Yang, Dakai; Liu, Jinwen; Xu, Wenrong; Qian, Hui; Yan, Yongmin

doi:10.1038/s41419-022-04764-2

Cited by 80 publications

(48 citation statements)

References 39 publications

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“…94 Notably, mesenchymal stem cell (MSC)exosomes alleviated liver fibrosis by triggering HSC ferroptosis mechanistically by promoting ferroptosis-like cell death, mitochondrial dysfunction, and lipid peroxidation in aHSCs. 95 In the future, the direct effect of HSC-derived exosomes on mitochondrial metabolism in HSCs should not be underestimated. The pathophysiological role of HSC-derived exosomes is summarized in Figure 1 and Table 1.…”

Section: Mitochondrial Metabolismmentioning

confidence: 99%

Unraveling the Emerging Niche Role of Hepatic Stellate Cell-derived Exosomes in Liver Diseases

Yin¹,

Li²,

Song³

et al. 2022

J Clin Transl Hepatol

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Hepatic stellate cells (HSCs) play an essential role in various liver diseases, and exosomes are critical mediators of intercellular communication in local and distant microenvironments. Cellular crosstalk between HSCs and surrounding multiple tissue-resident cells promotes or inhibits the activation of HSCs. Substantial evidence has revealed that HSC-derived exosomes are involved in the occurrence and development of liver diseases through the regulation of retinoid metabolism, lipid metabolism, glucose metabolism, protein metabolism, and mitochondrial metabolism. HSCderived exosomes are underpinned by vehicle molecules, such as mRNAs and microRNAs, that function in, and significantly affect, the processes of various liver diseases, such as acute liver injury, alcoholic liver disease, nonalcoholic fatty liver disease, viral hepatitis, fibrosis, and cancer. As such, numerous exosomes derived from HSCs or HSCassociated exosomes have attracted attention because of their biological roles and translational applications as potential targets for therapeutic targets. Herein, we review the pathophysiological and metabolic processes associated with HSC-derived exosomes, their roles in various liver diseases and their potential clinical application.

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Section: Mitochondrial Metabolismmentioning

confidence: 99%

Unraveling the Emerging Niche Role of Hepatic Stellate Cell-derived Exosomes in Liver Diseases

Yin¹,

Li²,

Song³

et al. 2022

J Clin Transl Hepatol

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“…Mechanically, human UCMSC-Exs-derived BECN1 induced LX2 ferroptosis by reducing system xc-/GPX4 activity. In contrast, the knockdown of BECN1 weakened the effect of human UCMSC-Exs on LX2 ferroptosis [84]. The data demonstrate that MSCs ameliorate end-stage liver diseases via modulating liver cell ferroptosis.…”

Section: Mscs Regulate Cell Ferroptosismentioning

confidence: 77%

Advance of Mesenchymal Stem Cells in Chronic End-Stage Liver Disease Control

Gao

Yin

Ren

2022

Stem Cells International

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The chronic liver diseases will slowly develop into liver fibrosis, cirrhosis, and even liver cancer if no proper control is performed with high efficiency. Up to now, the most effective treatment for end-stage liver diseases is liver transplantation. However, liver transplantation has the problems of donor deficiency, low matching rate, surgical complications, high cost, and immune rejection. These problems indicate that novel therapeutic strategies are urgently required. Mesenchymal stem cells (MSCs) are somatic stem cells with multidirectional differentiation potential and self-renewal ability. MSCs can secrete a large number of cytokines, chemokines, immunomodulatory molecules, and hepatotrophic factors, as well as produce extracellular vesicles. They alleviate liver diseases by differentiating to hepatocyte-like cells, immunomodulation, homing to the injured site, regulating cell ferroptosis, regulating cell autophagy, paracrine effects, and MSC-mitochondrial transfer. In this review, we focus on the main resources of MSCs, underlying therapeutic mechanisms, clinical applications, and efforts made to improve MSC-based cell therapy efficiency.

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“…And due to the unique characteristics of exosomes, it is a natural intercellular communication vehicle with abundant functional cargo, which might be delivered to other cells and mediate key cellular process. For example, recent study demonstrated that hUCMSC-Exo cargo BECN1 could induce HSC ferroptosis to achieve hepatic fibrosis mitigation [ 46 ]. Wang N et.al found that miR-6766-3p in 3D-human embryonic stem cell exosome could target TGFβRII-SMADS pathway and inactivate HSC in liver fibrosis [ 47 ].…”

Section: Discussionmentioning

confidence: 99%

ADSCs-derived exosomes ameliorate hepatic fibrosis by suppressing stellate cell activation and remodeling hepatocellular glutamine synthetase-mediated glutamine and ammonia homeostasis

Feng

Guo

et al. 2022

Stem Cell Res Ther

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Background Hepatic fibrosis is a common pathologic stage in chronic liver disease development, which might ultimately lead to liver cirrhosis. Accumulating evidence suggests that adipose-derived stromal cells (ADSCs)-based therapies show excellent therapeutic potential in liver injury disease owing to its superior properties, including tissue repair ability and immunomodulation effect. However, cell-based therapy still limits to several problems, such as engraftment efficiency and immunoreaction, which impede the ADSCs-based therapeutics development. So, ADSCs-derived extracellular vesicles (EVs), especially for exosomes (ADSC-EXO), emerge as a promise cell-free therapeutics to ameliorate liver fibrosis. The effect and underlying mechanisms of ADSC-EXO in liver fibrosis remains blurred. Methods Hepatic fibrosis murine model was established by intraperitoneal sequential injecting the diethylnitrosamine (DEN) for two weeks and then carbon tetrachloride (CCl4) for six weeks. Subsequently, hepatic fibrosis mice were administrated with ADSC-EXO (10 μg/g) or PBS through tail vein infusion for three times in two weeks. To evaluate the anti-fibrotic capacity of ADSC-EXO, we detected liver morphology by histopathological examination, ECM deposition by serology test and Sirius Red staining, profibrogenic markers by qRT-PCR assay. LX-2 cells treated with TGF-β (10 ng/ml) for 12 h were conducted for evaluating ADSC-EXO effect on activated hepatic stellate cells (HSCs). RNA-seq was performed for further analysis of the underlying regulatory mechanisms of ADSC-EXO in liver fibrosis. Results In this study, we obtained isolated ADSCs, collected and separated ADSCs-derived exosomes. We found that ADSC-EXO treatment could efficiently ameliorate DEN/CCl4-induced hepatic fibrosis by improving mice liver function and lessening hepatic ECM deposition. Moreover, ADSC-EXO intervention could reverse profibrogenic phenotypes both in vivo and in vitro, including HSCs activation depressed and profibrogenic markers inhibition. Additionally, RNA-seq analysis further determined that decreased glutamine synthetase (Glul) of perivenous hepatocytes in hepatic fibrosis mice could be dramatically up-regulated by ADSC-EXO treatment; meanwhile, glutamine and ammonia metabolism-associated key enzyme OAT was up-regulated and GLS2 was down-regulated by ADSC-EXO treatment in mice liver. In addition, glutamine synthetase inhibitor would erase ADSC-EXO therapeutic effect on hepatic fibrosis. Conclusions These findings demonstrated that ADSC-derived exosomes could efficiently alleviate hepatic fibrosis by suppressing HSCs activation and remodeling glutamine and ammonia metabolism mediated by hepatocellular glutamine synthetase, which might be a novel and promising anti-fibrotic therapeutics for hepatic fibrosis disease.

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HucMSC-derived exosomes delivered BECN1 induces ferroptosis of hepatic stellate cells via regulating the xCT/GPX4 axis

Cited by 80 publications

References 39 publications

Unraveling the Emerging Niche Role of Hepatic Stellate Cell-derived Exosomes in Liver Diseases

Unraveling the Emerging Niche Role of Hepatic Stellate Cell-derived Exosomes in Liver Diseases

Advance of Mesenchymal Stem Cells in Chronic End-Stage Liver Disease Control

ADSCs-derived exosomes ameliorate hepatic fibrosis by suppressing stellate cell activation and remodeling hepatocellular glutamine synthetase-mediated glutamine and ammonia homeostasis

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