Crosstalk between hepatic stellate cells and surrounding cells in hepatic fibrosis

Yang, Fangming; Li, Heng; Li, Yanmin; Hao, Yaokun; Wang, Chenxiao; Jia, Pan; Chen, Xinju; Ma, Suping; Xiao, Zhun

doi:10.1016/j.intimp.2021.108051

Cited by 33 publications

(18 citation statements)

References 115 publications

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“… 363 , 364 Activated HSCs could be killed by the immune surveillance ability of natural killer (NK) cells, suggesting therapeutic activation of NK cells could be an approach to scavenge activated HSCs. 449 , 450 However, as hyperactivated NK cells could also enhance inflammation and lead to the progression of fibrosis, specifically targeting the key pathogenic HSCs within the liver is important for this strategy. IFNγ, a potent anti-fibrogenic cytokine produced by NK cells, was conjugated to a cyclic peptide recognizing the platelet-derived growth factor beta receptor (PDGFβR) that was found strongly upregulated on activated HSCs.…”

Section: Signaling Pathways Driving Nafl/nash Development and Related...mentioning

confidence: 99%

Targeted therapeutics and novel signaling pathways in non-alcohol-associated fatty liver/steatohepatitis (NAFL/NASH)

Poulsen

et al. 2022

Sig Transduct Target Ther

133

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Non-alcohol-associated fatty liver/steatohepatitis (NAFL/NASH) has become the leading cause of liver disease worldwide. NASH, an advanced form of NAFL, can be progressive and more susceptible to developing cirrhosis and hepatocellular carcinoma. Currently, lifestyle interventions are the most essential and effective strategies for preventing and controlling NAFL without the development of fibrosis. While there are still limited appropriate drugs specifically to treat NAFL/NASH, growing progress is being seen in elucidating the pathogenesis and identifying therapeutic targets. In this review, we discussed recent developments in etiology and prospective therapeutic targets, as well as pharmacological candidates in pre/clinical trials and patents, with a focus on diabetes, hepatic lipid metabolism, inflammation, and fibrosis. Importantly, growing evidence elucidates that the disruption of the gut–liver axis and microbe-derived metabolites drive the pathogenesis of NAFL/NASH. Extracellular vesicles (EVs) act as a signaling mediator, resulting in lipid accumulation, macrophage and hepatic stellate cell activation, further promoting inflammation and liver fibrosis progression during the development of NAFL/NASH. Targeting gut microbiota or EVs may serve as new strategies for the treatment of NAFL/NASH. Finally, other mechanisms, such as cell therapy and genetic approaches, also have enormous therapeutic potential. Incorporating drugs with different mechanisms and personalized medicine may improve the efficacy to better benefit patients with NAFL/NASH.

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Section: Signaling Pathways Driving Nafl/nash Development and Related...mentioning

confidence: 99%

Targeted therapeutics and novel signaling pathways in non-alcohol-associated fatty liver/steatohepatitis (NAFL/NASH)

Poulsen

et al. 2022

Sig Transduct Target Ther

133

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“…A single stellate cell can wrap up to four blood sinusoids and alter its structure and function through interactions with surrounding cells (12). HSCs are the predominant cell type leading to liver fibrosis, the injury of LSECs can transform quiescence HSCs into myofibroblast like cells (activated HSCs) (36). The activities of HSCs mainly depend on the interactions with surrounding cells in liver sinusoids (37)(38)(39).…”

Section: The Intercellular Crosstalk Of Lsecs In Liver Physiological ...mentioning

confidence: 99%

“…Activated HSCs further act on quiescent HSCs and LSECs through autocrine TGF-β1, forming a positive feedback loop on the progression of liver fibrosis ( 119 ). HSCs begin to proliferate, contract and deposit a large amounts of collagen fibers and extracellular matrix molecules in the liver parenchyma, leading to organ stiffening and disrupting all cellular functions ( 36 ).…”

Section: Sinusoidal Crosstalk In Nash Related Fibrosismentioning

confidence: 99%

The Crosstalk Between Liver Sinusoidal Endothelial Cells and Hepatic Microenvironment in NASH Related Liver Fibrosis

Wang

2022

Front. Immunol.

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Chronic liver injury can be caused by many factors, including virus infection, alcohol intake, cholestasis and abnormal fat accumulation. Nonalcoholic steatohepatitis (NASH) has become the main cause of liver fibrosis worldwide. Recently, more and more evidences show that hepatic microenvironment is involved in the pathophysiological process of liver fibrosis induced by NASH. Hepatic microenvironment consists of various types of cells and intercellular crosstalk among different cells in the liver sinusoids. Liver sinusoidal endothelial cells (LSECs), as the gatekeeper of liver microenvironment, play an irreplaceable role in the homeostasis and alterations of liver microenvironment. Many recent studies have reported that during the progression of NASH to liver fibrosis, LSECs are involved in various stages mediated by a series of mechanisms. Therefore, here we review the key role of crosstalk between LSECs and hepatic microenvironment in the progression of NASH to liver fibrosis (steatosis, inflammation, and fibrosis), as well as promising therapeutic strategies targeting LSECs.

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“…Other studies suggest the crosstalk between immune cells and HSCs via miR-223-containing EVs which inhibit HSC activation [ 16 , 23 ]. However, due to the complex and dynamic interactions between liver cell types including hepatocytes, Kupffer cells and liver sinusoidal endothelial cells (LSEC) in progression of liver fibrosis [ 24 , 25 ], the anti-fibrotic mechanisms of miR-223 in HSCs remains incompletely understood. In addition, these previous studies rely on analyses from animal models or HSC immortalized cell lines that may not fully reflect biological and clinical relevance for humans.…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-223 Suppresses Human Hepatic Stellate Cell Activation Partly via Regulating the Actin Cytoskeleton and Alleviates Fibrosis in Organoid Models of Liver Injury

Ariyachet

Chuaypen

Kaewsapsak

et al. 2022

IJMS

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MicroRNAs (miRNAs) are small, non-coding RNAs that negatively regulate target mRNA expression, and altered expression of miRNAs is associated with liver pathological conditions. Recent studies in animal models have shown neutrophil/myeloid-specific microRNA-223 (miR-223) as a key regulator in the development of various liver diseases including fibrosis, where hepatic stellate cells (HSCs) are the key player in pathogenesis. However, the precise roles of miR-223 in human HSCs and its therapeutic potential to control fibrosis remain largely unexplored. Using primary human HSCs, we demonstrated that miR-223 suppressed the fibrogenic program and cellular proliferation while promoting features of quiescent HSCs including lipid re-accumulation and retinol storage. Furthermore, induction of miR-223 in HSCs decreased cellular motility and contraction. Mechanistically, miR-223 negatively regulated expression of smooth muscle α-actin (α-SMA) and thus reduced cytoskeletal activity, which is known to promote amplification of fibrogenic signals. Restoration of α-SMA in miR-223-overexpressing HSCs alleviated the antifibrotic effects of miR-223. Finally, to explore the therapeutic potential of miR-233 in liver fibrosis, we generated co-cultured organoids of HSCs with Huh7 hepatoma cells and challenged them with acetaminophen (APAP) or palmitic acid (PA) to induce hepatotoxicity. We showed that ectopic expression of miR-223 in HSCs attenuated fibrogenesis in the two human organoid models of liver injury, suggesting its potential application in antifibrotic therapy.

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Crosstalk between hepatic stellate cells and surrounding cells in hepatic fibrosis

Cited by 33 publications

References 115 publications

Targeted therapeutics and novel signaling pathways in non-alcohol-associated fatty liver/steatohepatitis (NAFL/NASH)

Targeted therapeutics and novel signaling pathways in non-alcohol-associated fatty liver/steatohepatitis (NAFL/NASH)

The Crosstalk Between Liver Sinusoidal Endothelial Cells and Hepatic Microenvironment in NASH Related Liver Fibrosis

MicroRNA-223 Suppresses Human Hepatic Stellate Cell Activation Partly via Regulating the Actin Cytoskeleton and Alleviates Fibrosis in Organoid Models of Liver Injury

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