In vitro reversion of activated primary human hepatic stellate cells

Taghdouini, Adil El; Najimi, Mustapha; Sancho‐Bru, Pau; Sokal, Étienne; Grunsven, Leo A. van

doi:10.1186/s13069-015-0031-z

Cited by 79 publications

(89 citation statements)

References 59 publications

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“…This phenomenon is consistent with the outcome of elegant fate-mapping studies in mice that demonstrated a subset of HSCs are able to revert to a quiescent-like phenotype (Kisseleva et al, 2012) during the resolution of fibrotic injury. HSCs that have been previously activated exhibit a primed phenotype with rapid and robust patterns of reactivation in response to subsequent injury (Kisseleva et al, 2012;Taghdouini et al, 2015). This observation could explain the accelerated fibrogenic features observed in the current study, compared to the clinical setting in which fibrosis can take months or even years to develop.…”

Section: Discussionmentioning

confidence: 64%

Editor’s Highlight: Modeling Compound-Induced FibrogenesisIn VitroUsing Three-Dimensional Bioprinted Human Liver Tissues

et al. 2016

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Compound-induced liver injury leading to fibrosis remains a challenge for the development of an Adverse Outcome Pathway useful for human risk assessment. Latency to detection and lack of early, systematically detectable biomarkers make it difficult to characterize the dynamic and complex intercellular interactions that occur during progressive liver injury. Here, we demonstrate the utility of bioprinted tissue constructs comprising primary hepatocytes, hepatic stellate cells, and endothelial cells to model methotrexate-and thioacetamide-induced liver injury leading to fibrosis. Repeated, low-concentration exposure to these compounds enabled the detection and differentiation of multiple modes of liver injury, including hepatocellular damage, and progressive fibrogenesis characterized by the deposition and accumulation of fibrillar collagens in patterns analogous to those described in clinical samples obtained from patients with fibrotic liver injury. Transient cytokine production and upregulation of fibrosis-associated genes ACTA2 and COL1A1 mimics hallmark features of a classic wound-healing response. A surge in proinflammatory cytokines (eg, IL-8, IL-1b) during the early culture time period is followed by concentration-and treatment-dependent alterations in immunomodulatory and chemotactic cytokines such as IL-13, IL-6, and MCP-1. These combined data provide strong proof-of-concept that 3D bioprinted liver tissues can recapitulate drug-, chemical-, and TGF-b1-induced fibrogenesis at the cellular, molecular, and histological levels and underscore the value of the model for further exploration of compound-specific fibrogenic responses. This novel system will enable a more comprehensive characterization of key attributes unique to fibrogenic agents during the onset and progression of liver injury as well as mechanistic insights, thus improving compound risk assessment.Key words: liver fibrosis in vitro; 3D bioprinted liver; compound-induced liver injury.Chronic liver injury progressing to fibrosis and liver failure can result from a wide range of insults including drug or chemical exposure, metabolic disease, alcoholism, or viral infection, and is a major health burden worldwide with 2% of all deaths attributable to liver cirrhosis Murray et al., 2012). Whereas the major precipitating factors underlying drug-and chemicalinduced fibrosis have been gleaned from animal models, the key initiating and series of adaptive events that perpetuate this response, especially in humans, are still not well understood. Regardless of etiology, progressive fibrotic liver injury is

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Section: Discussionmentioning

confidence: 64%

Editor’s Highlight: Modeling Compound-Induced FibrogenesisIn VitroUsing Three-Dimensional Bioprinted Human Liver Tissues

et al. 2016

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“…As one of saturated fatty acids, PA was found to stimulate inflammasome NLRP3 activation in cultured Kupffer cells [32], but the results in HSCs are contradictory when different HSC lines and various concentrations were used. One study reported that PA at 75 μM led to growth rest and decrease in HSC activation [33], and another study claimed that PA at 100 μM in combination with EGF at 40 ng/mL, FGF at 220 ng/mL, oleic acid at 100 μM, and retinol at 5 μM, had a net effect of reverting HSCs to a quiescent status [34]. Whereas, in the present study, we confirmed that PA at 200 μM elicited HSC activation through the activated inflammasome NLRP3 molecule.…”

Section: Discussionmentioning

confidence: 99%

Palmitic acid elicits hepatic stellate cell activation through inflammasomes and hedgehog signaling

Duan

Liu

2017

Life Sciences

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Aims: Activation of hepatic stellate cells (HSCs) plays a pivotal role at the center of the fibrogenic progression in nonalcoholic steatohepatitis (NASH). However, it is poorly understood that how various molecules interact within HSCs during the progression of NASH to fibrosis. The aim of the present study is to delineate how inflammasome molecules, hedgehog signaling and autophagy provoke HSC activation using palmitic acid (PA) as a major insult. Main methods: Inflammasome activation, hedgehog signaling activity and autophagy in PA-exposed HSCs were determined to investigate their role in activation of human and rodent HSC lines or primary HSCs. Key findings: PA treatment elicited HSC activation reflected by increased mRNA levels of transforming growth factor-β1, connective tissue growth factor, tissue inhibitor of metalloproteinase-1 and procollagen type I (α1). In addition, expression levels of NOD-like receptor protein 3 (NLRP3) and hedgehog signaling transcription factor Gli-1 were increased in PA-exposed HSCs. It's evident that PA treatment resulted in increased production of light chain 3-II and autophagosomes, as well as enhanced autophagy flux reflected by transduction of an adenoassociated viral vector. Whereas, reduced autophagy, which is often seen in the late stage of NASH, provoked inflammasome activation. Moreover, suppressing the Hh signaling pathway by LDE225 blocked production of light chain 3-II and autophagy flux. Significance: Saturated fatty acids, such as PA, stimulate HSC activation through inflammasomes and hedgehog signaling. Meanwhile, compromised autophagy may facilitate HSC activation, implicating valuable candidates for pharmacologic intervention against the progression of fibrogenesis in NASH.

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“…As well, in isolated human HSCs, the results are not consistent. Positive immunostaining for desmin has been observed in primary isolated human HSCs in some studies [23,31,38], while negative immunoreactivity for desmin was reported in others [61,71].…”

Section: Desminmentioning

confidence: 94%

“…The cultured hHSCs produced monocyte chemotactic protein-1 (MCP-1) [45], and responded to TGFb1 with increased PDGFRb [48]. It has been demonstrated that density gradient isolated human HSCs can be reverted to a quiescent-like phenotypes through synergistic action of epidermal growth factor (EGF), fibroblasts growth factor 2 (FGF2), dietary fatty acids (oleic acid, palmitic acid) and retinol, as demonstrated by the abundant presence of retinyl ester-positive intra-cytoplasmic lipid droplets, and low expression levels of activation markers [31].…”

Section: Liver Tissue Explantsmentioning

confidence: 99%

“…Especially, mouse models utilizing HSC specific markers has greatly advanced our understanding of the function of HSCs [24][25][26][27]. Meanwhile, significant advancement has been made in human liver pathology studies as well as in vitro studies using isolated primary human HSCs, for example, to study their reverting capacity and function in retinoid metabolism [28][29][30][31][32][33]. There is increasing interest in translating research from mouse models and mouse HSCs to human HSCs and human disease.…”

Section: Introductionmentioning

confidence: 99%

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Human hepatic stellate cell isolation and characterization

et al. 2017

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The hepatic stellate cells (HSCs) localize at the space of Disse in the liver and have multiple functions. They are identified as the major contributor to hepatic fibrosis. Significant understanding of HSCs has been achieved using rodent models and isolated murine HSCs; as well as investigating human liver tissues and human HSCs. There is growing interest and need of translating rodent study findings to human HSCs and human liver diseases. However, species-related differences impose challenges on the translational research. In this review, we focus on the current information on human HSCs isolation methods, human HSCs markers, and established human HSC cell lines.

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In vitro reversion of activated primary human hepatic stellate cells

Cited by 79 publications

References 59 publications

Editor’s Highlight: Modeling Compound-Induced FibrogenesisIn VitroUsing Three-Dimensional Bioprinted Human Liver Tissues

Editor’s Highlight: Modeling Compound-Induced FibrogenesisIn VitroUsing Three-Dimensional Bioprinted Human Liver Tissues

Palmitic acid elicits hepatic stellate cell activation through inflammasomes and hedgehog signaling

Human hepatic stellate cell isolation and characterization

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