scholarly journals Microengineered cultures containing human hepatic stellate cells and hepatocytes for drug development

2017 ◽  
Vol 9 (8) ◽  
pp. 662-677 ◽  
Author(s):  
Matthew D. Davidson ◽  
David A. Kukla ◽  
Salman R. Khetani
Keyword(s):  
Drug Development ◽  
High Throughput ◽  
Drug Screening ◽  
Hepatic Stellate Cells ◽  
Stellate Cells ◽  
Human Hepatocytes ◽  
Alcoholic Steatohepatitis

Micropatterned tri-cultures (MPTCs) containing human hepatocytes, hepatic stellate cells, and fibroblasts in a high-throughput format are used to mimic aspects of non-alcoholic steatohepatitis (NASH) for drug screening.

scholarly journals Palmitate and Fructose Interact to Induce Human Hepatocytes to Produce Pro-Fibrotic Transcriptional Responses in Hepatic Stellate Cells Exposed to Conditioned Media

2020 ◽  
Vol 54 (5) ◽  
pp. 1068-1082
Keyword(s):  
Differential Expression ◽  
Differentially Expressed Genes ◽  
Hepatic Stellate Cells ◽  
Stellate Cell ◽  
Stellate Cells ◽  
Human Hepatocytes ◽  
Conditioned Media ◽  
Differentially Expressed ◽  
Transcriptional Responses ◽  
Significant Differential Expression

BACKGROUND/AIMS: Excessive consumption of dietary fat and sugar is associated with an elevated risk of nonalcoholic fatty liver disease (NAFLD). Hepatocytes exposed to saturated fat or sugar exert effects on nearby hepatic stellate cells (HSCs); however, the mechanisms by which this occurs are poorly understood. We sought to determine whether paracrine effects of hepatocytes exposed to palmitate and fructose produced profibrotic transcriptional responses in HSCs. METHODS: We performed expression profiling of mRNA and lncRNA from HSCs treated with conditioned media (CM) from human hepatocytes treated with palmitate (P), fructose (F), or both (PF). RESULTS: In HSCs exposed to CM from palmitate-treated hepatocytes, we identified 374 mRNAs and 607 lncRNAs showing significant differential expression (log2 foldchange ≥ |1|; FDR ≤0.05) compared to control cells. In HSCs exposed to CM from PF-treated hepatocytes, the number of differentially expressed genes was much higher (1198 mRNAs and 3348 lncRNAs); however, CM from fructose-treated hepatocytes elicited no significant changes in gene expression. Pathway analysis of differentially expressed genes showed enrichment for hepatic fibrosis and hepatic stellate cell activation in P- (FDR =1.30E-04) and PF-(FDR =9.24E-06)
groups. We observed 71 lncRNA/nearby mRNA pairs showing differential expression under PF conditions. There were 90 mRNAs and 264 lncRNAs strongly correlated between the PF group and differentially expressed transcripts from a comparison of activated and quiescent HSCs, suggesting that some of the transcriptomic changes occurring in response to PF overlap with HSC activation. CONCLUSION: The results reported here have implications for dietary modifications in the prevention and treatment of NAFLD.

scholarly journals Hepatic Stellate Cell-Derived Microvesicles Prevent Hepatocytes from Injury Induced by APAP/H2O2

2016 ◽  
Vol 2016 ◽  
pp. 1-12 ◽  
Author(s):  
Renwei Huang ◽  
Qunwen Pan ◽  
Xiaotang Ma ◽  
Yan Wang ◽  
Yaolong Liang ◽  
...  
Keyword(s):  
Liver Injury ◽  
Hepatic Stellate Cells ◽  
Culture Medium ◽  
Caspase 3 ◽  
Cell Function ◽  
Stellate Cell ◽  
Annexin V ◽  
Stellate Cells ◽  
Human Hepatocytes ◽  
Injury Models

Hepatic stellate cells (HSCs), previously described for liver-specific mesenchymal stem cells (MSCs), appear to contribute to liver regeneration. Microvesicles (MVs) are nanoscale membrane fragments, which can regulate target cell function by transferring contents from their parent cells. The aim of this study was to investigate the effect of HSC-derived MVs on xenobiotic-induced liver injury. Rat and human hepatocytes, BRL-3A and HL-7702, were used to build hepatocytes injury models by n-acetyl-p-aminophenol n-(APAP) or H2O2treatment. MVs were prepared from human and rat HSCs, LX-2, and HST-T6 and, respectively, added to injured BRL-3A and HL-7702 hepatocytes. MTT assay was utilized to determine cell proliferation. Cell apoptosis was analyzed by flow cytometry and hoechst33258 staining. Western blot was used for analyzing the expression of activated caspase-3. Liver injury indicators, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and lactate dehydrogenase (LDH) in culture medium were also assessed. Results showed that (1) HSC-MVs derived from LX-2 and HST-T6 were positive to CD90 and annexin V surface markers; (2) HSC-MVs dose-dependently improved the viability of hepatocytes in both injury models; (3) HSC-MVs dose-dependently inhibited the APAP/H2O2induced hepatocytes apoptosis and activated caspase-3 expression and leakage of LDH, ALT, and AST. Our results demonstrate that HSC-derived MVs protect hepatocytes from toxicant-induced injury.

Chemokine (CC-motif) receptor-like 2 mRNA is expressed in hepatic stellate cells and is positively associated with characteristics of non-alcoholic steatohepatitis in mice and men

2017 ◽  
Vol 103 (1) ◽  
pp. 1-8 ◽  
Author(s):  
Sebastian Zimny ◽  
Rebekka Pohl ◽  
Lisa Rein-Fischboeck ◽  
Elisabeth M. Haberl ◽  
Sabrina Krautbauer ◽  
...  
Keyword(s):  
Hepatic Stellate Cells ◽  
Stellate Cells ◽  
Alcoholic Steatohepatitis

scholarly journals Amphiregulin activates human hepatic stellate cells and is upregulated in non alcoholic steatohepatitis

2015 ◽  
Vol 5 (1) ◽  
Author(s):  
Chad McKee ◽  
Barbara Sigala ◽  
Junpei Soeda ◽  
Angelina Mouralidarane ◽  
Maelle Morgan ◽  
...  
Keyword(s):  
Hepatic Stellate Cells ◽  
Stellate Cells ◽  
Alcoholic Steatohepatitis

scholarly journals High-Throughput Sequencing Strategy for miR-146b-regulated circRNA Expression in Hepatic Stellate Cells

2018 ◽  
Vol 24 ◽  
pp. 8699-8706 ◽  
Author(s):  
Na Cheng ◽  
Juhua Xiao ◽  
Shanfei Ge ◽  
Juntao Li ◽  
Jiansheng Huang ◽  
...  
Keyword(s):  
High Throughput ◽  
Hepatic Stellate Cells ◽  
High Throughput Sequencing ◽  
Stellate Cells ◽  
Sequencing Strategy

scholarly journals Heterogeneity of hepatic stellate cells in a mouse model of non‐alcoholic steatohepatitis (NASH)

Hepatology ◽  
2021 ◽  
Author(s):  
Sara Brin Rosenthal ◽  
Xiao Liu ◽  
Souradipta Ganguly ◽  
Debanjan Dhar ◽  
Martina P. Pasillas ◽  
...  
Keyword(s):  
Mouse Model ◽  
Hepatic Stellate Cells ◽  
Stellate Cells ◽  
Alcoholic Steatohepatitis

Organ-on-Chip Devices Toward Applications in Drug Development and Screening

2018 ◽  
Vol 12 (4) ◽  
Author(s):  
Christopher Uhl ◽  
Wentao Shi ◽  
Yaling Liu
Keyword(s):  
Drug Development ◽  
High Throughput ◽  
Drug Screening ◽  
Large Scale ◽  
Three Dimensional ◽  
3D Cell Culture ◽  
Throughput Capacity ◽  
Comprehensive Overview ◽  
The Past ◽  
High Throughput Drug Screening

As a necessary pathway to man-made organs, organ-on-chips (OOC), which simulate the activities, mechanics, and physiological responses of real organs, have attracted plenty of attention over the past decade. As the maturity of three-dimensional (3D) cell-culture models and microfluidics advances, the study of OOCs has made significant progress. This review article provides a comprehensive overview and classification of OOC microfluidics. Specifically, the review focuses on OOC systems capable of being used in preclinical drug screening and development. Additionally, the review highlights the strengths and weaknesses of each OOC system toward the goal of improved drug development and screening. The various OOC systems investigated throughout the review include, blood vessel, lung, liver, and tumor systems and the potential benefits, which each provides to the growing challenge of high-throughput drug screening. Published OOC systems have been reviewed over the past decade (2007–2018) with focus given mainly to more recent advances and improvements within each organ system. Each OOC system has been reviewed on how closely and realistically it is able to mimic its physiological counterpart, the degree of information provided by the system toward the ultimate goal of drug development and screening, how easily each system would be able to transition to large scale high-throughput drug screening, and what further improvements to each system would help to improve the functionality, realistic nature of the platform, and throughput capacity. Finally, a summary is provided of where the broad field of OOCs appears to be headed in the near future along with suggestions on where future efforts should be focused for optimized performance of OOC systems in general.

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