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High precision-cut liver slice model to study cell-autonomous antiviral defense of hepatocytes within their microenvironment. | LitMetric

AI Article Synopsis

  • Researchers found that liver cells (hepatocytes) infected by viruses are more sensitive to cell death when triggered by tumor necrosis factor (TNF), suggesting an internal immune mechanism.
  • They developed a method to create precision-cut liver slices (PCLS) from mouse and human livers, which can be used to study how these cells regulate their own apoptosis (cell death) after viral infections.
  • The study demonstrated that PCLS maintain metabolic functions and showed increased apoptosis in virus-infected liver slices when exposed to TNF, indicating that this model can help better understand liver cell sensitivity to apoptotic signals, especially in patients with liver diseases.

Article Abstract

Background & Aims: Increased sensitivity towards tumor necrosis factor (TNF)-induced cell death in virus-infected hepatocytes has revealed a so far unrecognized hepatocyte-intrinsic antiviral immune surveillance mechanism, for which no or model is available. We aimed to establish precision-cut liver slices (PCLS) as a model system to study hepatocyte-intrinsic regulation of apoptosis.

Methods: Preparation of PCLS from mouse and human liver tissue was optimized for minimal procedure-associated apoptosis. Functionality of liver cells in PCLS was characterized using extracellular flux analysis to determine mitochondrial respiration, and viral infection with recombinant adenovirus and lymphocytic choriomeningitis virus (LCMV) was used to probe for hepatocyte-intrinsic sensitivity towards apoptosis in PCLS. Apoptosis was detected by immunohistochemical staining for cleaved-caspase 3 and quantified by detection of effector caspase activity in PCLS.

Results: We established an optimized protocol for preparation of PCLS from human and mouse models using agarose-embedding of liver tissue to improve precision cutting and using organ-protective buffer solutions to minimize procedure-associated cell death. PCLS prepared from virus-infected livers showed preserved functional metabolic properties. Importantly, in PCLS from adenovirus- and LCMV-infected livers we detected increased induction of apoptosis after TNF challenge .

Conclusion: We conclude that PCLS can be used as model system to characterize hepatocyte-intrinsic sensitivity to cell death. This may also enable researchers to characterize human hepatocyte sensitivity to apoptosis in PCLS prepared from patients with acute or chronic liver diseases.

Lay Summary: Virus-infected hepatocytes show an increased sensitivity towards induction of cell death signaling through the TNF receptor. Studying this hepatocyte-intrinsic antiviral immune surveillance mechanism has been hampered by the absence of model systems that reciprocate the finding of increased apoptosis of virus-infected hepatocytes challenged with TNF. Herein, we report that an optimized protocol for generation of precision-cut liver slices can be used to study this hepatocyte-intrinsic surveillance mechanism .

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9019249PMC
http://dx.doi.org/10.1016/j.jhepr.2022.100465DOI Listing

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