Insulin‐dependent glucose consumption dynamics in 3D primary human liver cultures measured by a sensitive and specific glucose sensor with nanoliter input volume

Abstract

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Conditions for maintenance of hepatocyte differentiation and function in 3D cultures

“…To maintain a normal, healthy PHH phenotype, media with fasting glucose and insulin levels should be used. Recently, glucose and insulin consumption in hepatocytes have gained interest and with a newly developed method suitable for low volume spheroid cultures ( Kemas et al., 2021 ).…”

Organotypic and Microphysiological Human Tissue Models for Drug Discovery and Development—Current State-of-the-Art and Future Perspectives

“…In vitro, NAFLD can be emulated by supplementing culture media with pathophysiologically relevant levels of carbohydrates and free fatty acids as well as high concentrations of insulin. In PHH spheroids, NAFLD models recapitulate steatosis, insulin resistance, reduced glucose consumption, and the induction of genes involved in de novo lipogenesis and gluconeogenesis (Kozyra et al, 2018;Kemas et al, 2021) (Fig. 3A).…”

“…The life cycle of Plasmodium falciparum, berghei, or vivax malaria parasites from infection to the release of hepatic merozoites can be emulated in both MPCCs (March et al, 2013;Gural et al, 2018) and spheroids (Arez et al, 2019;Chua et al, 2019). Although various cell models are compatible with malaria infections, high and stable expression of CD81 and SRB1 is required for efficient sporozoite progression, which favors PHHs over hepatoma cell lines and iPSC-derived HLCs (March et (Hurrell et al, 2020;Kemas et al, 2021;Kostrzewski et al, 2017;Shlomai et al, 2014).…”

3D human liver spheroids for translational pharmacology and toxicology

“…In spheroids, insulin resistance and steatosis can easily be mimicked by increasing insulin, glucose, fructose and free fatty acid (FFA) concentrations in the medium in a similar fashion as seen in vivo 80,81 . Liver spheroids consisting of PHH and primary NPCs can moreover mimic the progression from steatosis to NASH in pathophysiological conditions purely driven by metabolic perturbations (elevated FFA levels) without the need to supply extrinsic cytokines 82 .…”

“…APAP, acetaminophen; COL1A1, collagen 1A1; FASN, fatty acid synthase; G6PC, glucose‐6‐phosphatase; HBV, hepatitis B virus; HCV, hepatitis C virus; IS, insulin‐sensitive; IR, insulin‐resistant; NAFLD, non‐alcoholic fatty liver disease; NASH, non‐alcoholic steatohepatitis; PCK1, phosphoenolpyruvate carboxykinase 1; PHH, primary human hepatocytes; SARS‐CoV‐2, severe acute respiratory syndrome coronavirus 2. Individual panels were modified with permission from 61,81,82 …”