Gaining New Biological and Therapeutic Applications into the Liver with 3D In Vitro Liver Models

Lee, Sang Woo; Jung, Da-Jung; Jeong, Gi Seok

doi:10.1007/s13770-020-00245-9

Cited by 14 publications

(17 citation statements)

References 141 publications

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“…The liver is composed of epithelial cells (hepatocytes and cholangiocytes) that work together with stromal, endothelial cells, mesenchymal cells and Kupffer cells to perform crucial metabolic functions ( Cotovio and Fernandes, 2020 ; Lee et al, 2020 ). Organoid cultures recapitulating this complexity have emerged as a useful in vitro system to model tissue behavior in a dish.…”

Section: Resultsmentioning

confidence: 99%

“…All cells were then suspended to a density of 1x10 6 cells/mL in hepatocyte Stage 3 media and plated in ultra low attachment (ULA) plates (Corning, cat. #3471) at the physiologically relevant (Ware et al, 2018;Leite et al, 2016;Tasnim et al, 2019) ratio of 1 : 0.5 : 2 : 0.2 hepatocyte : macrophage : MSC : endothelial cell. Aggregates were maintained for 10 days with media exchanges every other day.…”

Section: Cyp3a4 Activity Assay On Days 5-7 Of Stage 3 Hepatocyte Agmentioning

confidence: 99%

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iPSC-derived hepatocytes generated from NASH donors provide a valuable platform for disease modeling and drug discovery

Gurevich¹,

Burton²,

Munn³

et al. 2020

Biology Open

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Non-alcoholic fatty liver disease (NAFLD) affects 30 to 40% of adults and 10% of children in the US. About 20% of people with NAFLD develop non-alcoholic steatohepatitis (NASH), which may lead to cirrhosis and liver cancer, and is projected to be a leading cause of liver transplantation in the near future. Human induced pluripotent stem cells (iPSC) from NASH patients are useful for generating a large number of hepatocytes for NASH modeling applications and identification of potential drug targets. We developed a novel defined in vitro differentiation process to generate cryopreservable hepatocytes using an iPSC panel of NASH donors and apparently healthy normal (AHN) controls. iPSC-derived hepatocytes displayed stage specific phenotypic markers, hepatocyte morphology, with bile canaliculi. Importantly, both fresh and cryopreserved Definitive Endoderm and Hepatoblasts successfully differentiated to pure and functional hepatocytes with increased CYP3A4 activity in response to rifampicin and lipid accumulation upon fatty acid (FA) treatment. End stage hepatocytes integrated into three dimensional liver organoids and demonstrated increased levels of albumin secretion compared to aggregates consisting of hepatocytes alone. End stage hepatocytes derived from NASH donors demonstrated spontaneous lipidosis without fatty acid supplementation, recapitulating a feature of NASH hepatocytes in vivo. Cryopreserved hepatocytes generated by this protocol across multiple donors will provide a critical cell source to facilitate the fundamental understanding of NAFLD/NASH biology and potential high throughput screening applications for preclinical evaluation of therapeutic targets.

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Section: Resultsmentioning

confidence: 99%

Section: Cyp3a4 Activity Assay On Days 5-7 Of Stage 3 Hepatocyte Agmentioning

confidence: 99%

iPSC-derived hepatocytes generated from NASH donors provide a valuable platform for disease modeling and drug discovery

Gurevich¹,

Burton²,

Munn³

et al. 2020

Biology Open

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show abstract

“…Additionally, the liver primarily metabolizes toxins and drugs first absorbed by the gastrointestinal tract before entering the bloodstream. Indeed, the liver has a dual blood supply circulation system that primarily involves a nutrient-rich vein and oxygen-rich artery [9]. Constant and sufficient amounts of oxygen and nutrient supplements enable the high regeneration capacity of the liver, which is one of its important characteristics compared with other organs.…”

Section: Introductionmentioning

confidence: 99%

Establishing a 3D In Vitro Hepatic Model Mimicking Physiologically Relevant to In Vivo State

Kang

Sarsenova

Kim

et al. 2021

Cells

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Three-dimensional (3D) bioprinting is a promising technology to establish a 3D in vitro hepatic model that holds great potential in toxicological evaluation. However, in current hepatic models, the central area suffers from hypoxic conditions, resulting in slow and weak metabolism of drugs and toxins. It remains challenging to predict accurate drug effects in current bioprinted hepatic models. Here, we constructed a hexagonal bioprinted hepatic construct and incorporated a spinning condition with continuous media stimuli. Under spinning conditions, HepG2 cells in the bioprinted hepatic construct exhibited enhanced proliferation capacity and functionality compared to those under static conditions. Additionally, the number of spheroids that play a role in boosting drug-induced signals and responses increased in the bioprinted hepatic constructs cultured under spinning conditions. Moreover, HepG2 cells under spinning conditions exhibited intensive TGFβ-induced epithelial-to-mesenchymal transition (EMT) and increased susceptibility to acetaminophen (APAP)-induced hepatotoxicity as well as hepatotoxicity prevention by administration of N-acetylcysteine (NAC). Taken together, the results of our study demonstrate that the spinning condition employed during the generation of bioprinted hepatic constructs enables the recapitulation of liver injury and repair phenomena in particular. This simple but effective culture strategy facilitates bioprinted hepatic constructs to improve in vitro modeling for drug effect evaluation.

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“…Manipulation of the growth factors results in the generation of hepatocyte-like cells that synthesize bile acids, albumin, and alpha-1-anti-trypsin while engaging in detoxification, LDL uptake, and glycogen accumulation (8; 9). The HLOs have been used to study fibrosis, metabolic diseases, infectious diseases, and liver cancer (10)(11)(12).…”

Section: Introductionmentioning

confidence: 99%

Use of human tissue stem cell-derived organoid cultures to model enterohepatic circulation

Blutt

Crawford

Bomidi

et al. 2021

American Journal of Physiology-Gastrointestinal and Liver Physi

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The use of human tissue stem cell-derived organoids has advanced our knowledge of human physiologic and pathophysiological processes that are unable to be studied using other model systems. Increases in the understanding of human epithelial tissues including intestine, stomach, liver, pancreas, lung, and brain have been achieved using organoids. However, it is not yet clear whether these cultures recapitulate in vivo organ-to-organ signaling or communication. In this work, we demonstrate that mature stem cell-derived intestinal and liver organoid cultures each express functional molecules that modulate bile acid uptake and recycling. These organoid cultures can be physically coupled in a Transwell® system and display increased secretion of FGF19 (intestine) and downregulation of CYP7A (liver) in response to apical exposure of the intestine to bile acids. This work establishes that organoid cultures can be used to study and therapeutically modulate interorgan interactions and advance the development of personalized approaches to medical care.

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Gaining New Biological and Therapeutic Applications into the Liver with 3D In Vitro Liver Models

Cited by 14 publications

References 141 publications

iPSC-derived hepatocytes generated from NASH donors provide a valuable platform for disease modeling and drug discovery

iPSC-derived hepatocytes generated from NASH donors provide a valuable platform for disease modeling and drug discovery

Establishing a 3D In Vitro Hepatic Model Mimicking Physiologically Relevant to In Vivo State

Use of human tissue stem cell-derived organoid cultures to model enterohepatic circulation

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