Human Pluripotent Stem Cell-Derived Organoids as Models of Liver Disease

Ramli, Muhammad Nadzim Bin; Lim, Yee-Siang; Koe, Chwee Tat; Demircioğlu, Deniz; Tng, Weiquan John; Gonzales, Kevin Andrew Uy; Tan, Cheng; Szczerbinska, Iwona; Liang, Hongqing; Lynn, Soe EinSi; Zhang, Lu; Ariyachet, Chaiyaboot; Yu, Ka Man; Koh, Shu Hui; Yaw, Lai Ping; Jumat, Nur Halisah Binte; Lim, John; Wright, Graham D.; Shabbir, Asim; Dan, Yock Young; Ng, Huck‐Hui; Chan, Yun‐Shen

doi:10.1053/j.gastro.2020.06.010

Cited by 145 publications

(150 citation statements)

References 44 publications

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“…Liver organoids also emerge as alternative system with multiple hepatic cell types which mimic liver structure and diseases (147). For example, liver organoids from human pluripotent stem cells could be used as model of NAFLD liver when stimulated with free-fatty acids (148). Primary liver organoids according to the severity of NASH have also been successfully generated from mice.…”

Section: Resultsmentioning

confidence: 99%

Chronic Inflammation in Non-Alcoholic Steatohepatitis: Molecular Mechanisms and Therapeutic Strategies

et al. 2020

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Non-Alcoholic Steatohepatitis (NASH) is the progressive form of Non-Alcoholic Fatty Liver Disease (NAFLD), the main cause of chronic liver complications. The development of NASH is the consequence of aberrant activation of hepatic conventional immune, parenchymal, and endothelial cells in response to inflammatory mediators from the liver, adipose tissue, and gut. Hepatocytes, Kupffer cells and liver sinusoidal endothelial cells contribute to the significant accumulation of bone-marrow derived-macrophages and neutrophils in the liver, a hallmark of NASH. The aberrant activation of these immune cells elicits harmful inflammation and liver injury, leading to NASH progression. In this review, we highlight the processes triggering the recruitment and/or activation of hepatic innate immune cells, with a focus on macrophages, neutrophils, and innate lymphoid cells as well as the contribution of hepatocytes and endothelial cells in driving liver inflammation/fibrosis. On-going studies and preliminary results from global and specific therapeutic strategies to manage this NASH-related inflammation will also be discussed.

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Section: Resultsmentioning

confidence: 99%

Chronic Inflammation in Non-Alcoholic Steatohepatitis: Molecular Mechanisms and Therapeutic Strategies

et al. 2020

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“…Therefore, advances in our knowledge of the epigenetic mechanisms that regulate liver plasticity might open new avenues for the treatment of chronic liver disease and liver cancer. In this regard, 3D liver organoid cultures derived from adult liver biopsies or induced pluripotent stem cells have proven reliable models of homeostatic and regenerative cholangiocytes (Huch et al, 2013(Huch et al, , 2015Sampaziotis et al, 2017;Aloia et al, 2019;Rimland et al, 2020) and hepatocytes (Hu et al, 2018;Peng et al, 2018), steatohepatitis (Ouchi et al, 2019;Ramli et al, 2020), and primary liver cancer (Broutier et al, 2017;Nuciforo et al, 2018), thus representing promising platforms to uncover the molecular mechanisms underlying liver regeneration, disease, and cancer.…”

Section: Discussionmentioning

confidence: 99%

Epigenetic Regulation of Cell-Fate Changes That Determine Adult Liver Regeneration After Injury

Aloia

2021

Front. Cell Dev. Biol.

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The adult liver has excellent regenerative potential following injury. In contrast to other organs of the body that have high cellular turnover during homeostasis (e.g., intestine, stomach, and skin), the adult liver is a slowly self-renewing organ and does not contain a defined stem-cell compartment that maintains homeostasis. However, tissue damage induces significant proliferation across the liver and can trigger cell-fate changes, such as trans-differentiation and de-differentiation into liver progenitors, which contribute to efficient tissue regeneration and restoration of liver functions. Epigenetic mechanisms have been shown to regulate cell-fate decisions in both embryonic and adult tissues in response to environmental cues. Underlying their relevance in liver biology, expression levels and epigenetic activity of chromatin modifiers are often altered in chronic liver disease and liver cancer. In this review, I examine the role of several chromatin modifiers in the regulation of cell-fate changes that determine efficient adult liver epithelial regeneration in response to tissue injury in mouse models. Specifically, I focus on epigenetic mechanisms such as chromatin remodelling, DNA methylation and hydroxymethylation, and histone methylation and deacetylation. Finally, I address how altered epigenetic mechanisms and the interplay between epigenetics and metabolism may contribute to the initiation and progression of liver disease and cancer.

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“…Recently, there have been efforts to apply hiPSC-derived HLCs for pharmaceutical research and disease modeling (Avior et al, 2016;Ramli et al, 2020;Rowe and Daley, 2019;Takayama et al, 2018;Tian et al, 2016). Using hiPSCs, three-dimensional cell culture and organoid generation with better functionalities than those of two-dimensionally cultured hepatocytes (Kamei et al, 2019;Takayama et al, 2018) can be conducted for applications to in vitro NAFLD modeling.…”

Section: Discussionmentioning

confidence: 99%

In vitro nonalcoholic fatty liver disease model with cyclo-olefin-polymer-based microphysiological systems

Wen

Yamanaka

Terada

et al. 2020

Preprint

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Nonalcoholic fatty liver disease (NAFLD) is one of the common chronic liver conditions, whose treatment involves curing patients without liver transplantation. Understanding the mechanism of NAFLD initiation and progression would enable development of new diagnostic tools and drugs; however, until now, the underlying mechanisms of this condition remain largely unknown owing to the lack of experimental settings that can simplify the complicated NAFLD process in vitro. Microphysiological systems (MPSs) have long been used to recapture human pathophysiological conditions in vitro for applications in drug discovery. However, polydimethylsiloxane (PDMS) has been used in most of these MPSs as the structural material; it absorbs hydrophobic molecules, such as free fatty acids (FFAs), which are the key components that initiate NAFLD. Therefore, the current PDMS-based MPSs cannot be directly applied to in vitro NALFD modeling. In this work, we present an in vitro NAFLD model with an MPS made of cyclo-olefin polymer (COP), namely COP-MPS, to prevent absorption of FFAs. We demonstrated induction of the NAFLD-like phenotype in HepaRG hepatocyte-like cells cultured in the COP-MPS by introducing FFAs. The FFAs induced lipid accumulation in the HepaRG cells, resulting in inactivation of the apoptotic cells. We believe that the proposed COP-MPS can contribute toward investigations of NAFLD mechanisms and identification of new drugs to prevent the progression of liver disease and avoid liver transplantation.

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Human Pluripotent Stem Cell-Derived Organoids as Models of Liver Disease

Cited by 145 publications

References 44 publications

Chronic Inflammation in Non-Alcoholic Steatohepatitis: Molecular Mechanisms and Therapeutic Strategies

Chronic Inflammation in Non-Alcoholic Steatohepatitis: Molecular Mechanisms and Therapeutic Strategies

Epigenetic Regulation of Cell-Fate Changes That Determine Adult Liver Regeneration After Injury

In vitro nonalcoholic fatty liver disease model with cyclo-olefin-polymer-based microphysiological systems

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