In Vitro Modeling of Alcohol-Induced Liver Injury Using Human-Induced Pluripotent Stem Cells

Tian, Lipeng; Prasad, Neha; Jang, Yoon Young

doi:10.1007/7651_2014_168

Cited by 17 publications

(16 citation statements)

References 20 publications

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“… 116 More recently, it was observed that exposure to ethanol at the pathophysiological dosage induced apoptosis during differentiation of human iPSC-derived endoderm cells into hepatic progenitor cells and significantly reduced proliferative activity of mature stage hepatic cells. 123 Importantly, increased amounts of lipid droplets were detected in ethanol-treated iPSC-derived hepatocytes compared to controls, indicating the possibility of modeling ALD using human iPSCs.…”

Section: Response To Steroidsmentioning

confidence: 97%

“… 111 In recent years, human iPSCs have been generated from diverse human somatic cells, 112 – 117 and these cells can then be differentiated into a spectrum of mature human cell types, including functional hepatocytes. 112 – 114 , 116 , 118 – 123 This development has enabled us to access an unlimited supply of hepatocytes, which was one of the major challenges in the past. Moreover, human iPSCs retain the same genetic information of the donor (i.e., patient) tissues, making iPSCs a promising resource to study human diseases.…”

Section: Response To Steroidsmentioning

confidence: 99%

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Current Management of Alcoholic Hepatitis and Future Therapies

Saberi

Dadabhai

Jang

et al. 2016

JCTH

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Alcohol is one of the most common etiologies of liver disease, and alcoholic liver disease overall is the second most common indication for liver transplantation in the United States. It encompasses a spectrum of disease, including fatty liver disease, alcoholic hepatitis (AH), and alcoholic cirrhosis. AH can range from mild to severe disease, with severe disease being defined as: Discriminant Function (DF) ≥ 32, or Model for End-stage Liver Disease (MELD) ≥ 21, or presence of hepatic encephalopathy. Management of the mild disease consists mainly of abstinence and supportive care. Severe AH is associated with significant mortality. Currently, there is no ideal medical treatment for this condition. Besides alcohol cessation, corticosteroids have been used with conflicting results and are associated with an inherent risk of infection. Overall steroids have shown short term benefit when compared to placebo, but they have no obvious long term benefits. Pentoxifylline does not improve survival in patients with severe AH and is no longer recommended based on the results of the STOPAH (Steroid Or Pentoxifylline for Alcoholic Hepatitis) trial. Anti-tumor necrosis factor (TNF) agents are associated with increased risk of life threatening infections and death. Currently, early stage trials are underway, mainly targeting novel pathways based on disease pathogenesis, including modulation of innate immune system, inhibition of gut-liver axis and cell death pathways, and activation of transcription factor farnesyl X receptor (FXR). Future treatment may lie in human induced pluripotent stem cell (iPSC) technology, which is currently under investigation for the study of pathogenesis, drug discovery, and stem cell transplantation. Liver transplantation has been reported with good results in highly selected patients but is controversial due to limited organ supply.

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Section: Response To Steroidsmentioning

confidence: 97%

Section: Response To Steroidsmentioning

confidence: 99%

Current Management of Alcoholic Hepatitis and Future Therapies

Saberi

Dadabhai

Jang

et al. 2016

JCTH

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“…2,4 Lately, many research papers have described the generation of patient-and disease-specific human iPSC lines and have further modeled these liver diseases. [15][16][17][18][19][20][21][22][23][24] Disease-and patientspecific human iPSCs of glycogen-storage-disease, familial-hypercholesterolemia, and a-1-antitrypsin (AAT) deficiency liver disease have recapitulated important disease-specific pathological features and key disease phenotypes in vitro. 2,[15][16][17] Likewise, the restored function in the patient iPSC-derived hepatocytes in genetically corrected AAT-deficiency patient iPSC lines provides hope for future gene therapy.…”

Section: Liver Disease Modeling Using Human Ipscsmentioning

confidence: 99%

“…24 The use of human iPSC-derived hepatocytes to model and evaluate alcohol-induced liver injury in vitro have reported that alcohol negatively influence liver progenitor formation and proliferation of hepatocytes. 21,22 Interestingly, alcohol exposure appears to increase alcoholic liver disease associated phenotypes such as steatosis and HCC markers in the mature stage hepatocytes derived from human iPSCs. 21 More recently, human iPSC-derived hepatobiliary cells have been utilized to model biliary atresia and biliary fibrosis.…”

Section: Liver Disease Modeling Using Human Ipscsmentioning

confidence: 99%

Human-relevant preclinical in vitro models for studying hepatobiliary development and liver diseases using induced pluripotent stem cells

Chaudhari

Tian

et al. 2019

Exp Biol Med (Maywood)

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Pharmaceutical drug development and clinical testing is associated with billions of dollars, and often the time and money spent does not result in a viable drug formulation. The pharmaceutical industry has long relied on animal models for testing efficacy, toxicity and specificity of novel drugs. However, the studies cannot be fully relied upon, as animal models are not reflective of human pathophysiology and drug response, which results in drugs being pulled from development as late as at stage IV, after billions of dollars have already been invested in such an effort. With the advent of adult-induced pluripotent stem cell technology, came an era which offered the potential of pursing human relevant developmental and pathogenesis research and drug testing on patient-induced pluripotent stem cell-derived differentiated cells, consciously reflecting human responses with regard to drug safety, toxicity, efficacy, and side effects. Specifically, human-induced pluripotent stem cell-derived hepatobiliary cells and tissues may be a more human-relevant model system to address the biggest barrier to drug safety and approval: hepatotoxicity. In this review, we address the potential of human-induced pluripotent stem cell-based hepatobiliary differentiation technology as a means to study human liver development and hepatic cell fate determination, and to model liver diseases in an effort to develop a new human-relevant preclinical platform for drug development. Impact statement In this review, we address the potential of human-induced pluripotent stem cell-based hepatobiliary differentiation technology as a means to study human liver development and cell fate determination, and to model liver diseases in an effort to develop a new human-relevant preclinical platform for drug development.

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“…Alcohol-mediated changes in NMDA receptor function was also assessed in iPS-derived neural cells [83], indicating that iPSCs may offer a novel approach for better understanding the molecular mechanisms of alcohol use disorders [73, 84]. Exposure of iPSc to alcohol (100 mM) was also demonstrated to induce apoptosis and impair hepatic differentiation [85]. …”

Section: Effects Of Alcohol On Different Types Of Stem Cellsmentioning

confidence: 99%

Stem cells under the influence of alcohol: effects of ethanol consumption on stem/progenitor cells

Rocco

Baldari

Pani³

et al. 2018

Cell. Mol. Life Sci.

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Stem cells drive embryonic and fetal development. In several adult tissues, they retain the ability to self-renew and differentiate into a variety of specialized cells, thus contributing to tissue homeostasis and repair throughout life span. Alcohol consumption is associated with an increased risk for several diseases and conditions. Growing and developing tissues are particularly vulnerable to alcohol’s influence, suggesting that stem- and progenitor-cell function could be affected. Accordingly, recent studies have revealed the possible relevance of alcohol exposure in impairing stem-cell properties, consequently affecting organ development and injury response in different tissues. Here, we review the main studies describing the effects of alcohol on different types of progenitor/stem cells including neuronal, hepatic, intestinal and adventitial progenitor cells, bone-marrow-derived stromal cell, dental pulp, embryonic and hematopoietic stem cells, and tumor-initiating cells. A better understanding of the nature of the cellular damage induced by chronic and episodic heavy (binge) drinking is critical for the improvement of current therapeutic strategies designed to treat patients suffering from alcohol-related disorders.

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In Vitro Modeling of Alcohol-Induced Liver Injury Using Human-Induced Pluripotent Stem Cells

Cited by 17 publications

References 20 publications

Current Management of Alcoholic Hepatitis and Future Therapies

Current Management of Alcoholic Hepatitis and Future Therapies

Human-relevant preclinical in vitro models for studying hepatobiliary development and liver diseases using induced pluripotent stem cells

Stem cells under the influence of alcohol: effects of ethanol consumption on stem/progenitor cells

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