Abstract

The liver is one of the largest organs in the body and is responsible for a diverse repertoire of metabolic processes. Such processes include the secretion of serum proteins, carbohydrate and lipid metabolism, bile acid and urea synthesis, detoxification of drugs and metabolic waste products, and vitamin and carbohydrate storage. Currently, liver disease is one of the most prevalent causes of mortality in the USA with congenital liver defects contributing to a significant proportion of these deaths. Historically the study of liver disease has been hampered by a shortage of organ donors, the subsequent scarcity of healthy tissue, and the failure of animal models to fully recapitulate human liver function. In vitro culture of hepatocytes has also proven difficult because primary hepatocytes rapidly de-differentiate in culture. Recent advances in stem cell technology have facilitated the generation of induced pluripotent stem cells (iPSCs) from various somatic cell types from patients. Such cells can be differentiated to a liver cell fate, essentially providing a limitless supply of cells with hepatocyte characteristics that can mimic the pathophysiology of liver disease. Furthermore, development of the CRISPR-Cas9 system, as well as advancement of miniaturized differentiation platforms has facilitated the development of high throughput models for the investigation of hepatocyte differentiation and drug discovery. In this review, we will explore the latest advances in iPSC-based disease modeling and drug screening platforms and examine how this technology is being used to identify new pharmacological interventions, and to advance our understanding of liver development and mechanisms of disease. We will cover how iPSC technology is being used to develop predictive models for rare diseases and how information gained from large in vitro screening experiments can be used to directly inform clinical investigation.

Highlights

  • The liver is an endoderm-derived organ with dual endocrine and exocrine roles that are vital for the maintenance of physiological homeostasis

  • Patient derived induced pluripotent stem cells (iPSCs) have become a vital tool for researchers trying to uncover the regulatory mechanisms behind hepatic development, the underpinnings of congenital disease, and the mechanisms of drug metabolism and toxicity. iPSC derived hepatocytes provide a stable, readily available cell source for applications previously requiring human primary hepatocyte or hepatoma cell lines, including the investigation of defects in lipid metabolism [70, 106], protein accumulation [61], mitochondrial defects [77, 79], and toxicity screening [33, 97, 98]

  • It is worth noting that no differentiation protocol yet produces hepatocytes that are functionally identical to primary human liver cells, in regard to CYP450 enzyme expression which is essential for drug metabolism [107]

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Summary

Introduction

The liver is an endoderm-derived organ with dual endocrine and exocrine roles that are vital for the maintenance of physiological homeostasis. With advances in hepatic differentiation conditions, 3D culture platforms and generation of multi-tissue organoids it seems likely that improved iPSC–derived hepatocyte function will soon resemble that of primary human hepatocytes, facilitating their use in drug discovery, disease modeling, and regenerative therapy.

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