Human liver organoids: From generation to applications

Abstract

In the last decade, research into human hepatology has been revolutionized by the development of mini human livers in a dish. These liver organoids are formed by self-organizing stem cells and resemble their native counterparts in cellular content, multicellular architecture, and functional features. Liver organoids can be derived from the liver tissue or pluripotent stem cells generated from a skin biopsy, blood cells, or renal epithelial cells present in urine. With the development of liver organoids, a large part of previous hurdles in modeling the human liver is likely to be solved, enabling possibilities to better model liver disease, improve (personalized) drug testing, and advance bioengineering options. In this review, we address strategies to generate and use organoids in human liver disease modeling, followed by a discussion of their potential application in drug development and therapeutics, as well as their strengths and limitations.

Graphical abstract

FIGURE 1

Comparison of organoids with other systems to model liver disease. Abbreviations: 2D, two-dimensions; 3D, three dimensions; PHH, primary human hepatocytes. This figure was partly generated using Servier Medical Art, provided by Servier, licensed under a Creative Commons Attribution 3.0 unported license.

FIGURE 2

Applications of human liver organoids. Liver organoids can be isolated from healthy donors and liver disease patients for disease modeling, including response to external stimuli and stress signals, gene editing or cell communication in microfluidic devices. Likewise, liver disease patient-derived organoids can be used to predict the drug response supporting the therapeutic decision-making process (precision medicine). Organoids can also feature as a platform for drug discovery by providing a robust assessment of human drug sensitivity and hepatoxicity. Finally, liver organoids may themselves constitute a source for regenerative medicine-based therapeutics alone or coupled with tissue and/or genetic engineering. This figure was partly generated using Servier Medical Art, provided by Servier, licensed under a Creative Commons Attribution 3.0 unported license.

FIGURE 3

Generation and classification of human iPSC-derived, adult stem cell-derived and liver cancer-derived liver organoids. iPSC-derived liver organoids are established upon epithelial progenitor commitment, followed by hepatocyte and/or cholangiocyte maturation by culturing them with specific growth factors. The co-culture or concomitant differentiation of different iPSC germ layers can result in muli-tissue liver organoids, composed of parenchymal and non-parenchymal cells. Adult stem cells–derived liver organoids require their isolation, followed by culture in extracellular matrix in the presence of specific growth factors. Those organoids lack mesenchymal or immune components, and depending on the origin of adult stem cells and differentiation protocol are designated ICO, ECO, GCO, and HO. Finally, liver cancer organoids can be generated from cancer stem cells isolated from primary cancers and their classification follows the nomenclature of the parental tumor. Abbreviations: ECO, extrahepatic cholangiocyte organoid; GCO, gallbladder cholangiocyte organoids; HO, hepatocyte organoids; ICO, intrahepatic cholangiocyte organoid; iPSC, induced pluripotent stem cell. This figure was partly generated using Servier Medical Art, provided by Servier, licensed under a Creative Commons Attribution 3.0 unported license.