18 Chapter 1 as from adult or pluripotent stem cells. They have the ability to proliferate in vitro, while maintaining some of the functionalities of the organ of origin99. These structures have provided scientists with a revolutionary tool which allowed in vitro research to get one step closer to physiological relevance. While traditional 2D cell cultures rely on monolayers of one cell type, organoids allow more than one cell type to communicate with each other in a way that recapitulates the structure and functions of the tissue of origin more closely100. Another advantage of organoids over 2D cultures is the possibility of deriving patient-specific organoids, allowing for more tailored research101. Ever since their discovery, many organoid systems have been described, recapitulating the functional and structural properties of multiple organs, including intestine98, liver102,103, stomach104 and brain105. Organoids have been used for many purposes, including understanding organ development, modeling of genetic diseases, drug screening, regenerative medicine and the study of organ-specific metabolism99,106–108. While organoids are an excellent tool to study the effect of genetic diseases, as illustrated by an extensive number of publications109, they are also highly interesting for the study of different nutritional stressors on organ metabolism110. Moreover, they can also be used to understand the effects of different dietary interventions on the organ of study and its metabolic regulation111. As mentioned above, organoids can be isolated either from primary tissue or derived from stem cells, both adult and pluripotent99. Development of induced pluripotent stem cells (iPSCs) in 2006 by Yamanaka was regarded as a breakthrough in the field of stem cell biology112. Ever since, numerous protocols describing the differentiation of iPSCs into multiple cellular lineages have been published113–116. The hepatic lineage has been induced from iPSCs using multiple protocols which are commonly based on the use of growth factors Activin A and BMP4 to induce the definitive endoderm, followed by a combination of other growth factors to further commit the cells into hepatoblasts113,114,117–119. iPSCderived hepatocytes and hepatobiliary organoids recapitulate many features of the liver such as albumin production, lipid accumulation, and urea production. In some cases, upon further differentiation towards the hepatic-lineage, these organoids are referred to as “hepatocyte-like”. iPSC-derived hepatobiliary and hepatocyte-like organoids are, however, limited in their maturity level and are closer to fetal than to adult liver120,121. iPSC-derived hepatobiliary organoid models have been used to study different diseases such as alcoholic liver injury119 or genetic diseases such as Alagille syndrome (ALGS) and Tetralogy of Fallot (TOF)122.
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