Human ESC-derived expandable hepatic organoids enable therapeutic liver repopulation and pathophysiological modeling of alcoholic liver injury

Organoids to model liver disease

“…Cessation of alcohol consumption is the most important factor for a successful therapy that may involve anti-inflammatory treatments or liver transplantation in the most severe cases. Recently, Wang and colleagues developed an in vitro organoid model system that recapitulates typical features of ALD pathophysiology [67]. ESC-derived liver organoids were co-cultured with fetal liver mesenchymal cells and treated with ethanol.…”

“…Applying organoids to the study of liver diseases or drug screenings holds the potential to greatly reduce the number of animal models used for equivalent purposes. In light of all the excitement around the organoid technology with all its different advantages (Table 3) [36,37,44,67] or using co-culture protocols that re-introduce tissue-derived or engineered cell populations such as immune cells [87,88,[96][97][98] and cancer-associated fibroblasts [86] for cancer organoid cultures. Remarkably, a recent report described a protocol for the culture of patient-derived glioblastoma organoids that preserve and continuously generate diverse cell types, therefore maintaining a nearly-intact tumor microenvironment at the cellular level [99].…”

“…Recently, Wang and colleagues developed an in vitro organoid model system that recapitulates typical features of ALD pathophysiology. 67 ESC-derived liver organoids were co-cultured with foetal liver mesenchymal cells and treated with ethanol. Remarkably, compared to untreated controls, ethanol-treated organoids displayed several features of alcohol-induced liver injury such as increased CYP2E1 and CYP3A4 activity, oxidative stress, deposition of extracellular matrix, and apoptosis.…”

“…This reduction in cellular complexity clearly limits the usefulness of organoids for the study of complex pathophysiologic processes such as fibrosis, hepatitis and liver cancer, where several different cell types interact in a highly dynamic way. Improved versions of organoid culture protocols try to address these limitations using either systems that incorporate and allow the parallel culture and differentiation of various cell types such as stellate-like cells, Kupffer-like cells, and endothelial cells 36 , 37 , 44 , 67 or using co-culture protocols that re-introduce tissue-derived or engineered cell populations such as immune cells 87 , 88 , [96] , [97] , [98] and cancer-associated fibroblasts 86 for cancer organoid cultures. Remarkably, a recent report described a protocol for the culture of patient-derived glioblastoma organoids that preserve and continuously generate diverse cell types, therefore maintaining a nearly intact tumour microenvironment at the cellular level.…”

Production of Human Pluripotent Stem Cell-Derived Hepatic Cell Lineages and Liver Organoids: Current Status and Potential Applications

“…Therefore, this study suggested that liver organoids can be considered a good platform for HBV modelling, recapitulating the virus life cycle and consequent dysfunctions. Another example of disease modeling of acquired liver diseases using liver organoids is the study of alcoholic liver disease (ALD), the number one cause of liver-associated mortality in Western countries [89]. Upon EtOH treatment for 7 days, liver organoids displayed liver damage and reduction in cell viability, as well as upregulation of gene expression of fibrogenic markers, thus recapitulating ALD pathophysiology.…”