Hepatic organoids move from adolescence to maturity

Abstract

Since organoids were developed 15 years ago, they are now in their adolescence as a research tool. The ability to generate ‘tissue in a dish’ has created enormous opportunities for biomedical research. We examine the contributions that hepatic organoids have made to three areas of liver research: as a source of cells and tissue for basic research, for drug discovery and drug safety testing, and for understanding disease pathobiology. We discuss the features that enable hepatic organoids to provide useful models for human liver diseases and identify four types of advances that will enable them to become a mature (i.e., adult) research tool over the next 5 years. During this period, advances in single‐cell RNA sequencing and CRISPR technologies coupled with improved hepatic organoid methodology, which enables them to have a wider range of cell types that are present in liver and to be grown in microwells, will generate discoveries that will dramatically advance our understanding of liver development and the pathogenesis of liver diseases. It will generate also new approaches for treating liver fibrosis, which remains a major public health problem with few treatment options.

Characterization of Pro-Fibrotic Signaling Pathways using Human Hepatic Organoids

“…However, additional studies will have to be performed to characterize the mechanism(s) by which the Wnt/β-catenin and p38 MAPK pathways, along with the SMAD and STAT3 pathways that are also activated by TGFβ1 and PDGF receptors, jointly contribute to liver fibrosis. Moreover, microHOs can also be used in conjunction with other recently developed genomic methods to provide a deeper understanding of the mechanisms mediating liver fibrosis [85]. In summary, live cell imaging of human microHOs has identified GSK3β and p38 MAPK inhibitors as potential new therapies for liver fibrosis, and it is likely that other new therapies and their mechanism of action could subsequently be identified using this system.…”

“…Moreover, microHOs can also be used in conjunction with other recently developed genomic methods to provide a deeper understanding of the mechanisms mediating liver fibrosis [85]. In summary, live cell imaging of human microHOs has identified GSK3b and p38 MAPK inhibitors as potential new therapies for liver fibrosis, and it is likely that other new therapies and their mechanism of action could subsequently be identified using this system.…”