Liver regeneration using cultured liver bud

Abstract

Human induced pluripotent stem cells (iPSCs) have highly promising applications in regenerative medicine, drug discovery, and disease modeling, as well as in investigations of developmental biology. Although iPSC can theoretically be differentiated into any cell type, further developments are required for application to tissue replacement. In particular, most differentiation protocols produce fully matured populations of single cell types in two-dimensional cultures. Some tissues, including retinal pigment epithelium, comprise relatively simple structures of single cell types and can be replaced by monocultures of matured cells. However, gastrointestinal and liver tissues comprise multiple cell types in complex architectures. Therefore, the lack of blood perfusion and three-dimensional interactions between multiple cell types are fundamental obstacles to the application of iPSC to regenerative medicine. To address these critical technological gaps, we investigated in vivo developmental processes in the context of essential interactions between cell types. In particular, the development of endodermal organs starts with organ specification as monocellular epithelium and subsequent multicellular interactions result in three-dimensional organs. We previously demonstrated the development of three-dimensional functional human liver buds (iPSC-LBs) from iPSC by coculturing iPSC-derived hepatic endodermal cells with endothelial and mesenchymal cells. This “organ bud technology” has high potential for the application of regenerative medicine to complex tissues and provides a unique model system for analyzing complex human tissues that comprise multiple cell types. In this review, we present the current understanding of iPSC-LB in regenerative medicine and discuss its potential use as a tool for investigating the developmental biology of liver tissues.