229
scription profiles between iPSC-LB and two-dimensional cultured hepatocytes may
identify specific factors that support functional maturation. These analyses will pro-
vide critical improvements of liver bud technology using hPSC and will likely
reflect the growing importance of multicellular interactions between developing
hepatic endodermal cells and surrounding stromal cells.
Recent studies report the use of iPSC-derived hepatocytes as models of liver
disease. For example, alpha1-antitrypsin deficiency was the first heritable metabolic
disease to be modeled using iPSC-derived hepatocytes, and the resulting phenotypic
mimicry of the features of this disease provided the first proof of principle for the
use of iPSC-derived hepatocytes as disease models. Moreover, in combination with
recently developed gene-editing technologies that can be used to correct causative
mutations, iPSC-derived hepatocytes can be used as a drug-screening platform for
such diseases. Moreover, three-dimensional multi-lineage organ buds will likely
facilitate the establishment of these disease modeling and drug-screening
platforms.
12.4 Organ Bud Technology
The development of three-dimensional tissue architectures and artificial organs is a
long-standing aim of regenerative medicine. Using scaffolds to build three-
dimensional architecture is straightforward, and decellularized tissues have been
Endothelial cells
Human iPS cells
Hepatic specified
endoderm cells
Mesenchymal cells
Directed differentiation
in 2D culture
iPSC-liver bud formation in vitro
Liver bud maturation in vivo
Endothelialcells
atic specified
derm cells
Mesenchymalcells
Directed differentiation
in 2D culture Liverbudmaturationinvivo
day 1
iPSC-liver bud
Transplantation
Fig. 12.4 Strategy toward human iPSC-derived liver generation. Mimic early organogenesis
and recapitulate organogenic cellular interactions in vitro. Human iPSC-derived hepatic-specified
endoderm, mesenchymal cells, and endothelial cells were co-cultivated in vitro. Large-scale mor-
phogenetic changes were induced by the interactions between these cell types. In particular, con-
densation of the heterotypic cell mixture led to the formation of a large cellular mass and was
initiated by mesenchymal cells. The generated liver buds could be transplanted, and subsequent
blood perfusion may facilitate maturation to functional liver tissue
12 Liver Regeneration Using Cultured Liver Bud