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To address these critical technological gaps, we investigated in vivo developmen-
tal processes in the context of essential interactions between cell types. In particular,
the development of endodermal organs starts with organ specification as monocel-
lular epithelium and subsequent multicellular interactions result in three- dimensional
organs. We previously demonstrated the development of three-dimensional func-
tional human liver buds (iPSC-LBs) from iPSC by coculturing iPSC-derived hepatic
endodermal cells with endothelial and mesenchymal cells. This “organ bud technol-
ogy” 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.
Keywords Foregut • Endoderm • Development • iPSC • Organ bud • Liver bud •
Multiple cell types • Regenerative medicine
12.1 Basics of Liver Developmental Biology
The developmental biology of the liver has been mainly studied in mice and zebraf-
ish, and previous studies indicate that liver tissues arise from ventral foregut endo-
derm during embryonic development (Zaret and Grompe 2008 ; Ichikawa et al.
2014 ; Miyajima et al. 2014 ; Gordillo et al. 2015 ). After gastrulation, gut endoder-
mal cells form multiple tissues of various functions and shapes, including the lung,
liver, and pancreas (Fig. 12.1). Gut endoderm that is adjacent to the cardiac meso-
derm is the first site of hepatic-specific endoderm, and hepatic diverticulum with
endoderm cell lining then forms a pseudo-stratified architecture (Fig. 12.2)
(Si-Tayeb et al. 2010a). Subsequently, cells start expressing liver-specific genes,
including Prox1, Hhex, and AFP, and then delaminate from surrounding basal mem-
branes with laminin and collagen IV (Sosa-Pineda et al. 2000 ; Burke and Oliver
2002 ; Lee et al. 2005 ; Lokmane et al. 2008 ; Le lay and Kaestner 2010 ; Harrelson
et al. 2012 ). Liver tissue development then proceeds with the dissemination of cells
into the surrounding stroma and subsequent sprouting of liver buds. During this
stage, surrounding stroma other than endoderm is involved in the “budding” of gut
endoderm, and the liver forms from single cell-type monolayers of hepatic-specified
gut endoderm cells. Concomitantly, multi-lineage interactions are initiated with
mesenchymal and endothelial cells surrounding the gut tube (Fig. 12.2) (Matsumoto
et al. 2001 ). These cellular interactions are essential for the proliferation, migration,
and differentiation of various liver cell types. After the initial liver bud stage, nascent
liver tissues develop into multicellular organs, and blood perfusion starts immedi-
ately. Finally, the liver serves as a hematopoietic tissue during the embryonic period.
Because blood and liver maturation are coupled, blood cells likely participate in
K. Sekine et al.