A critical shortage of donor organs for treating end-stage organ failure highlights the urgent need for generating organs from human induced pluripotent stem cells (iPSCs)1. Despite many reports describing functional cell differentiation2,3,4, no studies have succeeded in generating a three-dimensional vascularized organ such as liver. Here we show the generation of vascularized and functional human liver from human iPSCs by transplantation of liver buds created in vitro (iPSC-LBs). Specified hepatic cells (immature endodermal cells destined to track the hepatic cell fate) self-organized into three-dimensional iPSC-LBs by recapitulating organogenetic interactions between endothelial and mesenchymal cells5. Immunostaining and gene-expression analyses revealed a resemblance between in vitro grown iPSC-LBs and in vivo liver buds. Human vasculatures in iPSC-LB transplants became functional by connecting to the host vessels within 48 hours. The formation of functional vasculatures stimulated the maturation of iPSC-LBs into tissue resembling the adult liver. Highly metabolic iPSC-derived tissue performed liver-specific functions such as protein production and human-specific drug metabolism without recipient liver replacement6. Furthermore, mesenteric transplantation of iPSC-LBs rescued the drug-induced lethal liver failure model. To our knowledge, this is the first report demonstrating the generation of a functional human organ from pluripotent stem cells. Although efforts must ensue to translate these techniques to treatments for patients, this proof-of-concept demonstration of organ-bud transplantation provides a promising new approach to study regenerative medicine.
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Gene Expression Omnibus
Microarray data, including that of human iPSC-LBs, human FLC-LBs, human adult liver tissues (ALT) and mouse liver tissue of various developmental stages, have been deposited in the Gene Expression Omnibus under accession number GSE46631.
We thank F. Kawamata, E. Yoshizawa, Y. Suzuki, S. Nakai, Y. Takahashi, N. Tsuchida and N. Sasaki for kindly providing technical support; J. Nakabayashi, K. Yasumura, R. Fujiwara, T. Amiya, A. Nakano, Y. Mitsuhashi and all of the members of our laboratory for help with several experiments and comments. We are also grateful to D. Fukumura, Y. Goshima, T. Hirose, M. Ichino, U. Yokoyama, T. Ogawa and R. K. Jain for critical evaluation of the manuscript. This work was supported by grants to H. Taniguchi from the Strategic Promotion of Innovative Research and Development (S-innovation, 62890004) of the Japan Science and Technology Agency (JST). This work was also supported by the Grants-in-Aid of the Ministry of Education, Culture, Sports, Science, and Technology of Japan to T. Takebe (no. 24106510, 24689052), N. Koike (no. 22390260) and H. Taniguchi (no. 21249071, 25253079); by the Specified Research Grant of the Takeda Science Foundation and a grant from the Japan IDDM network to H. Taniguchi; and by a grant of the Yokohama Foundation for Advanced Medical Science to T. Takebe.
This video shows formation of human induced pluripotent stem cell-derived liver bud by recapitulating organogenetic interactions.
This video shows the z stack images of patent human vasculatures inside the hiPSC-LB transplants at day 4.
This video shows the successful engraftment of hiPSC-Heps along with the functional vascular networks at day 4.
3D visualization of the direct connection among human and host vessels by whole mount immunostaining
This video shows the connection among the human and host vessels visualised by immunostaining of the explants. Volocity software was used to reconstruct 3D image.