Details

Autor(en) / Beteiligte

• Takebe, Takanori
• Sekine, Keisuke
• Enomura, Masahiro
• Koike, Hiroyuki
• Kimura, Masaki
• Ogaeri, Takunori
• Zhang, Ran-Ran
• Ueno, Yasuharu
• Zheng, Yun-Wen
• Koike, Naoto
• Aoyama, Shinsuke
• Adachi, Yasuhisa
• Taniguchi, Hideki

Titel

Vascularized and functional human liver from an iPSC-derived organ bud transplant

Ist Teil von

• Nature (London), 2013-07, Vol.499 (7459), p.481-484

Ort / Verlag

London: Nature Publishing Group UK

Erscheinungsjahr

2013

Quelle

MEDLINE

Beschreibungen/Notizen

• Vascularized, functional human liver is generated from human induced pluripotent stem cells (iPSCs) by transplantation of liver buds created in vitro (iPSC-LBs); hepatic cells self-organized into three-dimensional iPSC-LBs, and human vasculatures in iPSC-LB transplants became functional by connecting to host vessels, stimulating maturation of iPSC-LBs into tissue resembling adult liver and performing liver-specific functions. Induced liver bud a step towards organ regeneration In this proof-of-concept study, Hideki Taniguchi and colleagues recapitulate the cellular rearrangements that take place in the embryo during the development of an organ bud — in this case a liver bud — using an in vitro system composed of human induced pluripotent stem (iPS) cells specified on the hepatic lineage in mixed culture with human endothelial and mesenchymal cells. Transplantation of the resulting liver buds led to the generation of vascularized and functional human liver tissue in immunodeficient mice. This work highlights organ bud creation and transplantation as a promising new approach to regenerative treatment of organ failure. 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 differentiation 2 , 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 cells 5 . 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 replacement 6 . 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.