Massive and Reproducible Production of Liver Buds Entirely from Human Pluripotent Stem Cells

Takanori Takebe; Keisuke Sekine; Masaki Kimura; Emi Yoshizawa; Satoru Ayano; Masaru Koido; Shizuka Funayama; Noriko Nakanishi; Tomoko Hisai; Tatsuya Kobayashi; Toshiharu Kasai; Rina Kitada; Akira Mori; Hiroaki Ayabe; Yoko Ejiri; Naoki Amimoto; Yosuke Yamazaki; Shimpei Ogawa; Momotaro Ishikawa; Yasujiro Kiyota; Yasuhiko Sato; Kohei Nozawa; Satoshi Okamoto; Yasuharu Ueno; Hideki Taniguchi

Massive and Reproducible Production of Liver Buds Entirely from Human Pluripotent Stem Cells

2017

Summary: Organoid technology provides a revolutionary paradigm toward therapy but has yet to be applied in humans, mainly because of reproducibility and scalability challenges. Here, we overcome these limitations by evolving a scalable organ bud production platform entirely from human induced pluripotent stem cells (iPSC). By conducting massive “reverse” screen experiments, we identified three progenitor populations that can effectively generate liver buds in a highly reproducible manner: hepatic endoderm, endothelium, and septum mesenchyme. Furthermore, we achieved human scalability by developing an omni-well-array culture platform for mass producing homogeneous and miniaturized liver buds on a clinically relevant large scale (>108). Vascularized and functional liver tissues generated entirely from iPSCs significantly improved subsequent hepatic functionalization potentiated by stage-matched developmental progenitor interactions, enabling functional rescue against acute liver failure via transplantation. Overall, our study provides a stringent manufacturing platform for multicellular organoid supply, thus facilitating clinical and pharmaceutical applications especially for the treatment of liver diseases through multi-industrial collaborations. : With the goal of clinical translation of liver bud transplant therapy, Takebe et al. established a massive organoid production platform from endoderm, endothelial, and mesenchymal progenitor populations specified entirely from human iPSCs, reproducibly demonstrating functionality both in vitro and in vivo. Keywords: iPSC, liver bud, organoid, transplantation, self-organization, endothelial, mesenchymal, liver failure, clinical grade

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