Cell Rep. 2017 Dec 5;21(10):2661-2670. doi: 10.1016/j.celrep.2017.11.005.

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

Takebe T¹, Sekine K², Kimura M², Yoshizawa E², Ayano S³, Koido M², Funayama S², Nakanishi N², Hisai T², Kobayashi T², Kasai T², Kitada R², Mori A², Ayabe H², Ejiri Y³, Amimoto N⁴, Yamazaki Y⁴, Ogawa S⁵, Ishikawa M⁶, Kiyota Y⁶, Sato Y⁷, Nozawa K⁸, Okamoto S², Ueno Y², Taniguchi H⁹.

Abstract

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.