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

被引：301

作者：

Takebe, Takanori ^{[1
,2
,3
,4
,5
]}

Sekine, Keisuke ^{[1
]}

Kimura, Masaki ^{[1
]}

Yoshizawa, Emi ^{[1
]}

Ayano, Satoru ^{[6
]}

Koido, Masaru ^{[1
]}

Funayama, Shizuka ^{[1
]}

Nakanishi, Noriko ^{[1
]}

Hisai, Tomoko ^{[1
]}

Kobayashi, Tatsuya ^{[1
]}

Kasai, Toshiharu ^{[1
]}

Kitada, Rina ^{[1
]}

Mori, Akira ^{[1
]}

Ayabe, Hiroaki ^{[1
]}

Ejiri, Yoko ^{[6
]}

Amimoto, Naoki ^{[7
]}

Yamazaki, Yosuke ^{[7
]}

Ogawa, Shimpei ^{[8
]}

Ishikawa, Momotaro ^{[9
]}

Kiyota, Yasujiro ^{[9
]}

Sato, Yasuhiko ^{[10
]}

Nozawa, Kohei ^{[11
]}

Okamoto, Satoshi ^{[1
]}

Ueno, Yasuharu ^{[1
]}

Taniguchi, Hideki ^{[1
,2
]}

机构：

[1] Yokohama City Univ, Dept Regenerat Med, Grad Sch Med, Kanazawa Ku, Fukuura 3-9, Yokohama, Kanagawa 2360004, Japan

[2] Yokohama City Univ, Adv Med Res Ctr, Kanazawa Ku, Fukuura 3-9, Yokohama, Kanagawa 2360004, Japan

[3] Japan Sci & Technol Agcy, PRESTO, 4-1-8 Honcho, Kawaguchi, Saitama 3320012, Japan

[4] Cincinnati Childrens Hosp Med Ctr, Dept Pediat, Div Gastroenterol Hepatol & Nutr & Dev Biol, 3333 Burnet Ave, Cincinnati, OH 45229 USA

[5] Cincinnati Childrens Hosp Med Ctr, Ctr Stem Cell & Organoid Med CuSTOM, Cincinnati, OH 45229 USA

[6] Kuraray Co Ltd, Molding Component Business Dept, Tsukuba, Ibaraki 3050841, Japan

[7] Healios KK, Minato Ku, 2-4-1 Hamamatsucho, Tokyo 1056115, Japan

[8] Ajinomoto Co Inc, Inst Innovat, Kawasaki Ku, 1-1 Suzuki Cho, Kawasaki, Kanagawa 2108681, Japan

[9] Nikon Inc, Tokyo, Japan

[10] Carl Zeiss Microscopy Co Ltd, Tokyo, Japan

[11] Sekisui Med Co Ltd, Tokyo, Japan

来源：

CELL REPORTS | 2017年 / 21卷 / 10期

基金：

日本科学技术振兴机构;

关键词：

SEPTUM TRANSVERSUM MESENCHYME; HEPATIC STELLATE CELLS; FUNCTIONAL HUMAN LIVER; HEPATOCYTE TRANSPLANTATION; GENERATION; MOUSE; DIFFERENTIATION; LINEAGE;

D O I：

10.1016/j.celrep.2017.11.005

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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-wellarray culture platform for mass producing homogeneous and miniaturized liver buds on a clinically relevant large scale (>10(8)). 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.

引用

页码：2661 / 2670

页数：10

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