title: Nutritional modulation of mouse and human liver bud growth through a branched-chain amino acid metabolism.
abstract: Liver bud progenitors experience a transient amplification during the early organ growth phase, yet the mechanism responsible is not fully understood. Collective evidence highlights the specific requirements in stem cell metabolism for expanding organ progenitors during organogenesis and regeneration. Here, transcriptome analyses show that progenitors of the mouse and human liver bud growth stage specifically express the gene branched chain aminotransferase 1, encoding a known breakdown enzyme of branched-chain amino acids (BCAAs) for energy generation. Global metabolome analysis confirmed the active consumption of BCAAs in the growing liver bud, but not in the later fetal or adult liver. Consistently, maternal dietary restriction of BCAAs during pregnancy significantly abrogated the conceptus liver bud growth capability through a striking defect in hepatic progenitor expansion. Under defined conditions, the supplementation of L-valine specifically among the BCAAs promoted rigorous growth of the human liver bud organoid in culture by selectively amplifying self-renewing bi-potent hepatic progenitor cells. These results highlight a previously underappreciated role of branched-chain amino acid metabolism in regulating mouse and human liver bud growth that can be modulated by maternal nutritionin vivoor cultural supplementin vitro.
authors.affiliation: Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, 3-9, Fukuura, Kanazawa-ku, Yokohama, Kanagawa 236-0004, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Koike
authors.affiliation: Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, 3-9, Fukuura, Kanazawa-ku, Yokohama, Kanagawa 236-0004, Japan.
authors.forename: Ran-Ran
authors.initials: RR
authors.lastname: Zhang
authors.affiliation: Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, 3-9, Fukuura, Kanazawa-ku, Yokohama, Kanagawa 236-0004, Japan.
authors.forename: Yasuharu
authors.initials: Y
authors.lastname: Ueno
authors.affiliation: Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, 3-9, Fukuura, Kanazawa-ku, Yokohama, Kanagawa 236-0004, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Sekine
authors.affiliation: Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, 3-9, Fukuura, Kanazawa-ku, Yokohama, Kanagawa 236-0004, Japan.
authors.forename: Yun-Wen
authors.initials: YW
authors.lastname: Zheng
authors.affiliation: Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, 3-9, Fukuura, Kanazawa-ku, Yokohama, Kanagawa 236-0004, Japan ttakebe@yokohama-cu.ac.jp rtanigu@yokohama-cu.ac.jp.|Advanced Medical Research Center, Yokohama City University, Yokohama, Kanagawa 236-0004, Japan.|PRESTO, Japan Science and Technology Agency, 4-1-8, Honcho, Kawaguchi, Saitama 332-0012, Japan.
authors.forename: Takanori
authors.identifier: 0000-0002-6989-3041
authors.initials: T
authors.lastname: Takebe
authors.affiliation: Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, 3-9, Fukuura, Kanazawa-ku, Yokohama, Kanagawa 236-0004, Japan ttakebe@yokohama-cu.ac.jp rtanigu@yokohama-cu.ac.jp.|Advanced Medical Research Center, Yokohama City University, Yokohama, Kanagawa 236-0004, Japan.
authors.forename: Hideki
authors.identifier: 0000-0002-6186-9266
authors.initials: H
authors.lastname: Taniguchi
mesh_terms: D000597:Amino Acids, Branched-Chain / Q000378:metabolism*; D000818:Animals; D005333:Fetus / Q000187:drug effects / Q000196:embryology / Q000378:metabolism; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000196:embryology* / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D009747:Nutritional Physiological Phenomena / Q000187:drug effects; D000637:Transaminases / Q000378:metabolism*; D059467:Transcriptome / Q000187:drug effects / Q000235:genetics; D014633:Valine / Q000494:pharmacology
chemical_list: D000597:Amino Acids, Branched-Chain; C094227:Bcat1 protein, mouse; D000637:Transaminases; D014633:Valine
keywords: Branched chain aminotransferase 1; Induced pluripotent stem cells; L-valine; Liver bud; Metabolism