Nutritional modulation of mouse and human liver bud growth through a branched-amino acid metabolism [RESEARCH REPORT]

Hiroyuki Koike, Ran-Ran Zhang, Yasuharu Ueno, Keisuke Sekine, Yun-wen Zheng, Takanori Takebe, and Hideki Taniguchi

Liver bud progenitors experience a transient amplification during early organ growth phase, yet the responsible mechanism was not fully understood. Collective evidence highlighted the specific requirements in stem cell metabolism for expanding organ progenitors during organogenesis and regeneration. Here, transcriptome analyses showed progenitors of mouse and human liver bud growth stage specifically expressed branched chain aminotransferase1 gene, a known breakdown enzyme of branched-chain amino acid (BCAA) for energy generation. Global metabolome analysis confirmed the active consumption of BCAA in the growing liver bud, but not in the later fetal or adult liver. Consistently, maternal dietary restriction of BCAA 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 among different BCAAs specifically promoted the 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 nutrition in vivo or cultural supplement in vitro.

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