Nutritional modulation of mouse and human liver bud growth through a branched-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 nutrition in vivo or cultural supplement in vitro.

Single-cell analysis of progenitor cell dynamics and lineage specification in the human fetal kidney

“…CagAgr2 (the fish homolog of AGR2) is expressed in the renal collecting system from gibel carp (Xia et al, 2009) and in the intrahepatic, hilar and extrahepatic biliary tree in embryonic and adult human samples (Lepreux et al, 2011), and Adh1 is expressed in the urothelium of the developing mouse kidney (Mitchell et al, 2006). BCAT1 (branched chain aminotransferase 1) has not been studied in the kidney nor its expression reported; it has been shown to regulate early liver bud growth in the developing mice and in human embryonic stem cell-derived liver organoids (Koike et al, 2017). …”

Multiomics Analyses of HNF4α Protein Domain Function during Human Pluripotent Stem Cell Differentiation

“…Although the liver is regarded as one of the body's metabolic centers, less is known about the amino acid metabolism dynamics during early hepatogenesis. A recent study reported that l -valine is essential to murine liver bud growth and promotes the propagation of human hepatic progenitor organoids (Koike et al., 2017). This study did not investigate whether valine was required for human liver bud formation, but we note that valine consumption was significantly reduced in both DBD Mut and SUMO Mut cells at the hepatic progenitor stage.…”

Single-cell analysis of progenitor cell dynamics and lineage specification of the human fetal kidney

“…Table 1). While BCAT1 has not been studied in the kidney nor its expression reported, it has been recently shown to regulate early liver bud growth in the developing mice and in human embryonic stem cell derived liver organoids (Koike et al, 2017). Specific to the immature podocytes (Cluster 9) we find the expression of Olfactomedin 3 (OLFM3) (Fig.…”