Threonine metabolism and embryonic stem cell self-renewal

Embryonic stem cells (ESCs) undergo unlimited self-renewal while maintaining a pluripotency, which is defined as the ability to develop into cells of all three embryonic germ layers. ESC self-renewal is characterized by special proliferative and epigenetic properties and a unique metabolic profile. One of the key features of this specialized nutritional metabolism is a stringent requirement for the amino acid threonine. Until recently, little was known about amino acid metabolism in stem cells beyond their general role in protein synthesis. Recent findings demonstrating a central role for threonine metabolism in multiple aspects of stem cell biology will be presented in this review.

Amino acid catabolism supplies essential building blocks for biosynthetic pathways and for chemical modification of chromatin. In a series of recent studies employing combinative approaches of metabolomics, nutrition and genetics, the amino acid threonine was identified as an essential nutrient for mouse ESC (mESC). An unexpected finding from these studies was that in addition to its well known importance as protein precursor, threonine dehydrogenase-mediated threonine catabolism provides essential metabolic building blocks for use in multiple biosynthetic pathways and epigenetic modifications required for self-renewal and maintenance of pluripotency.

Recent studies on threonine catabolism in mESCs suggest that amino acids can play both powerful biosynthetic and signaling roles in stem cells. These results described in mESCs should stimulate a new research area on the effect of amino acid metabolism in stem cell self-renewal and differentiation.