Expression and function of Gllut transporters in the expansion and differentiation of hematopoietic stem cells towards distinct lineage fates – GLUTStem

Extensive research has been undertaken to elucidate the roles of cytokines in the proliferation and differentiation of hematopoietic stem cells. However, the importance of metabolism in these processes has only been cursorily assessed. During the past few years, our group has begun to approach this question, focusing on glucose transport and metabolism. Glucose provides cells with a major source of energy in the form of ATP but it is also crucial for the synthesis of glycerol, non-essential amino acids and vitamins, and contributes to the generation of reducing equivalents in the form of NADPH. Briefly, based in part on the high expression of the glucose transporter Glut1, we identified a new subset of lymphocyte progenitors in the human thymus (Swainson et al., PNAS, 2005). Furthermore, we have determined that the differentiation of human CD34+ hematopoietic progenitors towards the erythroid lineage is associated with a 3-log increase in Glut1 transcription, resulting in a significantly enhanced transport of an oxidized form of ascorbic acid, dehydroascorbic acid, but not of glucose itself (Montel-Hagen et al., Cell, 2008). Interestingly, we did not detect augmented Glut1 expression upon differentiation of CD34+ progenitors towards other hematopoietic lineages, despite massive increases in glucose uptake (our unpublished observations). It is therefore critical to assess the potential roles of other Glut-type transporters during progenitor/stem cell expansion and subsequent differentiation towards both myeloid and lymphoid lineages. Notably, there are at least 13 Glut family members, but their expression profiles, regulation and function in hematopoietic progenitors and upon differentiation towards distinct lineage fates are not known. Moreover, several Gluts have recently been revealed to show distinct substrate specificities; transporting fructose, dehydroascorbic acid and urate rather than glucose. The ensemble of the experiments proposed here will allow us to determine the expression profiles of these Glut transporters during hematopoiesis and their role(s) during the differentiation process. The specificities and requirements for these Glut transporters may provide new avenues for manipulating hematopoietic stem cell expansion and differentiation towards distinct lineage fates.