THE BITTER TASTE RECEPTOR AGONIST DENATONIUM INHIBITS STEMNESS CHARACTERISTICS IN HEMATOPOIETIC STEM CELLS

Bone marrow microenvironmental stimuli profoundly impact hematopoietic stem cell fate and biology. As G protein-coupled receptors, the bitter taste receptors (T2Rs) are key in transmitting extracellular stimuli into an intracellular response, within the oral cavity but also in extraoral tissues. Their expression in the bone marrow (BM)-derived cells suggests their involvement in sensing the BM microenvironmental fluctuation. In the present study, we demonstrated that umbilical cord blood (UCB)-derived CD34+ cells express fully functional T2Rs along with the signal transduction cascade components and their activation by the prototypical agonist, denatonium benzoate, significantly modulated genes involved in stemness maintenance and regulation of cell trafficking. The activation of these specific pathways was confirmed in functional in vitro experiments. Denatonium exposure exerted an antiproliferative effect on UCB-derived CD34+ cells, mainly affecting the most undifferentiated progenitor frequency. It also reduced their clonogenicity and repopulating potential in vitro. In addition, the T2R signaling activation impaired the UCB-derived CD34+ cell trafficking, mainly reducing the migration toward the chemoattractant agent CXCL12 and modulating the expression of the adhesion molecules CD62L, CD49d, and CD29. In conclusion, our results in UCB-derived CD34+ cells expand the observation of T2R expression in the setting of BM resident cells and shed light on the role of T2Rs in the extrinsic regulation of hematopoietic stem cell functions. To identify changes in gene expression in response to DEN exposition in UCB-derived CD34+ cells, we performed GEP analysis after in vitro activation of the T2R pathway by DEN on two pools of UCB-derived CD34+ cells using GeneChip Human Transcriptome Array 2.0