The Role of Kit and Thrombopoietin in Regulation of Hematopoietic Stem Cells

Abstract: The hematopoietic stem cell (HSC) is postulated to be the ultimate hematopoietic precursor providing production of mature blood cells, and is characterized by a life long capacity for self-renewal and multilineage differentiation. In a healthy human, the HSC produces 1,000,000,000,000 cells per day, illustrating the high turnover within the hematopoietic system and the need for replenishments by HSCs. The mechanisms behind self-renewal are largely unresolved, and we have therefore investigated the potential role of the cytokine receptors Kit and c-Mpl and their respective ligands, Kit ligand and Thrombopoietin (Thpo), in regulation of HSC self-renewal. Using mice that have partial (KitW41/W41) and complete (Thpo-/-) loss of function mutations of the Kit receptor and Thpo ligand respectively, we have demonstrated a reduction of bone marrow HSCs during steady-state conditions, a reduction that is further exacerbated with age, suggesting important roles of Kit and Thpo in steady-state maintenance of hematopoiesis. In addition, decreased regeneration of the HSC compartment of myeloablated mice post transplantation argues for an important role of these two cytokines in regulating HSCs during conditions of stress. We can further provide evidence that link this inability to increased cell cycle turnover within the HSC compartment in the absence of Kit and Thpo. Further, we provide evidence for Kit being important in Thpo independent residual hematopoiesis. Taken together, our findings suggest that Kit and c-Mpl and their respective ligands, Kit ligand and Thpo regulate HSC maintenance, and might exert this function by playing a role in keeping the bone marrow HSCs quiescent.