Hemopoietic stem cell proliferation in Belgrade rats: to complete the parable

The Belgrade laboratory (b/b) rat is a mutant animal suffering of a severe anemia, resulting from a severe intracellular iron deficiency. This deficiency is determined by an impaired intracellular transport of iron due to a block located between the endocytic vesicles and the cytosolic iron transport to mitochondria. This results in a complex series of disturbances affecting hemopoietic stem and progenitor cells, as well as growth factor production. The gene affected by the "b" mutation is unknown. This review summarizes the current knowledge on b/b rat hemopoiesis, with the focus on pluripotent hemopoietic progenitors, such as Spleen Colony Forming Units scored at day 8 after transplantation (CFU-Sd8) and more primitive stem cells (pre-CFU-S) responsible for Marrow Repopulating Ability. A special effort was made to describe the effects of b/b mutation on hemopoietic stem cells distinguishing between the alterations connected to the primary defect (intracellular iron deficiency), and those secondary to severe anemia (severe chronic hypoxia). The intracellular iron deficiency is responsible for a reversible cytostatic effect on CFU-Sd8, while the overcoming of this proliferative block reveals that the size of bone marrow CFU-Sd8 population is limited by the level of oxygenation. The size of pre-CFU-S population is also limited by the level of oxygenation, implying that, in contrast to the normal situation, in b/b rats pre-CFU-S are actively proliferating and therefore sensitive to hypo;da. This review also explains how to get more reliable data on the effects of intracellular iron deficiency and hypoxia on the proliferation of hemopoietic stem and progenitor cells and points to the potential importance of b/b rat phenomenon for fundamental research in cell biology and in the search of new ways to restrain the proliferation of malignant cells.