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

Abstract

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 hypoxia. 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.

The influence of ferucarbotran on the chondrogenesis of human mesenchymal stem cells

“…Iron has a well known fundamental role in many cellular metabolic processes, including electron transport, deoxyribonucleotide synthesis, oxygen transport and essential redox reactions involving hemoproteins [31, 32]. The incorporation of iron oxides into the normal iron metabolism makes them appealing as contrast agents for cell labeling [33].…”

“…Maintained viability of iron oxide-labeled hMSCs is a mandatory prerequisite for any application of stem cells for cell tracking studies. Iron has a well known fundamental role in many cellular metabolic processes, including electron transport, deoxyribonucleotide synthesis, oxygen transport and essential redox reactions involving hemoproteins (31,32). The incorporation of iron oxides into the normal iron metabolism makes them appealing as contrast agents for cell labeling (33), but previous studies also showed that iron oxides can impair the viability of stem cells when they are internalized in too high quantities (13,34).…”

Dynamics of Erythropoietic Biomarkers in Response to Treatment With Erythropoietin in Belgrade Rats

“…The levels of RBC and HGB are significantly decreased and progressively decline over time ( Sladic-Simic et al, 1966 ). In addition, a decrease in platelets and leukocytosis are also observed in these animals ( Ivanovic, 1997 ).…”

Pathophysiology of the Belgrade rat

“…The mean value for erythrocytes in the peripheral blood was significantly decreased and a progressive decline in hemoglobin values occurred with age (Sladic-Simic et al, 1966). Adult b/b rats are distinguished by lower body weight than +/b rats (Thompson et al, 2007a), and characterized by pinkish retinal reflex and white ears, in contrast with the bright red of +/b animals (Ivanovic, 1997). Anemia was also accompanied by a decrease in platelets count and leukocytosis (Ivanovic, 1997).…”

“…For example, early and late erythroid progenitors (BFU-E and CFU-E; Pavlovic-Kentera et al, 1989), granulocyte–monocyte progenitors (Stojanovic et al, 1990), and megakaryocyte progenitors (Rolovic et al, 1991) are significantly diminished. In addition, intensive splenic hematopoiesis has been described in b/b rats, indicated by increased iron uptake by spleen, expression of erythroid differentiation markers and elevated erythropoietin serum levels (Pavlovic-Kentera et al, 1989; Biljanovic-Paunovic et al, 1992; Ivanovic, 1997). Indeed, while 42-day-old +/b rats have a spleen weight fraction of 0.32 ± 0.1, age- and diet-matched b/b rats have a spleen weight fraction of 1.50 ± 0.13 (both values are % body weight; n = 3–4; P <0.05; J. Kim and M. Wessling-Resnick, personal observations).…”