HEMATOPOIETIC STEM-CELLS IN THE HEREDITARILY ANEMIC BELGRADE LABORATORY (B B) RAT/

The Belgrade (b/b) rat has hereditary hypochromic microcytic anemia as the consequence of intracellular iron deficiency. Studies in the b/b rat have also demonstrated alteration in hematopoiesis at the progenit or cell level. In the present study, investigations were extended to t he bone marrow hematopoietic stem cells as determined by measurements of marrow repopulating ability (MRA) and day 8 spleen colony-forming u nits (CFU-S-8). A reduced number of CFU-S-8 per femur was found, toget her with a low incidence per 10(5) bone marrow cells and a nondetectab le proliferation rate. The proliferation rate did not increase after t reating b/b rat bone marrow cells in vitro with a stimulator for CFU-S proliferation, indicating a proliferative block. The treatment of b/b rats with iron enhanced the proliferation rate and partially increase d the number of CFU-S-8 in bone marrow. Chronic transfusion of b/b rat s with washed RBC from non-anemic animals restored both the number and the proliferative response of bone marrow CFU-S-8. The MEW of b/b rat s was reduced, but in proportion to the decrease in the bone marrow ce llularity of these animals. MRA (pre-CFU-S) of b/b rats recovered comp letely after both iron treatment and chronic transfusions, suggesting that changes in the pre-CFU-S pool are secondary rather than directly induced by the genetic defect. These results indicate the importance f or stem cell proliferation of normal oxygenation-the arterial oxygen c ontent in b/b rats is six times lower than in (+/+, b/+) rats-which re covered after the iron treatment and was completely restored after chr onic transfusions. High-dose iron therapy abrogated the proliferative block of CFU-S-8, but number of CFU-S-8 was not completely recovered i n spite of normalized oxygenation, indicating a possible suppressive e ffect of iron overload on the marrow microenvironment.