Ivanović Z, Milenković P, Vasiljevska M, Dekić M
Institute for Medical Research, Belgrade, Yugoslavia.
Exp Hematol. 1995 Oct;23(11):1218-23.
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 progenitor cell level. In the present study, investigations were extended to the bone marrow hematopoietic stem cells as determined by measurements of marrow repopulating ability (MRA) and day 8 spleen colony-forming units (CFU-S-8). A reduced number of CFU-S-8 per femur was found, together with a low incidence per 10(5) bone marrow cells and a nondetectable proliferation rate. The proliferation rate did not increase after treating 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 increased the number of CFU-S-8 in bone marrow. Chronic transfusion of b/b rats with washed RBC from non-anemic animals restored both the number and the proliferative response of bone marrow CFU-S-8. The MRA of b/b rats was reduced, but in proportion to the decrease in the bone marrow cellularity of these animals. MRA (pre-CFU-S) of b/b rats recovered completely 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 for stem cell proliferation of normal oxygenation--the arterial oxygen content in b/b rats is six times lower than in (+/+, b/+) rats--which recovered after the iron treatment and was completely restored after chronic transfusions. High-dose iron therapy abrogated the proliferative block of CFU-S-8, but number of CFU-S-8 was not completely recovered in spite of normalized oxygenation, indicating a possible suppressive effect of iron overload on the marrow microenvironment.
贝尔格莱德（b/b）大鼠因细胞内铁缺乏而患有遗传性低色素性小细胞贫血。对b/b大鼠的研究还表明，在祖细胞水平上造血发生了改变。在本研究中，通过测量骨髓再填充能力（MRA）和第8天脾集落形成单位（CFU-S-8），将研究扩展到骨髓造血干细胞。发现每根股骨的CFU-S-8数量减少，每10(5)个骨髓细胞中的发生率较低，且增殖率无法检测到。在用CFU-S增殖刺激剂体外处理b/b大鼠骨髓细胞后，增殖率没有增加，表明存在增殖阻滞。用铁治疗b/b大鼠可提高增殖率，并部分增加骨髓中CFU-S-8的数量。用非贫血动物的洗涤红细胞对b/b大鼠进行慢性输血，可恢复骨髓CFU-S-8的数量和增殖反应。b/b大鼠的MRA降低，但与这些动物骨髓细胞数量的减少成比例。b/b大鼠的MRA（前CFU-S）在铁治疗和慢性输血后均完全恢复，这表明前CFU-S池的变化是继发性的，而非直接由遗传缺陷引起。这些结果表明正常氧合对干细胞增殖的重要性——b/b大鼠的动脉氧含量比（+/+，b/+）大鼠低六倍——铁治疗后恢复，慢性输血后完全恢复。高剂量铁疗法消除了CFU-S-8的增殖阻滞，但尽管氧合正常化，但CFU-S-8的数量并未完全恢复，这表明铁过载可能对骨髓微环境有抑制作用。
