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Transferrin receptor-mediated suppression of in vitro hematopoiesis by transferrin-gallium
C R Chitambar1, A Craig, R C Ash
1Department of Medicine, Medical College of Wisconsin, Milwaukee 53226.
The expression of transferrin receptors on cells is felt to reflect iron requirements for proliferation or for hemoglobin production. We have recently shown that transferrin-gallium (Tf-Ga) complexes bind to cellular transferrin receptors and inhibit cellular iron incorporation. In this study, Tf-Ga in a dose-dependent manner inhibited the growth of erythroid (erythroid burst-forming units [BFU-E]-derived), granulocyte-macrophage (granulocyte-macrophage colony-forming units [CFU-GM]-derived) and mixed (mixed CFU [CFU-GEMM]-derived) hematopoietic colonies. Although major differences in the response of the different progenitor cells to Tf-Ga were not seen, CFU-GEMM-derived colonies appeared to be more sensitive to growth inhibition by Tf-Ga. The inhibitory effects on colony growth were reversible after 48 h of exposure of marrow cells to Tf-Ga, suggesting that the initial effects of Tf-Ga were mainly cytostatic and that continuous exposure of cells to Tf-Ga was required for maximal growth inhibition. Transferrin-iron (Tf-Fe) added to the Tf-Ga-containing cultures restored colony growth; however, this effect was best seen when Tf-Fe was added at day 0 of incubation. Tf-Fe added on days 3 or 7 failed to restore GEMM colonies and restored only a fraction of BFU-E and GM colonies. Tf-Ga appears to inhibit hematopoietic progenitor cell growth by interfering with cellular iron utilization during an early phase of progenitor cell proliferation. The use of Tf-Ga may allow further exploration of the role of iron and the Tf receptor in the regulation of hematopoietic progenitor cell growth.
The expression of transferrin receptors on cells is felt to reflect iron requirements for proliferation or for hemoglobin production. We have recently shown that transferrin-gallium (Tf-Ga) complexes bind to cellular transferrin receptors and inhibit cellular iron incorporation. In this study, Tf-Ga in a dose-dependent manner inhibited the growth of erythroid (erythroid burst-forming units [BFU-E]-derived), granulocyte-macrophage (granulocyte-macrophage colony-forming units [CFU-GM]-derived) and mixed (mixed CFU [CFU-GEMM]-derived) hematopoietic colonies. Although major differences in the response of the different progenitor cells to Tf-Ga were not seen, CFU-GEMM-derived colonies appeared to be more sensitive to growth inhibition by Tf-Ga. The inhibitory effects on colony growth were reversible after 48 h of exposure of marrow cells to Tf-Ga, suggesting that the initial effects of Tf-Ga were mainly cytostatic and that continuous exposure of cells to Tf-Ga was required for maximal growth inhibition. Transferrin-iron (Tf-Fe) added to the Tf-Ga-containing cultures restored colony growth; however, this effect was best seen when Tf-Fe was added at day 0 of incubation. Tf-Fe added on days 3 or 7 failed to restore GEMM colonies and restored only a fraction of BFU-E and GM colonies. Tf-Ga appears to inhibit hematopoietic progenitor cell growth by interfering with cellular iron utilization during an early phase of progenitor cell proliferation. The use of Tf-Ga may allow further exploration of the role of iron and the Tf receptor in the regulation of hematopoietic progenitor cell growth.