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IL-3-Dependent Early Erythropoiesis Is Stimulated by Autocrine Transforming Growth Factor Beta

Genetic Technologies Pty Ltd., Melbourne, Australia

Key Words. AC133 antigen • Adult stem cells • Erythropoiesis • Proliferation • IL-3 • Multiparameter flow cytometry • Stem cell culture

Ralph Bohmer, Ph.D., Genetic Technologies Pty Ltd., P.O. Box 115, Fitzroy, Victoria 3065, Australia. Telephone: 61-3-8412-7020; Fax: 61-3-9417-6863; e-mail: ralph.bohmer{at}genetype.com.au

Autocrine/paracrine transforming growth factor beta (TGF-ß) is an important regulator of stem cell quiescence and generally suppresses stem cell proliferation. However, we show here that during the first few days of an erythroid cell culture from adult blood stem cells, the presence of neutralizing antibodies against TGF-ß had a suppressive effect on subsequent erythropoiesis, indicating a stimulatory action of autocrine TGF-ß. The suppression occured in the form of a delay in erythroblast proliferation rather than a reduction in final erythroid colony numbers. The inhibitory effect of anti-TGF-ß occured in the presence of interleukin-3 (IL-3) but not in cultures with only stem cell factor and erythropoietin. Erythroblasts expressing gamma-globin (⁺) were more strongly suppressed than erythroblasts expressing only beta-globin (^-ß⁺), so that stem cell treatment with anti-TGF-ß caused a decrease in the proportion of ⁺ cells. Anti-TGF-ß had an inhibitory effect on erythropoiesis only when administered during the first 4 days of culture, that is, before the onset of globin expression and dependence on erythropoietin. The decreasing effect of anti-TGF-ß with delayed addition coincided with a decreasing dependence on IL-3. CD133⁺ stem cells were more strongly suppressed by anti-TGF-ß than the complementary CD133^-CD34⁺ stem cells, and the latter were also much less dependent on IL-3. The treatment of very early stem cell cultures with a pulse of added TGF-ß1 in the presence of IL-3 increased the subsequent proliferation of erythroblasts. Taken together, the data suggest that IL-3-driven early erythropoiesis from immature peripheral blood stem cells is stimulated by autocrine TGF-ß.