DIFFERENTIAL-EFFECTS OF TRANSFORMING GROWTH-FACTOR-BETA-1 ON DISTINCTDEVELOPMENTAL STAGES OF MURINE MEGAKARYOCYTOPOIESIS

The effect of transforming growth factor-beta 1 (TGF beta 1) on three developmental stages of megakaryocytopoiesis was investigated. Using a murine bone marrow agar culture system, titrated doses of TCF beta 1 were added to cultures assaying primitive high proliferative megakaryo cyte progenitors, committed megakaryocyte precursors, and nondividing, endoreduplicating megakaryocytes. The growth of high proliferative me gakaryocyte colony-forming cells (HPP-CFU-Mk) that require the growth factors interleukins-1, 3 and 6 (IL-1 + IL-3 + IL-6) for colony detect ion was abrogated by the addition of 1 ng TGF beta 1/ml. The sensitivi ty of committed megakaryocyte progenitors (colony-forming unit-megakar yocyte, CFU-Mk) to TGF beta 1 depended on the growth factor combinatio n. TGF beta 1 (1 ng/ml) completely inhibited megakaryocyte colony form ation from CFU-Mk only in cultures stimulated by low doses of IL-3. TC F beta 1 (>10 ng/ml) could only marginally inhibit megakaryocyte colon y formation generated in the presence of either high doses of IL-3 or the combination of low dose IL-3 + IL-6. TGF beta 1 inhibited bath IL- 3-dependent and IL-6-dependent megakaryocyte growth but tenfold higher doses of TGF beta 1 were required to inhibit growth generated by the combination of IL-3 + IL-6. The data showed that the capacity of TCF b eta 1 to inhibit distinct differentiation stages of the megakaryocytop oietic lineage depended on the concentration and combination of growth factors involved. (C) 1994 Wiley-Liss, Inc.