Transforming growth factor beta 1 is an inducer of erythroid differentiation.

Abstract

SummaryNormal human bone marrow cells, highly enriched for burst-forming units-erythroid (BFU-E), were cultured in serum-free medium, in the presence and absence of various factors, to investigate the mechanisms involved in regulating erythroid differentiation. In cultures containing interleukin 3 (IL-3), Steel factor (SF), and erythropoietin (Ep), benzidene-positive erythroblasts first became detectable on day 6. Their numbers then rapidly increased until, by day 16, >99% of the cells, which were 20,000-fold amplified over input numbers, were benzidene-positive. It is interesting to note that omission of either SF or Ep from this assay markedly enhanced the rate of differentiation and reduced total cell numbers, whereas omission of IL-3 had no effect on the rate of differentiation and only slightly reduced cell numbers. Of various agents tested, the most potent erythroid differentiation inducer (and inhibitor of cell proliferation) was found to be transforming growth factor ~81 (TGF-~I). This cytokine stimulated both the rapid appearance of hemoglobin-positive cells and an early cessation of cell proliferation. Using fluorescently tagged antibodies to glycophorin A and fluorescence-activated cell sorter (FACS) analysis, this phenomenon was shown to be due to an early induction of erythroid differentiation rather than an aberrant production of hemoglobin. Methylcellulose assays indicated that the well-documented reduction of BFU-E colony numbers observed with TGF-~31 may actually be due to a TGF-Bl-induced "conversion" of BFU-E into colony-forming units-erythroid (CFU-E). Thus, in vivo, TGF-fll might serve, in part, to decrease the number of mature erythrocytes by stimulating BFU-E to skip a number of cell divisions and differentiate early.

Neutralization of Autocrine Transforming Growth Factor‐β in Human Cord Blood CD34+CD38−Lin−Cells Promotes Stem‐Cell‐Factor‐Mediated Erythropoietin‐Independent Early Erythroid Progenitor Development and Reduces Terminal Differentiation

“…In agreement with previous studies [18][19][20], the enhanced development of late erythroid progenitors induced by TGF-β1 suggests that it plays a role in late erythroid maturation. To further test this, CD34 +…”

“…Colony-forming unitsgranulocyte-macrophage (CFU-GM) were assayed in the presence of rhGM-CSF and IL-3. After 12-14 days of incubation, colonies were counted and classified, as reported elsewhere [16,20,29].…”

“…In vitro, it has been identified as a cell cycle inhibitor for early, but not late, erythroid progenitors [15,16]. Other studies, using erythroleukemia cell lines and nontransformed human cells, showed that TGF-β1 triggered late erythroid differentiation and promoted maturation processes such as hemoglobin (Hb) synthesis [16][17][18][19][20]. The balance between positive and negative cytokine signals regulating the cell cycle may govern the regulation of differentiation in the erythroid compartment [21,22].…”

Unexpected macrophage-independent dyserythropoiesis in Gaucher disease

“…Transforming growth factor β1 (TGF-β1) is known to accelerate the erythroid differentiation, allowing full terminal differentiation toward enucleated red cells. 37,38 TGF-β1 also induces a massive inhibition of cell proliferation that mainly involves cell cycle arrest rather than apoptosis. 38 We observed similar effects, albeit to a lesser extent, in GD during in vitro erythropoiesis.…”

TGFβ-induced SMAD2 phosphorylation predicts inhibition of thymidine incorporation in CD34+ cells from healthy donors, but not from patients with AML after MDS

“…[6][7][8] TGF␤ interferes with other growth factors which stimulate the proliferation of CD34 + hematopoietic progenitor cells such as thrombopoietin (TPO), 9 and it antagonizes TPO-induced growth of megakaryoblastic M-07e cells. 10 TGF␤ signaling occurs through two transmembrane receptors which upon ligand binding phosphorylate intracellular Sma-and Mad-related (SMAD) proteins.…”