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Neutralization of autocrine transforming growth factor-beta in human cord blood CD34(+)CD38(-)Lin(-) cells promotes stem-cell- factor-mediated erythropoietin-independent early erythroid progenitor development and reduces terminal differentiation

  1. Author:
    Akel, S.
    Petrow-Sadowski, C.
    Laughlin, M. J.
    Ruscetti, F. W.

  2. Author Address

    NCI, Ctr Canc Res, Basic Res Lab, Leukocyte Biol Sect, Bldg 567,Room 254, Frederick, MD 21702 USA NCI, Ctr Canc Res, Basic Res Lab, Leukocyte Biol Sect, Frederick, MD 21702 USA SAIC Frederick, Intramural Res Support Program, Frederick, MD USA Case Western Reserve Univ, Ireland Canc Ctr, Allogene Transplant Program, Cleveland, OH 44106 USA Ruscetti FW NCI, Ctr Canc Res, Basic Res Lab, Leukocyte Biol Sect, Bldg 567,Room 254, Frederick, MD 21702 USA
    1. Year: 2003
  2. Journal: Stem Cells
    1. 21
    2. 5
    3. Pages: 557-567
  4. Type of Article: Article
  1. Abstract:

    Transforming growth factor (TGF)-beta1 exerts autocrine and paracrine effects on hematopoiesis. Here, we have attempted to evaluate the effect of endogenous TGF-beta1 on early erythroid development from primitive human hematopoietic stem cells (HSCs) and to assess the effects of TGF-beta1 on different phases of erythropoiesis. Cord blood CD34(+)CD38(-) lineage- marker-negative (Lin(-)) cells were cultured in serum-free conditions using various combinations of stem cell factor (SCF), erythropoietin (Epo), and TGF-beta-neutralizing antibody. Generation of erythroid progenitors was assessed using colony assay and flow cytometry. Terminal erythroid differentiation was examined when SCF/Epo-stimulated cells were recultured in the presence of Epo with and without TGF-beta1. Anti-TGF-beta augmented the proliferation of CD34(+)CD38(- )Lin(-) cells (day 21) in SCF-stimulated (6.4-fold +/- 1.5- fold) and SCF/Epo-stimulated (2.9-fold +/- 1.2-fold) cultures. Cells stimulated by SCF/Epo underwent similar levels of erythroid differentiation with and without anti-TGF-beta. While SCF alone stimulated the production of tryptase-positive mast cells, cells stimulated by SCF/anti-TGF-beta were predominantly erythroid (CD36(+)CD14(-) and glycophorin A positive). A distinct expansion of erythroid progenitors (CD34(+)CD36(+)CD14(-)) with the potential to form erythroid colonies was seen, revealing early Epo-independent erythroid development. In contrast, the kinetics of erythroid progenitor generation from primitive HSCs indicate that TGF-beta1 is not inhibitory in late erythropoiesis, but it accelerated the conversion of large BFU-E into colony-forming units-erythroid. Finally, TGF-beta1 accelerated Epo-induced terminal erythroid differentiation and resulted in a greater level of enucleation (22% +/- 6% versus 7% +/- 3%) in serum-free conditions. Serum addition stimulated enucleation (54% +/- 18%), which was lower (26% +/- 14%) with anti-TGF-beta, suggesting that optimal erythroid enucleation is Epo dependent, requiring serum factors including TGF-beta1.

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