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Transforming growth factor-beta(1) induces apoptosis in CD34(+)CD38(-/low) cells that express Bcl-2 at a low level.

Abstract

OBJECTIVE

Transforming growth factor-beta(1) (TGF-beta(1)) strongly inhibits the proliferation and differentiation of primitive CD34(+)CD38(-) hematopoietic cells. In contrast, Flt3 ligand (FL) is a positive effector of CD34(+)CD38(-/low) cell proliferation. Because apoptosis plays a critical role in hematopoietic development, TGF-beta(1) and FL were analyzed as possible modulators of apoptosis. Specifically, this report examined expression of apoptotic promoters Bax and Bad and apoptotic inhibitors Bcl-2 and Bcl-x (all members of the Bcl-2 protein family). Protein levels were determined in fresh and cultured CD34(+)CD38(+) cells and CD34(+)CD38(-/low) cells with and without treatment with TGF-beta(1) and FL.

MATERIALS AND METHODS

Cells fractions were purified by sorting CD34(+)-enriched mononuclear cells from mobilized peripheral blood. Expression of Bcl-2, Bcl-x, Bax, and Bad and the extent of apoptosis were determined by flow cytometric analysis of freshly isolated cells and cells cultured with TGF-beta(1) and FL effectors.

RESULTS

TGF-beta(1) reduced CD34(+)CD38(+) cell expansion and arrested cell division. Inhibition of growth was not accompanied by an increase in apoptosis. In CD34(+)CD38(-)(/low) cells, serum TGF-beta(1) and added TGF-beta(1) inhibited cell growth and significantly increased apoptotic cell death. Freshly isolated CD34(+)CD38(+) and CD34(+)CD38(-/low) cells expressed Bcl-2 at similar low levels. However, after 3 days, Bcl-2 expression was markedly higher in cultured CD34(+)CD38(+) cells. TGF-beta(1) significantly increased Bax expression in both fractions after 3 days cultivation (p = 0.0034). Thus, addition of TGF beta-1 further reduced the already low Bcl-2:Bax ratio in CD34(+)CD38(-/low) cells.

CONCLUSIONS

Compared to CD34(+)CD38(+) cells, CD34(+)CD38(-/low) cells were slow to up-regulate expression of Bcl-2 during ex vivo culture. TGF-beta(1) up-regulated Bax expression by both CD34(+)CD38(+) and CD34(+)CD38(-)(/low) cells and promoted apoptosis in the latter fraction. This suggests that the preferential induction of apoptosis in primitive cells by TGF-beta(1) may be due to its further reduction of the Bcl-2:Bax ratio.

Links

  • Publisher Full Text
  • Authors+Show Affiliations

    ,

    Pacific Northwest Regional Blood Services, American Red Cross, Portland, OR 97208, USA. xiaom@usa,redcross.org

    ,

    Source

    Experimental hematology 29:9 2001 Sep pg 1098-108

    MeSH

    ADP-ribosyl Cyclase
    ADP-ribosyl Cyclase 1
    Antigens, CD
    Antigens, CD34
    Antigens, Differentiation
    Apoptosis
    Carrier Proteins
    Cell Division
    Flow Cytometry
    Hematopoietic Stem Cells
    Humans
    Membrane Glycoproteins
    Membrane Proteins
    NAD+ Nucleosidase
    Proto-Oncogene Proteins
    Proto-Oncogene Proteins c-bcl-2
    Transforming Growth Factor beta
    Transforming Growth Factor beta1
    bcl-2-Associated X Protein
    bcl-Associated Death Protein
    bcl-X Protein

    Pub Type(s)

    Journal Article

    Language

    eng

    PubMed ID

    11532351

    Citation

    Xiao, M, et al. "Transforming Growth Factor-beta(1) Induces Apoptosis in CD34(+)CD38(-/low) Cells That Express Bcl-2 at a Low Level." Experimental Hematology, vol. 29, no. 9, 2001, pp. 1098-108.
    Xiao M, Oppenlander BK, Dooley DC. Transforming growth factor-beta(1) induces apoptosis in CD34(+)CD38(-/low) cells that express Bcl-2 at a low level. Exp Hematol. 2001;29(9):1098-108.
    Xiao, M., Oppenlander, B. K., & Dooley, D. C. (2001). Transforming growth factor-beta(1) induces apoptosis in CD34(+)CD38(-/low) cells that express Bcl-2 at a low level. Experimental Hematology, 29(9), pp. 1098-108.
    Xiao M, Oppenlander BK, Dooley DC. Transforming Growth Factor-beta(1) Induces Apoptosis in CD34(+)CD38(-/low) Cells That Express Bcl-2 at a Low Level. Exp Hematol. 2001;29(9):1098-108. PubMed PMID: 11532351.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Transforming growth factor-beta(1) induces apoptosis in CD34(+)CD38(-/low) cells that express Bcl-2 at a low level. AU - Xiao,M, AU - Oppenlander,B K, AU - Dooley,D C, PY - 2001/9/5/pubmed PY - 2001/9/28/medline PY - 2001/9/5/entrez SP - 1098 EP - 108 JF - Experimental hematology JO - Exp. Hematol. VL - 29 IS - 9 N2 - OBJECTIVE: Transforming growth factor-beta(1) (TGF-beta(1)) strongly inhibits the proliferation and differentiation of primitive CD34(+)CD38(-) hematopoietic cells. In contrast, Flt3 ligand (FL) is a positive effector of CD34(+)CD38(-/low) cell proliferation. Because apoptosis plays a critical role in hematopoietic development, TGF-beta(1) and FL were analyzed as possible modulators of apoptosis. Specifically, this report examined expression of apoptotic promoters Bax and Bad and apoptotic inhibitors Bcl-2 and Bcl-x (all members of the Bcl-2 protein family). Protein levels were determined in fresh and cultured CD34(+)CD38(+) cells and CD34(+)CD38(-/low) cells with and without treatment with TGF-beta(1) and FL. MATERIALS AND METHODS: Cells fractions were purified by sorting CD34(+)-enriched mononuclear cells from mobilized peripheral blood. Expression of Bcl-2, Bcl-x, Bax, and Bad and the extent of apoptosis were determined by flow cytometric analysis of freshly isolated cells and cells cultured with TGF-beta(1) and FL effectors. RESULTS: TGF-beta(1) reduced CD34(+)CD38(+) cell expansion and arrested cell division. Inhibition of growth was not accompanied by an increase in apoptosis. In CD34(+)CD38(-)(/low) cells, serum TGF-beta(1) and added TGF-beta(1) inhibited cell growth and significantly increased apoptotic cell death. Freshly isolated CD34(+)CD38(+) and CD34(+)CD38(-/low) cells expressed Bcl-2 at similar low levels. However, after 3 days, Bcl-2 expression was markedly higher in cultured CD34(+)CD38(+) cells. TGF-beta(1) significantly increased Bax expression in both fractions after 3 days cultivation (p = 0.0034). Thus, addition of TGF beta-1 further reduced the already low Bcl-2:Bax ratio in CD34(+)CD38(-/low) cells. CONCLUSIONS: Compared to CD34(+)CD38(+) cells, CD34(+)CD38(-/low) cells were slow to up-regulate expression of Bcl-2 during ex vivo culture. TGF-beta(1) up-regulated Bax expression by both CD34(+)CD38(+) and CD34(+)CD38(-)(/low) cells and promoted apoptosis in the latter fraction. This suggests that the preferential induction of apoptosis in primitive cells by TGF-beta(1) may be due to its further reduction of the Bcl-2:Bax ratio. SN - 0301-472X UR - https://www.unboundmedicine.com/medline/citation/11532351/Transforming_growth_factor_beta_1__induces_apoptosis_in_CD34_+_CD38__/low__cells_that_express_Bcl_2_at_a_low_level_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0301-472X(01)00680-4 DB - PRIME DP - Unbound Medicine ER -