Abstract
We have previously shown that early human CD34high hematopoietic progenitors are maintained quiescent in part through autocrine transforming growth factor-beta 1 (TGF-beta 1). We also demonstrated that, in the presence of interleukin-3, interleukin-6, granulocyte colony-stimulating factor, and erythropoietin, TGF-beta 1 antisense oligonucleotides or anti-TGF-beta serum have an additive effect with KIT ligand (Steel factor [SF]), which suggests that they control different pathways of regulation in these conditions. This finding also suggests that autocrine TGF-beta 1 might suppress c-kit expression in primitive human hematopoietic progenitors. We have now distinguished two subpopulations of CD34high cells. One subpopulation expresses a c-kit mRNA that can be downmodulated by exogenous TGF-beta 1 within 6 hours. Another subpopulation of early CD34high cells expresses a low or undetectable level of c-kit mRNA, but its expression can be upmodulated within 6 hours by anti-TGF-beta. These effects disappear 48 hours after induction and cannot be maintained longer than 72 hours, even if TGF-beta 1 or anti-TGF-beta serum are added every day. Similar kinetics, although delayed, are observed with KIT protein expression. On the contrary, no specific effect of TGF-beta 1 was observed on c-fms, GAPDH, and transferrin receptor gene expression in these early progenitors. These results clarify the complex interaction between TGF-beta 1 and SF in normal early hematopoietic progenitors. SF does not switch off the TGF-beta 1 inhibitory pathway. Autocrine TGF-beta 1 appears to maintain these cells in a quiescent state, suppressing cell division by downmodulating the receptor of SF, a key cytokine costimulator of early progenitors.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antibodies, Monoclonal / pharmacology
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Antigens, CD / analysis*
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Antigens, CD34
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Biomarkers, Tumor / analysis
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Cell Separation / methods
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Erythropoietin / pharmacology
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Fetal Blood / cytology
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Gene Expression
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Glyceraldehyde-3-Phosphate Dehydrogenases / biosynthesis
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Granulocyte Colony-Stimulating Factor / pharmacology
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Hematopoietic Cell Growth Factors / pharmacology*
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Hematopoietic Stem Cells / cytology*
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Hematopoietic Stem Cells / drug effects
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Hematopoietic Stem Cells / metabolism
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Humans
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Infant, Newborn
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Interleukin-3 / pharmacology
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Interleukin-6 / pharmacology
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Kinetics
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Proto-Oncogene Proteins / analysis*
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Proto-Oncogene Proteins / biosynthesis
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Proto-Oncogene Proteins c-kit
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Proto-Oncogenes
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RNA, Messenger / analysis
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RNA, Messenger / biosynthesis
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Receptor Protein-Tyrosine Kinases / analysis*
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Receptor Protein-Tyrosine Kinases / biosynthesis
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Receptor, Macrophage Colony-Stimulating Factor / biosynthesis
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Receptors, Colony-Stimulating Factor / analysis*
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Receptors, Colony-Stimulating Factor / biosynthesis
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Receptors, Transferrin / biosynthesis
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Recombinant Proteins / pharmacology
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Transforming Growth Factor beta / immunology
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Transforming Growth Factor beta / pharmacology*
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Transforming Growth Factor beta / physiology
Substances
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Antibodies, Monoclonal
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Antigens, CD
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Antigens, CD34
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Biomarkers, Tumor
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Hematopoietic Cell Growth Factors
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Interleukin-3
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Interleukin-6
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Proto-Oncogene Proteins
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RNA, Messenger
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Receptors, Colony-Stimulating Factor
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Receptors, Transferrin
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Recombinant Proteins
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Transforming Growth Factor beta
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Erythropoietin
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Granulocyte Colony-Stimulating Factor
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Glyceraldehyde-3-Phosphate Dehydrogenases
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Proto-Oncogene Proteins c-kit
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Receptor Protein-Tyrosine Kinases
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Receptor, Macrophage Colony-Stimulating Factor