Early CD34high cells can be separated into KIThigh cells in which transforming growth factor-beta (TGF-beta) downmodulates c-kit and KITlow cells in which anti-TGF-beta upmodulates c-kit.
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.
Sansilvestri
P
P
Centre National de la Recherche Scientifique UPR 9044, Villejuif, France.
Cardoso
A A
AA
Batard
P
P
Panterne
B
B
Hatzfeld
A
A
Lim
B
B
Lévesque
J P
JP
Monier
M N
MN
Hatzfeld
J
J
D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015703:Antigens, CD / Q000032:analysis*; D018952:Antigens, CD34; D014408:Biomarkers, Tumor / Q000032:analysis; D002469:Cell Separation / Q000379:methods; D004921:Erythropoietin / Q000494:pharmacology; D005312:Fetal Blood / Q000166:cytology; D015870:Gene Expression; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000096:biosynthesis; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D016298:Hematopoietic Cell Growth Factors / Q000494:pharmacology*; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007231:Infant, Newborn; D007377:Interleukin-3 / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology; D007700:Kinetics; D011518:Proto-Oncogene Proteins / Q000032:analysis* / Q000096:biosynthesis; D019009:Proto-Oncogene Proteins c-kit; D011519:Proto-Oncogenes; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis; D020794:Receptor Protein-Tyrosine Kinases / Q000032:analysis* / Q000096:biosynthesis; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000096:biosynthesis; D016184:Receptors, Colony-Stimulating Factor / Q000032:analysis* / Q000096:biosynthesis; D011990:Receptors, Transferrin / Q000096:biosynthesis; D011994:Recombinant Proteins / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000276:immunology / Q000494:pharmacology* / Q000502:physiology
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D018952:Antigens, CD34; D014408:Biomarkers, Tumor; D016298:Hematopoietic Cell Growth Factors; D007377:Interleukin-3; D015850:Interleukin-6; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D016184:Receptors, Colony-Stimulating Factor; D011990:Receptors, Transferrin; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; D004921:Erythropoietin; D016179:Granulocyte Colony-Stimulating Factor; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D019009:Proto-Oncogene Proteins c-kit; D020794:Receptor Protein-Tyrosine Kinases; D016186:Receptor, Macrophage Colony-Stimulating Factor