Early CD34high cells can be separated into KIThigh cells in which transforming growth factor-β (TGF-B) downmodulates c-kit and KITlow cells in which anti-TGF-β upmodulates c-kit

• Published in: Blood 1995-09, Vol.86 (5), p.1729-1735
• Main Authors: SANSILVESTRI, P, CARDOSO, A. A, BATARD, P, PANTERNE, B, HATZFELD, A, LIM, B, LEVESQUE, J.-P, MONIER, M.-N, HATZFELD, J
• Format: Article
• Language: English
• Subjects: Antibodies, Monoclonal - pharmacology; Antigens, CD - analysis; Antigens, CD34; Biological and medical sciences; Biomarkers, Tumor - analysis; Cell differentiation, maturation, development, hematopoiesis; Cell physiology; Cell Separation - methods; Erythropoietin - pharmacology; Fetal Blood - cytology; Fundamental and applied biological sciences. Psychology; Gene Expression; Glyceraldehyde-3-Phosphate Dehydrogenases - biosynthesis; Granulocyte Colony-Stimulating Factor - pharmacology; Hematopoietic Cell Growth Factors - pharmacology; Hematopoietic Stem Cells - cytology; Hematopoietic Stem Cells - drug effects; Hematopoietic Stem Cells - metabolism; Humans; Infant, Newborn; Interleukin-3 - pharmacology; Interleukin-6 - pharmacology; Kinetics; Molecular and cellular biology; Proto-Oncogene Proteins - analysis; Proto-Oncogene Proteins - biosynthesis; Proto-Oncogene Proteins c-kit; Proto-Oncogenes; Receptor Protein-Tyrosine Kinases - analysis; Receptor Protein-Tyrosine Kinases - biosynthesis; Receptor, Macrophage Colony-Stimulating Factor - biosynthesis; Receptors, Colony-Stimulating Factor - analysis; Receptors, Colony-Stimulating Factor - biosynthesis; Receptors, Transferrin - biosynthesis; Recombinant Proteins - pharmacology; RNA, Messenger - analysis; RNA, Messenger - biosynthesis; Transforming Growth Factor beta - immunology; Transforming Growth Factor beta - pharmacology; Transforming Growth Factor beta - physiology
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V86.5.1729.bloodjournal8651729

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.