title: Density of the Notch ligand Delta1 determines generation of B and T cell precursors from hematopoietic stem cells.
abstract: Notch signaling regulates multiple cell fate decisions by hematopoietic precursors. To address whether different amounts of Notch ligand influence lineage choices, we cultured murine bone marrow lin(-)Sca-1(+)c-kit+ cells with increasing densities of immobilized Delta1(ext-IgG) consisting of the extracellular domain of Delta1 fused to the Fc domain of human IgG1. We found that relatively lower densities of Delta1(ext-IgG) enhanced the generation of Sca-1(+)c-kit+ cells, Thy1(+)CD25+ early T cell precursors, and B220(+)CD43(-/lo) cells that, when cocultured with OP9 stroma cells, differentiated into CD19+ early B cell precursors. Higher densities of Delta1(ext-IgG) also enhanced the generation of Sca-1(+)c-kit+ precursor cells and promoted the development of Thy1(+)CD25+ cells, but inhibited the development of B220(+)CD43(-/lo) cells. Analyses of further isolated precursor populations suggested that the enhanced generation of T and B cell precursors resulted from the effects on multipotent rather than lymphoid-committed precursors. The results demonstrate the density-dependent effects of Delta1 on fate decisions of hematopoietic precursors at multiple maturational stages and substantiate the previously unrecognized ability of Delta1 to enhance the development of both early B and T precursor cells.
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors.forename: Mari H
authors.initials: MH
authors.lastname: Dallas
authors.forename: Barbara
authors.initials: B
authors.lastname: Varnum-Finney
authors.forename: Colleen
authors.initials: C
authors.lastname: Delaney
authors.forename: Keizo
authors.initials: K
authors.lastname: Kato
authors.forename: Irwin D
authors.initials: ID
authors.lastname: Bernstein
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D002454:Cell Differentiation / Q000502:physiology*; D002460:Cell Line; D017931:DNA Primers; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D007136:Immunoglobulins; D016130:Immunophenotyping; D008024:Ligands; D008214:Lymphocytes / Q000166:cytology* / Q000378:metabolism / Q000502:physiology; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018121:Receptors, Cytokine / Q000378:metabolism*; D051880:Receptors, Notch; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D000072056:Transcription Factor HES-1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D017931:DNA Primers; D018398:Homeodomain Proteins; D007136:Immunoglobulins; D008024:Ligands; D008565:Membrane Proteins; D018121:Receptors, Cytokine; D051880:Receptors, Notch; D000072056:Transcription Factor HES-1; C498762:CRLF2 protein, human; C489734:Hes1 protein, mouse; C410591:Tslpr protein, mouse