Combined effects of Notch signaling and cytokines induce a multiple log increase in precursors with lymphoid and myeloid reconstituting ability.
We investigated whether combined signaling induced by engineered Notch ligands and hematopoietic growth factors influences hematopoietic stem-cell differentiation. We show that incubation of murine marrow precursors with Delta1(ext-IgG), a Notch ligand consisting of the Delta1 extracellular domain fused to the Fc portion of human immunoglobulin G1 (IgG1), and growth factors stem cell factor (SCF), interleukin 6 (IL-6), IL-11, and Flt3-l inhibited myeloid differentiation and promoted a several-log increase in the number of precursors capable of short-term lymphoid and myeloid repopulation. Addition of IL7 promoted early T-cell development, whereas addition of granulocyte-macrophage colony-stimulating factor (GM-CSF) led to terminal myeloid differentiation. These results support a role for combinatorial effects by Notch and cytokine-induced signaling pathways in regulating hematopoietic cell fate and suggest the usefulness of Notch ligand in increasing hematopoietic precursor numbers for clinical stem-cell transplantation.
Varnum-Finney
Barbara
B
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
Brashem-Stein
Carolyn
C
Bernstein
Irwin D
ID
D000818:Animals; D020296:Animals, Congenic; D016026:Bone Marrow Transplantation; D002455:Cell Division; D019070:Cell Lineage / Q000187:drug effects; D002478:Cells, Cultured / Q000637:transplantation; D016207:Cytokines / Q000494:pharmacology*; D005803:Genes, Immunoglobulin; D006410:Hematopoiesis / Q000187:drug effects / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects; D007141:Immunoglobulin Fc Fragments / Q000235:genetics; D007074:Immunoglobulin G / Q000235:genetics; D017370:Interleukin-11 / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D008565:Membrane Proteins / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D017434:Protein Structure, Tertiary; D011828:Radiation Chimera; D051880:Receptors, Notch; D011993:Recombinant Fusion Proteins / Q000502:physiology; D015398:Signal Transduction; D013047:Specific Pathogen-Free Organisms; D019089:Stem Cell Factor / Q000494:pharmacology; D016176:T-Lymphocyte Subsets / Q000166:cytology
D016207:Cytokines; D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G; D017370:Interleukin-11; D015850:Interleukin-6; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D008565:Membrane Proteins; D051880:Receptors, Notch; D011993:Recombinant Fusion Proteins; D019089:Stem Cell Factor; C064045:delta protein; C084881:flt3 ligand protein