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 hernatopoietic 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 Flt3-1 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 hernatopoietic cell fate and suggest the usefulness of Notch ligand in increasing hematopoietic precursor numbers for clinical stem-cell transplantation.