Delta-1 enhances marrow and thymus repopulating ability of human CD34(+)CD38(-) cord blood cells.
We investigated the effect of Notch signaling, a known regulator of cell fate in numerous developmental systems, on human hematopoietic precursors. We show that activation of endogenous Notch signaling in human CD34(+)CD38(-) cord blood precursors with immobilized Delta-1 in serum-free cultures containing fibronectin and hematopoietic growth factors inhibited myeloid differentiation and induced a 100-fold increase in the number of CD34(+) cells compared with control cultures. Immobilized Delta-1 also induced a multifold expansion of cells with the phenotype of common lymphoid precursors (CD34(+)CD7(+)CD45RA(+)) and promoted the development of cytoplasmic CD3(+) T/NK cell precursors. IL-7 enhanced the promotion of T/NK cell differentiation by immobilized Delta-1, but granulocytic differentiation occurred when G-CSF was added. Transplantation into immunodeficient mice showed a substantial increase in myeloid and B cell engraftment in the marrow and also revealed thymic repopulation by CD3(+) T cells due to cells being cultured for a longer period with immobilized Delta-1. These data suggest that Delta-1 can enhance myeloid and lymphoid marrow-repopulating ability and promote the generation of thymus-repopulating T cell precursors.
Ohishi
Kohshi
K
Clinical Research Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue N., Seattle, Washington 98195, USA.
Varnum-Finney
Barbara
B
Bernstein
Irwin D
ID
D036541:ADP-ribosyl Cyclase / Q000378:metabolism; D051997:ADP-ribosyl Cyclase 1; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D018952:Antigens, CD34 / Q000378:metabolism; D051792:Basic Helix-Loop-Helix Proteins; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005312:Fetal Blood / Q000166:cytology / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D005353:Fibronectins / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D006410:Hematopoiesis / Q000187:drug effects / Q000502:physiology*; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D066298:In Vitro Techniques; D007231:Infant, Newborn; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D008565:Membrane Proteins / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D010446:Peptide Fragments / Q000494:pharmacology; D051880:Receptors, Notch; D015398:Signal Transduction; D033581:Stem Cell Transplantation; D013950:Thymus Gland / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000072056:Transcription Factor HES-1; D014183:Transplantation, Heterologous
D036541:ADP-ribosyl Cyclase; D051997:ADP-ribosyl Cyclase 1; D015703:Antigens, CD; D018952:Antigens, CD34; D051792:Basic Helix-Loop-Helix Proteins; D005353:Fibronectins; D018398:Homeodomain Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D010446:Peptide Fragments; D051880:Receptors, Notch; D000072056:Transcription Factor HES-1; C489734:Hes1 protein, mouse; C064045:delta protein; C078493:HES1 protein, human; C498154:CD38 protein, human; C498155:Cd38 protein, mouse