Human homologues of Delta-1 and Delta-4 function as mitogenic regulators of primitive human hematopoietic cells.
Delta-mediated Notch signaling controls cell fate decisions during invertebrate and murine development. However, in the human, functional roles for Delta have yet to be described. This study reports the characterization of Delta-1 and Delta-4 in the human. Human Delta-4 was found to be expressed in a wide range of adult and fetal tissues, including sites of hematopoiesis. Subsets of immature hematopoietic cells, along with stromal and endothelial cells that support hematopoiesis, were shown to express Notch and both Delta-1 and Delta-4. Soluble forms of human Delta-1 (h Delta-1) and h Delta-4 proteins were able to augment the proliferation of primitive human hematopoietic progenitors in vitro. Intravenous transplantation of treated cultures into immune-deficient mice revealed that h Delta-1 is capable of expanding pluripotent human hematopoietic repopulating cells detected in vivo. This study provides the first evidence for a role of Delta ligands as a mitogenic regulator of primitive hematopoietic cells in the human. (Blood. 2001;97:1960-1967)
Developmental Stem Cell Biology, The John P. Robarts Research Institute, London, ON, Canada.
F N
FN
Karanu
B
B
Murdoch
T
T
Miyabayashi
M
M
Ohno
M
M
Koremoto
L
L
Gallacher
D
D
Wu
A
A
Itoh
S
S
Sakano
M
M
Bhatia
D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D001798:Blood Proteins / Q000235:genetics / Q000502:physiology*; D002135:Calcium-Binding Proteins; D002454:Cell Differentiation; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured / Q000187:drug effects / Q000637:transplantation; D005312:Fetal Blood / Q000166:cytology; D018507:Gene Expression Regulation, Developmental; D006085:Graft Survival; D006133:Growth Substances / Q000235:genetics / Q000502:physiology*; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007231:Infant, Newborn; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008938:Mitosis / Q000187:drug effects / Q000502:physiology*; D008969:Molecular Sequence Data; D051881:Receptor, Notch1; D051883:Receptor, Notch2; D011956:Receptors, Cell Surface / Q000096:biosynthesis / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D016511:Severe Combined Immunodeficiency / Q000628:therapy; D015398:Signal Transduction; D012995:Solubility; D014157:Transcription Factors; D014183:Transplantation, Heterologous
D048868:Adaptor Proteins, Signal Transducing; D001798:Blood Proteins; D002135:Calcium-Binding Proteins; C424126:DLL4 protein, human; D006133:Growth Substances; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C497761:NOTCH1 protein, human; C497764:NOTCH2 protein, human; C497762:Notch1 protein, mouse; C497765:Notch2 protein, mouse; D051881:Receptor, Notch1; D051883:Receptor, Notch2; D011956:Receptors, Cell Surface; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; C064045:delta protein