Human homologues of Delta-1 and Delta-4 function as mitogenic regulators of primitive human hematopoietic cells

• Published in: Blood 2001-04, Vol.97 (7), p.1960-1967
• Main Authors: Karanu, Francis N., Murdoch, Barbara, Miyabayashi, Tomoyuki, Ohno, Mitsuhara, Koremoto, Masahide, Gallacher, Lisa, Wu, Dongmei, Itoh, Akira, Sakano, Seiji, Bhatia, Mickie
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing; Adult; Amino Acid Sequence; Animals; Biological and medical sciences; Blood Proteins - genetics; Blood Proteins - physiology; Calcium-Binding Proteins; Cell Differentiation; Cell differentiation, maturation, development, hematopoiesis; Cell Division - drug effects; Cell physiology; Cells, Cultured - drug effects; Cells, Cultured - transplantation; Fetal Blood - cytology; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation, Developmental; Graft Survival; Growth Substances - genetics; Growth Substances - physiology; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells - cytology; Hematopoietic Stem Cells - drug effects; Hematopoietic Stem Cells - metabolism; Humans; Infant, Newborn; Intercellular Signaling Peptides and Proteins; Intracellular Signaling Peptides and Proteins; Membrane Proteins - biosynthesis; Membrane Proteins - genetics; Membrane Proteins - pharmacology; Membrane Proteins - physiology; Mice; Mice, Inbred NOD; Mice, SCID; Mitosis - drug effects; Mitosis - physiology; Molecular and cellular biology; Molecular Sequence Data; Receptor, Notch1; Receptor, Notch2; Receptors, Cell Surface - biosynthesis; Receptors, Cell Surface - genetics; Recombinant Fusion Proteins - pharmacology; Sequence Alignment; Sequence Homology, Amino Acid; Severe Combined Immunodeficiency - therapy; Signal Transduction; Solubility; Transcription Factors; Transplantation, Heterologous
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V97.7.1960

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 (hDelta-1) and hDelta-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 hDelta-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.