Dose-dependent effects of the Notch ligand Delta1 on ex vivo differentiation and in vivo marrow repopulating ability of cord blood cells.
Pubmed ID: 15976178
Pubmed Central ID: PMC1366491
Publication Date: 10/15/2005
Affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, D2-373, Seattle, WA 98109, USA.
MeSH Terms: Humans, Cell Proliferation, Cells, Cultured, Receptors, Cytokine, Cell Differentiation, Dose-Response Relationship, Drug, Fetal Blood, Hematopoietic Stem Cells, Ligands, Receptor, Notch1, Receptor, Notch2, Receptors, Cell Surface, Signal Transduction, Transcription Factors
Grants: K23 HL0774446, P30 DK056465, P30 DK56465, P50 HL054881, P50 HL54881, R24 HL074445, R24 HL74445
Authors: Delaney C, Varnum-Finney B, Aoyama K, Brashem-Stein C, Bernstein ID
Cite As: Delaney C, Varnum-Finney B, Aoyama K, Brashem-Stein C, Bernstein ID. Dose-dependent effects of the Notch ligand Delta1 on ex vivo differentiation and in vivo marrow repopulating ability of cord blood cells. Blood 2005 Oct 15;106(8):2693-9. Epub 2005 Jun 23.
Although significant advances have been made over the last decade with respect to our understanding of stem cell biology, progress has been limited in the development of successful techniques for clinically significant ex vivo expansion of hematopoietic stem and progenitor cells. We here describe the effect of Notch ligand density on induction of Notch signaling and subsequent cell fate of human CD34+CD38- cord blood progenitors. Lower densities of Delta1(ext-IgG) enhanced the generation of CD34+ cells as well as CD14+ and CD7+ cells, consistent with early myeloid and lymphoid differentiation, respectively. However, culture with increased amounts of Delta1(ext-IgG) induced apoptosis of CD34+ precursors resulting in decreased cell numbers, without affecting generation of CD7+ cells. RNA interference studies revealed that the promotion of lymphoid differentiation was primarily mediated by Delta1 activation of Notch1. Furthermore, enhanced generation of NOD/SCID repopulating cells was seen following culture with lower but not higher densities of ligand. These studies indicate critical, quantitative aspects of Notch signaling in affecting hematopoietic precursor cell-fate outcomes and suggest that density of Notch ligands in different organ systems may be an important determinant in regulating cell-fate outcomes. Moreover, these findings contribute to the development of methodology for manipulation of hematopoietic precursors for therapeutic purposes.