Soluble Jagged-1 is able to inhibit the function of its multivalent form to induce hematopoietic stem cell self-renewal in a surrogate in vitro assay.
Stem cells reside in customized microenvironments (niches) that contribute to their unique ability to divide asymmetrically to give rise to self and to a daughter cell with distinct properties. Notch receptors and their ligands are highly conserved and have been shown to regulate cell-fate decisions in multiple developmental systems through local cell interactions. To assess whether Notch signaling may regulate hematopoiesis to maintain cells in an immature state, we examined the functional role of the recombinant, secreted form of the Notch ligand Jagged-1 during mouse hematopoietic stem cell (HSC) and progenitor cell proliferation and maturation. We found that ligand immobilization on stromal layer or on Sepharose-4B beads is required for the induction of self-renewing divisions of days 28-35 cobblestone area-forming cell. The free, soluble Jagged-1, however, has a dominant-negative effect on self-renewal in the stem-cell compartment. In contrast, free as well as immobilized Jagged-1 promotes growth factor-induced colony formation of committed hematopoietic progenitor cells. Therefore, we propose that differences in Jagged-1 presentation and developmental stage of the Notch receptor-bearing cells influence Notch ligand-binding results toward activation or inhibition of downstream signaling. Moreover, these results suggest potential clinical use of recombinant Notch ligands for expanding human HSC populations in vitro.
Vas
Virág
V
Stem Cell Biology, National Medical Center, Budapest, Hungary.
Szilágyi
László
L
Pálóczi
Katalin
K
Uher
Ferenc
F
D000818:Animals; D002135:Calcium-Binding Proteins; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D002455:Cell Division / Q000187:drug effects / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D005260:Female; D006133:Growth Substances / Q000494:pharmacology; D006410:Hematopoiesis / Q000187:drug effects / Q000235:genetics*; D016298:Hematopoietic Cell Growth Factors / Q000378:metabolism / Q000494:pharmacology; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins; D000072100:Jagged-1 Protein; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D011506:Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface / Q000187:drug effects / Q000378:metabolism*; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014157:Transcription Factors
D002135:Calcium-Binding Proteins; D006133:Growth Substances; D016298:Hematopoietic Cell Growth Factors; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; C000606274:Jag1 protein, mouse; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; C497762:Notch1 protein, mouse; D011506:Proteins; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface; D000072099:Serrate-Jagged Proteins; D014157:Transcription Factors