Differential Effects of Notch Ligands Delta-1 and Jagged-1 in Human Lymphoid Differentiation

Jaleco, Ana C.; Neves, Hélia; Hooijberg, Erik; Gameiro, Paula; Clode, Nuno; Haury, Matthias; Henrique, Domingos; Parreira, Leonor

doi:10.1084/jem.194.7.991

Cited by 307 publications

(237 citation statements)

References 51 publications

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“…Forced expression of Delta1 in these stromal cell lines induces murine and human progenitor cells to develop into T cells, in some studies up to DP and SP stages. [39][40][41][42] The striking T-cell generating effect of Delta could not be reproduced by expression of Jagged in stroma cell lines, 39 although Jagged, in another study, did inhibit development into B cells. 41 Furthermore, ab-lineage T-cell development was normal in Jagged2-deficient mice.…”

Section: Notch and Wnt Signaling In T-cell Development And T-all F Wementioning

confidence: 99%

Notch and Wnt signaling in T-lymphocyte development and acute lymphoblastic leukemia

2006

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Many acute lymphoblastic leukemias can be considered as malignant counterparts of cells in the various stages of normal lymphoid development in bone marrow and thymus. T-cell development in the thymus is an ordered and tightly controlled process. Two evolutionary conserved signaling pathways, which were first discovered in Drosophila, control the earliest steps of T-cell development. These are the Notch and Wnt-signaling routes, which both are deregulated in several types of leukemias. In this review we discuss both pathways, with respect to their signaling mechanisms, functions during T-cell development and their roles in development of leukemias, especially T-cell acute lymphoblastic leukemia.

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Section: Notch and Wnt Signaling In T-cell Development And T-all F Wementioning

confidence: 99%

Notch and Wnt signaling in T-lymphocyte development and acute lymphoblastic leukemia

2006

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“…81 The reconstitution of NOD/SCID mice was improved for cells expanded at low concentrations of the Notch ligand unlike cells expanded with higher ligand concentrations which appeared to cause apoptosis. 82 Thus the optimal concentration of Notch ligands in ex vivo culture has yet to be established and the differing effects of Notch ligands has not been fully studied; for instance Delta-1, unlike Jagged-1, inhibits B-cell differentiation 83 and decreases CFU-GM, CFU-G and CFU-M. 84 Wnt signaling Wnt-mediated signaling involves the binding of Wnt proteins to their receptor-coreceptor complexes, frizzled-LRP, which leads to the accumulation of b-catenin and its translocation to the nucleus. In the nucleus, b-catenin forms a bipartite transcription-factor complex with T-cell factor to activate target genes, such as cyclin D1 and c-Myc.…”

Section: Stromamentioning

confidence: 99%

Ex vivo expansion of umbilical cord blood stem cells for transplantation: growing knowledge from the hematopoietic niche

Hofmeister

Zhang

Knight

et al. 2006

Bone Marrow Transplant

200

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Umbilical cord blood transplantation (UCBT) in adults is limited by the small number of primitive hematopoietic stem cells (HSC) in each graft, resulting in delayed engraftment post transplant, and both short-and longterm infectious complications. Initial efforts to expand UCB progenitors ex vivo have resulted in expansion of mature rather than immature HSC, confounded by the inability to accurately and reliably measure long-term reconstituting cells. Ex vivo expansion of UCB HSC has failed to improve engraftment because of resulting defects that promote apoptosis, disrupt marrow homing and initiate cell cycling. Here we discuss the future of ex vivo expansion, which we suggest will include the isolation of immature hematopoietic progenitors on the basis of function rather than surface phenotype and will employ both cytokines and stroma to maintain and expand the stem cell niche. We suggest that ex vivo expansion could be enhanced by manipulating newly discovered signaling pathways (Notch, Wnt, bone morphogenetic protein 4 and Tie2/angiopoietin-1) and intracellular mediators (phosphatase and tensin homolog and glycogen synthase kinase-3) in a manner that promotes HSC expansion with less differentiation. Improved methods for ex vivo expansion will make UCBT available to more patients, decrease engraftment times and allow more rapid immune reconstitution post transplant.

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“…Signaling through Notch1 is crucial in the early stages of T cell development (10 -12). In culture, ligand-induced Notch signaling drives human CB CD34 ϩ cells to differentiate into T/NK cell precursors (13). Furthermore, Notch signaling drives the T/NK precursors toward differentiation into T and NK cells, although the results for the NK cells are controversial.…”

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confidence: 99%

Notch Activation Induces the Generation of Functional NK Cells from Human Cord Blood CD34-Positive Cells Devoid of IL-15

Haraguchi

Suzuki²,

Koyama³

et al. 2009

The Journal of Immunology

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The development of NK cells from hematopoietic stem cells is thought to be dependent on IL-15. In this study, we demonstrate that stimulation of human cord blood CD34 ؉ cells by a Notch ligand, Delta4, along with IL-7, stem cell factor, and Fms-like tyrosine kinase 3 ligand, but no IL-15, in a stroma-free culture induced the generation of cells with characteristics of functional NK cells, including CD56 and CD161 Ag expression, IFN-␥ secretion, and cytotoxic activity against K562 and Jurkat cells. Addition of ␥-secretase inhibitor and anti-human Notch1 Ab to the culture medium almost completely blocked NK cell emergence. Addition of anti-human IL-15-neutralizing Ab did not affect NK cell development in these culture conditions. The presence of IL-15, however, augmented cytotoxicity and was required for a more mature NK cell phenotype. CD56 ؉ cells generated by culture with IL-15, but without Notch stimulation, were negative for CD7 and cytoplasmic CD3, whereas CD56 ؉ cells generated by culture with both Delta4 and IL-15 were CD7 ؉ and cytoplasmic CD3 ؉ from the beginning and therefore more similar to in vivo human NK cell progenitors. Together, these results suggest that Notch signaling is important for the physiologic development of NK cells at differentiation stages beyond those previously postulated.

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Differential Effects of Notch Ligands Delta-1 and Jagged-1 in Human Lymphoid Differentiation

Cited by 307 publications

References 51 publications

Notch and Wnt signaling in T-lymphocyte development and acute lymphoblastic leukemia

Notch and Wnt signaling in T-lymphocyte development and acute lymphoblastic leukemia

Ex vivo expansion of umbilical cord blood stem cells for transplantation: growing knowledge from the hematopoietic niche

Notch Activation Induces the Generation of Functional NK Cells from Human Cord Blood CD34-Positive Cells Devoid of IL-15

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