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Blood, 15 November 2005, Vol. 106, No. 10, pp. 3498-3506. Prepublished online as a Blood First Edition Paper on July 19, 2005; DOI 10.1182/blood-2005-02-0496. This Article Full Text (PDF) Supplemental Table and Figures All Versions of this Article: 2005-02-0496v1 106/10/3498    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by De Smedt, M. Articles by Plum, J. Search for Related Content PubMed PubMed Citation Articles by De Smedt, M. Articles by Plum, J. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted February 4, 2005 Accepted July 13, 2005 Different thresholds of Notch signaling bias human precursor cells towards B, NK, monocytic/dendritic cell or T cell lineage in thymus microenvironment Magda De Smedt, Inge Hoebeke, Katia Reynvoet, Georges Leclercq, and Jean Plum* Department of Clinical Chemistry, Microbiology and Immunology, University Hospital Ghent, Ghent University, Ghent, Belgium * Corresponding author; email: jean.plum{at}ugent.be. Notch receptors are involved in lineage decisions in multiple developmental scenarios including hematopoiesis. Here, we treated hybrid human-mouse fetal thymus organ culture with the -secretase inhibitor DAPT to establish the role of Notch signalling in human hematopoietic lineage decisions. The effect of inhibition of Notch signalling was studied starting from cord blood CD34+, or thymic CD34+CD1-, CD34+CD1+ or CD4ISP progenitors. Treatment of cord blood CD34+ cells with low DAPT concentrations results in aberrant CD4ISP and CD4/CD8 DP thymocytes which are negative for intracellular TCR. Upon culture with intermediate and high DAPT concentrations thymic CD34+CD1- cells still generate aberrant intracellular TCR- DP cells, which have undergone DJ but not VDJ recombination. Inhibition of Notch signalling shifts differentiation into non-T cells in a thymic microenvironment depending on the starting progenitor cells: thymic CD34+CD1+ cells do not generate non-T cells, thymic CD34+CD1- cells generate NK cells and monocytic/dendritic cells, and cord blood CD34+Lin- cells generate B, NK, and monocytic/dendritic cells in the presence of DAPT. Our data indicate that Notch signalling is crucial to direct human progenitor cells into the T cell lineage, whereas it has a negative impact on B, NK and monocytic/dendritic cell generation in a dose dependent way. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: K. Haraguchi, T. Suzuki, N. Koyama, K. Kumano, F. Nakahara, A. Matsumoto, Y. Yokoyama, M. Sakata-Yanagimoto, S. Masuda, T. Takahashi, et al. Notch Activation Induces the Generation of Functional NK Cells from Human Cord Blood CD34-Positive Cells Devoid of IL-15 J. Immunol., May 15, 2009; 182(10): 6168 - 6178. [Abstract] [Full Text] [PDF] S. Gonzalez-Garcia, M. Garcia-Peydro, E. Martin-Gayo, E. Ballestar, M. Esteller, R. Bornstein, J. L. de la Pompa, A. A. Ferrando, and M. L. Toribio CSL-MAML-dependent Notch1 signaling controls T lineage-specific IL-7R{alpha} gene expression in early human thymopoiesis and leukemia J. Exp. Med., April 13, 2009; 206(4): 779 - 791. [Abstract] [Full Text] [PDF] T. Taghon, I. Van de Walle, G. De Smet, M. De Smedt, G. Leclercq, B. Vandekerckhove, and J. 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Zhao, M. R. Parkhurst, Z. Zheng, C. J. Cohen, J. P. Riley, L. Gattinoni, N. P. Restifo, S. A. Rosenberg, and R. A. Morgan Extrathymic Generation of Tumor-Specific T Cells from Genetically Engineered Human Hematopoietic Stem Cells via Notch Signaling Cancer Res., March 15, 2007; 67(6): 2425 - 2429. [Abstract] [Full Text] [PDF] M. Garcia-Peydro, V. G. de Yebenes, and M. L. Toribio Notch1 and IL-7 Receptor Interplay Maintains Proliferation of Human Thymic Progenitors while Suppressing Non-T Cell Fates J. Immunol., September 15, 2006; 177(6): 3711 - 3720. [Abstract] [Full Text] [PDF] R. Ceredig, M. Rauch, G. Balciunaite, and A. G. Rolink Increasing Flt3L availability alters composition of a novel bone marrow lymphoid progenitor compartment Blood, August 15, 2006; 108(4): 1216 - 1222. [Abstract] [Full Text] [PDF] K. G. Leong and A. Karsan Recent insights into the role of Notch signaling in tumorigenesis Blood, March 15, 2006; 107(6): 2223 - 2233. [Abstract] [Full Text] [PDF]

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