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Different thresholds of Notch signaling bias human precursor cells toward B-, NK-, monocytic/dendritic-, or T-cell lineage in thymus microenvironment

Magda De Smedt (UGent) , Inge Hoebeke (UGent) , Katia Reynvoet (UGent) , Georges Leclercq (UGent) and Jean Plum (UGent)
(2005) BLOOD. 106(10). p.3498-3506
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Abstract
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 gamma-secretase inhibitor 7 (N-[N-(3,5-difluorophenyl)-Lalanyl]-S-phenyl-glycine t-butyl ester) (DAPT) to establish the role of Notch signaling in human hematopoietic lineage decisions. The effect of inhibition of Notch signaling 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 double-positive (DP) thymocytes, which are negative for intracellular T-cell receptor beta (TCR beta). On culture with intermediate and high DAPT concentrations, thymic CD34(+)CD1(-) cells still generate aberrant intracellular TCR beta(-) DIP cells that have undergone DJ but not VDJ recombination. Inhibition of Notch signaling 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 INK cells and monocytic/dendritic cells, and cord blood CD34(+)Lin(-) cells generate B, INK, and monocytic/dendritic cells in the presence of DAPT Our data indicate that Notch signaling 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 fashion.
Keywords
HUMAN CORD-BLOOD, HEMATOPOIETIC STEM-CELLS, THYMOCYTE DEVELOPMENT, PROGENITOR CELLS, GENE-EXPRESSION, ALPHA-BETA, ORGAN-CULTURE, FATE, RECEPTOR, INACTIVATION

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Chicago
De Smedt, Magda, Inge Hoebeke, Katia Reynvoet, Georges Leclercq, and Jean Plum. 2005. “Different Thresholds of Notch Signaling Bias Human Precursor Cells Toward B-, NK-, Monocytic/dendritic-, or T-cell Lineage in Thymus Microenvironment.” Blood 106 (10): 3498–3506.
APA
De Smedt, Magda, Hoebeke, I., Reynvoet, K., Leclercq, G., & Plum, J. (2005). Different thresholds of Notch signaling bias human precursor cells toward B-, NK-, monocytic/dendritic-, or T-cell lineage in thymus microenvironment. BLOOD, 106(10), 3498–3506.
Vancouver
1.
De Smedt M, Hoebeke I, Reynvoet K, Leclercq G, Plum J. Different thresholds of Notch signaling bias human precursor cells toward B-, NK-, monocytic/dendritic-, or T-cell lineage in thymus microenvironment. BLOOD. 2005;106(10):3498–506.
MLA
De Smedt, Magda, Inge Hoebeke, Katia Reynvoet, et al. “Different Thresholds of Notch Signaling Bias Human Precursor Cells Toward B-, NK-, Monocytic/dendritic-, or T-cell Lineage in Thymus Microenvironment.” BLOOD 106.10 (2005): 3498–3506. Print.
@article{324594,
  abstract     = {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 gamma-secretase inhibitor 7 (N-[N-(3,5-difluorophenyl)-Lalanyl]-S-phenyl-glycine t-butyl ester) (DAPT) to establish the role of Notch signaling in human hematopoietic lineage decisions. The effect of inhibition of Notch signaling 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 double-positive (DP) thymocytes, which are negative for intracellular T-cell receptor beta (TCR beta). On culture with intermediate and high DAPT concentrations, thymic CD34(+)CD1(-) cells still generate aberrant intracellular TCR beta(-) DIP cells that have undergone DJ but not VDJ recombination. Inhibition of Notch signaling 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 INK cells and monocytic/dendritic cells, and cord blood CD34(+)Lin(-) cells generate B, INK, and monocytic/dendritic cells in the presence of DAPT Our data indicate that Notch signaling 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 fashion.},
  author       = {De Smedt, Magda and Hoebeke, Inge and Reynvoet, Katia and Leclercq, Georges and Plum, Jean},
  issn         = {0006-4971},
  journal      = {BLOOD},
  language     = {eng},
  number       = {10},
  pages        = {3498--3506},
  title        = {Different thresholds of Notch signaling bias human precursor cells toward B-, NK-, monocytic/dendritic-, or T-cell lineage in thymus microenvironment},
  url          = {http://dx.doi.org/10.1182/blood-2005-02-0496},
  volume       = {106},
  year         = {2005},
}

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