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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
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.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
HUMAN CORD-BLOOD, HEMATOPOIETIC STEM-CELLS, THYMOCYTE DEVELOPMENT, PROGENITOR CELLS, GENE-EXPRESSION, ALPHA-BETA, ORGAN-CULTURE, FATE, RECEPTOR, INACTIVATION
journal title
BLOOD
Blood
volume
106
issue
10
pages
3498 - 3506
Web of Science type
Article
Web of Science id
000233187700035
JCR category
HEMATOLOGY
JCR impact factor
10.131 (2005)
JCR rank
2/60 (2005)
JCR quartile
1 (2005)
ISSN
0006-4971
DOI
10.1182/blood-2005-02-0496
language
English
UGent publication?
yes
classification
A1
copyright statement
I have transferred the copyright for this publication to the publisher
id
324594
handle
http://hdl.handle.net/1854/LU-324594
date created
2006-01-09 11:55:00
date last changed
2011-05-27 13:00:59
@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},
  keyword      = {HUMAN CORD-BLOOD,HEMATOPOIETIC STEM-CELLS,THYMOCYTE DEVELOPMENT,PROGENITOR CELLS,GENE-EXPRESSION,ALPHA-BETA,ORGAN-CULTURE,FATE,RECEPTOR,INACTIVATION},
  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},
}

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, M., 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.