Different thresholds of Notch signaling bias human precursor cells toward B-, NK-, monocytic/dendritic-, or T-cell lineage in thymus microenvironment
| Autor: | Inge Hoebeke, Magda De Smedt, Georges Leclercq, Katia Reynvoet, Jean Plum |
|---|---|
| Rok vydání: | 2005 |
| Předmět: |
Cellular differentiation
T cell Receptors Antigen T-Cell alpha-beta Immunology Notch signaling pathway Dose-Response Relationship Immunologic Thymus Gland Biology Gene Rearrangement T-Lymphocyte Biochemistry Natural killer cell Mice Organ Culture Techniques Antigens CD Endopeptidases medicine Leukocytes Animals Aspartic Acid Endopeptidases Humans Enzyme Inhibitors Antigen-presenting cell Triglycerides gamma-Aminobutyric Acid Receptors Notch Stem Cells Cell Biology Hematology Dendritic cell Natural killer T cell Fetal Blood Cell biology medicine.anatomical_structure Stem cell Amyloid Precursor Protein Secretases Signal Transduction |
| Zdroj: | Blood. 106(10) |
| ISSN: | 0006-4971 |
| Popis: | 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 γ-secretase inhibitor 7 (N-[N-(3,5-difluorophenyl)-l-alanyl]-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 β (TCRβ). On culture with intermediate and high DAPT concentrations, thymic CD34+CD1- cells still generate aberrant intracellular TCRβ- DP 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 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 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|