Notch1-induced delay of human hematopoietic progenitor cell differentiation is associated with altered cell cycle kinetics

Nadia Carlesso, Jon C. Aster, Jeffrey Sklar, David T. Scadden

Research output: Contribution to journalArticle

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Abstract

Hematopoiesis is a balance between proliferation and differentiation that may be modulated by environmental signals. Notch receptors and their ligands are highly conserved during evolution and have been shown to regulate cell fate decisions in multiple developmental systems. To assess whether Notch1 signaling may regulate human hematopoiesis to maintain cells in an immature state, we transduced a vesicular stomatitis virus G-protein (VSV-G) pseudo-typed bicistronic murine stem cell virus (MSCV)-based retroviral vector expressing a constitutively active form of Notch1 (ICN) and green fluorescence protein into the differentiation competent HL-60 cell line and primary cord blood-derived CD34+ cells. In addition, we observed endogenous Notch1 expression on the surface of both HL-60 cells and primary CD34+ cells, and therefore exposed cells to Notch ligand Jagged2, expressed on NIH3T3 cells. Both ligand-independent and ligand-dependent activation of Notch resulted in delayed acquisition of differentiation markers by HL-60 cells and cord blood CD34+ cells. In addition, primary CD34+ cells retained their ability to form immature colonies, colony-forming unit-mix (CFU-mix), whereas control cells lost this capacity. Activation of Notch1 correlated with a decrease in the fraction of HL-60 cells that were in G0/G1 phase before acquisition of a mature cell phenotype. This enhanced progression through G1 was noted despite preservation of the proliferative rate of the cells and the overall length of the cell cycle. These findings show that Notch1 activation delays human hematopoietic differentiation and suggest a link of Notch differentiation effects with altered cell cycle kinetics.

Original languageEnglish
Pages (from-to)838-848
Number of pages11
JournalBlood
Volume93
Issue number3
StatePublished - Feb 1 1999
Externally publishedYes

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Hematopoietic Stem Cells
Cell Differentiation
Cell Cycle
Cells
Ligands
Kinetics
Chemical activation
HL-60 Cells
Blood
Notch Receptors
Differentiation Antigens
Stem cells
Viruses
Hematopoiesis
Fetal Blood
Fluorescence
Stem Cells
Cell Cycle Resting Phase
G1 Phase
Proteins

ASJC Scopus subject areas

  • Hematology

Cite this

Notch1-induced delay of human hematopoietic progenitor cell differentiation is associated with altered cell cycle kinetics. / Carlesso, Nadia; Aster, Jon C.; Sklar, Jeffrey; Scadden, David T.

In: Blood, Vol. 93, No. 3, 01.02.1999, p. 838-848.

Research output: Contribution to journalArticle

Carlesso, Nadia ; Aster, Jon C. ; Sklar, Jeffrey ; Scadden, David T. / Notch1-induced delay of human hematopoietic progenitor cell differentiation is associated with altered cell cycle kinetics. In: Blood. 1999 ; Vol. 93, No. 3. pp. 838-848.
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