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TISSUE-SPECIFIC STEM CELLS

The Interaction of the Wnt and Notch Pathways Modulates Natural Killer Versus T Cell Differentiation

^aClinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA;
^bDepartment of Pediatrics, University of Washington School of Medicine, Seattle, Washington, USA;
^cHoward Hughes Medical Institute, Department of Pharmacology, and Institute for Stem Cell and Regenerative Medicine, University of Washington School of Medicine, Seattle, Washington, USA;
^dDivision of Hematology, University of Washington School of Medicine, Seattle, Washington, USA

Key Words. Umbilical cord blood • Wnt • Notch • Natural killer cells • T cells

Correspondence: Irwin D. Bernstein, M.D., Clinical Research Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. N., D2-373, Seattle, Washington 98109, USA. Telephone: 206-667-4886; Fax: 206-667-6084; e-mail: ibernste{at}fhcrc.org

Received February 13, 2007; accepted for publication July 9, 2007.
First published online in STEM CELLS EXPRESS   July 19, 2007.



The Wnt and Notch signaling pathways have been independently shown to play a critical role in regulating hematopoietic cell fate decisions. We previously reported that induction of Notch signaling in human CD34⁺CD38^– cord blood cells by culture with the Notch ligand Delta1 resulted in more cells with T or natural killer (NK) lymphoid precursor phenotype. Here, we show that addition of Wnt3a to Delta1 further increased the percentage of CD34^–CD7⁺ and CD34^–CD7⁺cyCD3⁺ cells with increased expression of CD3 and preT. In contrast, culture with Wnt3a alone did not increase generation of CD34^–CD7⁺ precursors or expression of CD3 or preT gene. Furthermore, Wnt3a increased the amount of activated Notch1, suggesting that Wnt modulates Notch signaling by affecting Notch protein levels. In contrast, addition of a Wnt signaling inhibitor to Delta1 increased the percentage of CD56⁺ NK cells. Overall, these results demonstrate that regulation of Notch signaling by the Wnt pathway plays a critical role in differentiation of precursors along the early T or NK differentiation pathways.

Disclosure of potential conflicts of interest is found at the end of this article.

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