Pluripotent, cytokine-dependent, hematopoietic stem cells are immortalized by constitutive Notch1 signaling

Hematopoietic stem cells give rise to progeny that either self-renew in an undifferentiated state or lose self-renewal capabilities and commit to lymphoid or myeloid lineages. Here we evaluated whether hematopoietic stem cell self-renewal is affected by the Notch pathway. Notch signaling controls ce...

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Veröffentlicht in:Nature medicine 2000-11, Vol.6 (11), p.1278-1281
Hauptverfasser: Varnum-Finney, Barbara, Xu, Lanwei, Brashem-Stein, Carolyn, Nourigat, Cynthia, Flowers, David, Bakkour, Sonia, Pear, Warren S, Bernstein, Irwin D
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Sprache:eng
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Zusammenfassung:Hematopoietic stem cells give rise to progeny that either self-renew in an undifferentiated state or lose self-renewal capabilities and commit to lymphoid or myeloid lineages. Here we evaluated whether hematopoietic stem cell self-renewal is affected by the Notch pathway. Notch signaling controls cell fate choices in both invertebrates and vertebrates 1 , 2 , 3 , 4 , 5 , 6 , 7 by inhibiting certain differentiation pathways, thereby permitting cells to either differentiate along an alternative pathway or to self-renew 1 . Notch receptors are present in hematopoietic precursors and Notch signaling enhances the in vitro generation of human and mouse hematopoietic precursors 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , determines T- or B-cell lineage specification from a common lymphoid precursor 16 , 17 and promotes expansion of CD8 + cells 18 , 19 , 20 . Here, we demonstrate that constitutive Notch1 signaling in hematopoietic cells established immortalized, cytokine-dependent cell lines that generated progeny with either lymphoid or myeloid characteristics both in vitro and in vivo . These data support a role for Notch signaling in regulating hematopoietic stem cell self-renewal. Furthermore, the establishment of clonal, pluripotent cell lines provides the opportunity to assess mechanisms regulating stem cell commitment and demonstrates a general method for immortalizing stem cell populations for further analysis.
ISSN:1078-8956
1546-170X
DOI:10.1038/81390