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J Clin Invest. 2011 Mar;121(3):1207-16. doi: 10.1172/JCI43868.

Notch2 governs the rate of generation of mouse long- and short-term repopulating stem cells.

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1
Pediatric Oncology, Clinical Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.

Abstract

HSCs either self-renew or differentiate to give rise to multipotent cells whose progeny provide blood cell precursors. However, surprisingly little is known about the factors that regulate this choice of self-renewal versus differentiation. One candidate is the Notch signaling pathway, with ex vivo studies suggesting that Notch regulates HSC differentiation, although a functional role for Notch in HSC self-renewal in vivo remains controversial. Here, we have shown that Notch2, and not Notch1, inhibits myeloid differentiation and enhances generation of primitive Sca-1(+)c-kit(+) progenitors following in vitro culture of enriched HSCs with purified Notch ligands. In mice, Notch2 enhanced the rate of formation of short-term repopulating multipotential progenitor cells (MPPs) as well as long-term repopulating HSCs, while delaying myeloid differentiation in BM following injury. However, consistent with previous reports, once homeostasis was achieved, neither Notch1 nor Notch2 affected repopulating cell self-renewal. These data indicate a Notch2-dependent role in assuring orderly repopulation by HSCs, MPPs, myeloid cells, and lymphoid cells during BM regeneration.

PMID:
21285514
PMCID:
PMC3049401
DOI:
10.1172/JCI43868
[Indexed for MEDLINE]
Free PMC Article
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