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

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...

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Published inThe Journal of clinical investigation Vol. 121; no. 3; pp. 1207 - 1216
Main Authors Varnum-Finney, Barbara, Halasz, Lia M, Sun, Mingyi, Gridley, Thomas, Radtke, Freddy, Bernstein, Irwin D
Format Journal Article
LanguageEnglish
Published United States American Society for Clinical Investigation 01.03.2011
Subjects
Animals
Biomedical research
Bone Marrow Cells - cytology
Cell Differentiation
Cells, Cultured
Cellular signal transduction
Homeostasis
Ligands
Mice
Mice, Transgenic
Microscopy, Fluorescence - methods
Physiological aspects
Receptor, Notch1 - metabolism
Receptor, Notch2 - metabolism
Regeneration
Signal Transduction
Stem cells
Stem Cells - cytology
United States
Switzerland
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Summary: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.
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Authorship note: Barbara Varnum-Finney and Lia M. Halasz contributed equally to this work.
ISSN:0021-9738
1558-8238
DOI:10.1172/jci43868