title: Notch2 governs the rate of generation  of mouse long- and short-term  repopulating stem cells.
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.
authors.affiliation: Pediatric Oncology, Clinical Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors.forename: Barbara
authors.initials: B
authors.lastname: Varnum-Finney
authors.forename: Lia M
authors.initials: LM
authors.lastname: Halasz
authors.forename: Mingyi
authors.initials: M
authors.lastname: Sun
authors.forename: Thomas
authors.initials: T
authors.lastname: Gridley
authors.forename: Freddy
authors.initials: F
authors.lastname: Radtke
authors.forename: Irwin D
authors.initials: ID
authors.lastname: Bernstein
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D002454:Cell Differentiation; D002478:Cells, Cultured; D008024:Ligands; D051379:Mice; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence / Q000379:methods; D051881:Receptor, Notch1 / Q000378:metabolism; D051883:Receptor, Notch2 / Q000378:metabolism*; D012038:Regeneration; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology*
chemical_list: D008024:Ligands; C497762:Notch1 protein, mouse; C497765:Notch2 protein, mouse; D051881:Receptor, Notch1; D051883:Receptor, Notch2