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Duncan, A.W. et al. Integration of Notch and Wnt signaling in hematopoietic stem cell maintenance. Nat. Immunol. 6, 314-322

Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA.
Nature Immunology (Impact Factor: 24.97). 04/2005; 6(3):314-22. DOI: 10.1038/ni1164
Source: PubMed

ABSTRACT A fundamental question in hematopoietic stem cell (HSC) biology is how self-renewal is controlled. Here we show that the molecular regulation of two critical elements of self-renewal, inhibition of differentiation and induction of proliferation, can be uncoupled, and we identify Notch signaling as a key factor in inhibiting differentiation. Using transgenic Notch reporter mice, we found that Notch signaling was active in HSCs in vivo and downregulated as HSCs differentiated. Inhibition of Notch signaling led to accelerated differentiation of HSCs in vitro and depletion of HSCs in vivo. Finally, intact Notch signaling was required for Wnt-mediated maintenance of undifferentiated HSCs but not for survival or entry into the cell cycle in vitro. These data suggest that Notch signaling has a dominant function in inhibiting differentiation and provide a model for how HSCs may integrate multiple signals to maintain the stem cell state.

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    • "The inhibition of Notch1 signalling enhanced the differentiation of HSCs in vitro but depleted the HSCs in vivo. It was shown in this study that Notch1 cooperates with Wnt signalling to maintain HSCs in undifferentiated state (Duncan et al. 2005). In contrast, another study that addressed the loss of function of canonical Notch signalling in murine adult HSCs ruled out any physiological roles for this pathway in these cells. "
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    ABSTRACT: The NOTCH pathway is an evolutionarily conserved signalling network, which is fundamental in regulating developmental processes in invertebrates and vertebrates (Gazave et al. in BMC Evol Biol 9:249, 2009). It regulates self-renewal (Butler et al. in Cell Stem Cell 6:251-264, 2010), differentiation (Auderset et al. in Curr Top Microbiol Immunol 360:115-134, 2012), proliferation (VanDussen et al. in Development 139:488-497, 2012) and apoptosis (Cao et al. in APMIS 120:441-450, 2012) of diverse cell types at various stages of their development. NOTCH signalling governs cell-cell interactions and the outcome of such responses is highly context specific. This makes it impossible to generalize about NOTCH functions as it stimulates survival and differentiation of certain cell types, whereas inhibiting these processes in others (Meier-Stiegen et al. in PLoS One 5:e11481, 2010). NOTCH was first identified in 1914 in Drosophila and was named after the indentations (notches) present in the wings of the mutant flies (Bigas et al. in Int J Dev Biol 54:1175-1188, 2010). Homologs of NOTCH in vertebrates were initially identified in Xenopus (Coffman et al. in Science 249:1438-1441, 1990) and in humans NOTCH was first identified in T-Acute Lymphoblastic Leukaemia (T-ALL) (Ellisen et al. in Cell 66:649-61, 1991). NOTCH signalling is integral in neurogenesis (Mead and Yutzey in Dev Dyn 241:376-389, 2012), myogenesis (Schuster-Gossler et al. in Proc Natl Acad Sci U S A 104:537-542, 2007), haematopoiesis (Bigas et al. in Int J Dev Biol 54:1175-1188, 2010), oogenesis (Xu and Gridley in Genet Res Int 2012:648207, 2012), differentiation of intestinal cells (Okamoto et al. in Am J Physiol Gastrointest Liver Physiol 296:G23-35, 2009) and pancreatic cells (Apelqvist et al. in Nature 400:877-881, 1999). The current review will focus on NOTCH signalling in normal and malignant blood cell production or haematopoiesis.
    Journal of Cell Communication and Signaling 02/2015; 9(1). DOI:10.1007/s12079-015-0271-0
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    • "The role of Notch signalling in adult vertebrate HPCs maintenance remained controversial, largely because gainand loss-of-function studies have not produced consistent results. It has been suggested to be dispensable for adult haematopoiesis through two complementary approaches blocking the canonical Notch signalling within HPCs (one with a dominant negative form of the mastermind-like protein, and the other inactivating the RBP-J gene) (Duncan et al., 2005) (Maillard et al., 2008). However, recent studies support a role for Notch in the regeneration of HPCs after injury (Butler et al., 2010) (Varnum-Finney et al., 2011) and more recently, a role of endothelial Jagged-1 was highlighted for homeostatic and regenerative haematopoiesis (Poulos et al., 2013). "
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    ABSTRACT: Understanding the role of Notch and its ligands within the different bone marrow niches could shed light on the mechanisms regulating haematopoietic progenitor cells (HPCs) maintenance and self-renewal. Here, we report that murine bone marrow HPCs activation by the vascular Notch Delta-4 ligand maintains a significant proportion of cells specifically in the G0 state. Furthermore, Delta-4/Notch pathway limits significantly the loss of the in vivo short-term reconstitutive potential upon transplantation of Delta-4 activated HPCs into lethally irradiated recipient mice. Both effects are directly correlated with the decrease of cell cycle genes transcription such as CYCLIN-D1, -D2, and -D3, and the upregulation of stemness related genes transcription such as BMI1, GATA2, HOXB4 and C-MYC. In addition, the transcriptional screening also highlights new downstream post-transcriptional factors, named PUMILIO1 and -2, as part of the stem signature associated with the Delta-4/Notch signalling pathway.
    Stem Cell Research 11/2014; 13(3):431–441. DOI:10.1016/j.scr.2014.10.002 · 3.91 Impact Factor
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    • "MSI1 regulates NOTCH signaling, and LGR5 is a target of the WNT pathway. Each of these pathways has been shown to be critical for the metastasis and in stem cell biology (Duncan et al., 2005; Reya & Clevers, 2005; de Sousa et al., 2011; Malanchi et al., 2012). It is however important to note that TNC did not altered the antigen profile of breast CSCs, suggesting that CSC activities were established prior to metastasis, and TNC is may be critical for maintenance of stem cell functions (Oskarsson et al., 2011). "
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    ABSTRACT: Cancer stem cells (CSCs), which comprise a small fraction of cancer cells, are believed to constitute the origin of most human tumors. Considerable effort has been focused on identifying CSCs in multiple tumor types and identifying genetic signatures that distinguish CSCs from normal tissue stem cells. Many studies also suggest that CSCs serve as the basis of metastases. Yet, experimental evidence that CSCs are the basis of disseminated metastases has lagged behind the conceptual construct of CSCs. Recent work, however, has demonstrated that CSCs may directly or indirectly contribute to the generation of metastasis. Moreover, CSC heterogeneity may be largely responsible for the considerable complexity and organ specificity of metastases. In this review, we discuss the role of CSCs in metastasis and their potential as therapeutic targets.
    Pharmacology [?] Therapeutics 02/2013; 138(2). DOI:10.1016/j.pharmthera.2013.01.014 · 7.75 Impact Factor
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