Notch1 activation increases hematopoietic stem cell self-renewal in vivo and favors lymphoid over myeloid lineage outcome

Stier, Sebastian; Cheng, Tao; Dombkowski, David; Carlesso, Nadia; Scadden, David T.

doi:10.1182/blood.v99.7.2369

Cited by 352 publications

(276 citation statements)

References 53 publications

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“…Notch1 activation has been shown to enhance self-renewal, increases the stem-cell pool, alters differentiation processes and promotes cell-cycle progression. 24 The erythroid/myeloid differentiation arrest that we found at E9.5 in EGFP þ cells Notch regulates yolk sac hematopoietic progenitors I Cortegano et al derived from Tie2 þ N1ICD expressing progenitors was accompanied by an increase in the number of erythroid/ myeloid c-Kit þ immature cell progenitors. Also, FACSpurified EGFP þ Tie2-Cre;N1ICD cells cultured on OP9 grew at a 10-fold higher rate than WT or EGFP À Tie2-Cre;N1ICD cells (Figure 6a).…”

Section: E)mentioning

confidence: 70%

“…Numerous reports based on in vitro and in vivo experiments strongly support a role for Notch in the self-renewal of hematopoietic stem and progenitor cells, and alterations to the Notch pathway disrupt hematopoietic differentiation. [22][23][24][25] Targeted inactivation of the Notch signaling components Notch1, RPBJk, Jag1 and Mib1 showed that Notch is essential for definitive hematopoiesis in the intraembryonic P-Sp/AGM region. 26,27 The tyrosine kinase receptor-2 (Tie2) is expressed on vascular endothelium and on HSCs, and Tie2 þ cells contain hemangioblasts able to differentiate into hematopoietic and endothelial lineages.…”

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confidence: 99%

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Notch1 regulates progenitor cell proliferation and differentiation during mouse yolk sac hematopoiesis

et al. 2014

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Loss-of-function studies have demonstrated the essential role of Notch in definitive embryonic mouse hematopoiesis. We report here the consequences of Notch gain-of-function in mouse embryo hematopoiesis, achieved by constitutive expression of Notch1 intracellular domain (N1ICD) in angiopoietin receptor tyrosine kinase receptor-2 (Tie2)-derived enhanced green fluorescence protein (EGFP þ ) hematovascular progenitors. At E9.5, N1ICD expression led to the absence of the dorsal aorta hematopoietic clusters and of definitive hematopoiesis. The EGFP þ transient multipotent progenitors, purified from E9.5 to 10.5 Tie2-Cre;N1ICD yolk sac (YS) cells, had strongly reduced hematopoietic potential, whereas they had increased numbers of hemogenic endothelial cells. Late erythroid cell differentiation stages and mature myeloid cells (Gr1 þ , MPO þ ) were also strongly decreased. In contrast, EGFP þ erythro-myeloid progenitors, immature and intermediate differentiation stages of YS erythroid and myeloid cell lineages, were expanded. Tie2-Cre;N1ICD YS had reduced numbers of CD41 þ þ megakaryocytes, and these produced reduced below-normal numbers of immature colonies in vitro and their terminal differentiation was blocked. Cells from Tie2-Cre;N1ICD YS had a higher proliferation rate and lower apoptosis than wild-type (WT) YS cells. Quantitative gene expression analysis of FACS-purified EGFP þ YS progenitors revealed upregulation of Notch1-related genes and alterations in genes involved in hematopoietic differentiation. These results represent the first in vivo evidence of a role for Notch signaling in YS transient definitive hematopoiesis. Our results show that constitutive Notch1 activation in Tie2 þ cells hampers YS hematopoiesis of E9.5 embryos and demonstrate that Notch signaling regulates this process by balancing the proliferation and differentiation dynamics of lineage-restricted intermediate progenitors.

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Section: E)mentioning

confidence: 70%

mentioning

confidence: 99%

Notch1 regulates progenitor cell proliferation and differentiation during mouse yolk sac hematopoiesis

et al. 2014

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“…3). Alternatively, CLPs can differentiate to T-cells through Notch1 activation, which is negatively regulated by PAX5 [166][167][168] . Recent studies have shown the role of FOXP1 in the transition of pro-B cells to pre-B cells, a step which is also controlled by IRF4/MUM1 and IRF8 169,170 .…”

Section: Do Lymphoid Malignancies Arise From Mutations That Deregulatmentioning

confidence: 99%

Somatic stem cells and the origin of cancer

2006

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647Most human cancers derive from a single cell targeted by genetic and epigenetic alterations that initiate malignant transformation. Progressively, these early cancer cells give rise to different generations of daughter cells that accumulate additional mutations, acting in concert to drive the full neoplastic phenotype 1,2 . As we have currently deciphered many of the gene pathways disrupted in cancer, our knowledge about the nature of the normal cells susceptible to transformation upon mutation has remained more elusive. Adult stem cells are those that show long-term replicative potential, together with the capacities of self-renewal and multi-lineage differentiation. These stem cell properties are tightly regulated in normal development, yet their alteration may be a critical issue for tumorigenesis. This concept has arisen from the striking degree of similarity noted between somatic stem cells and cancer cells, including the fundamental abilities to self-renew and differentiate. Given these shared attributes, it has been proposed that cancers are caused by transforming mutations occurring in tissue-specific stem cells 3-9 . This hypothesis has been functionally supported by the observation that among all cancer cells within a particular tumor, only a minute cell fraction has the exclusive potential to regenerate the entire tumor cell population 3,10-13 ; these cells with stem-like properties have been termed cancer stem cells. Cancer stem cells can originate from mutation in normal somatic stem cells that deregulate their physiological programs. Alternatively, mutations may target more committed progenitor cells or even mature cells, which become reprogrammed to acquire stem-like functions 14,15 In any case, mutated genes should promote expansion of stem/progenitor cells, thus increasing their predisposition to cancer development by expanding self-renewal and pluripotency over their normal tendency towards relative quiescency and proper differentiation.

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“…66,68 Up-regulated Notch1 and STAT3 signaling may contribute to improved proliferation capacity and multipotency of SASCs from injured muscle because both Notch1 and STAT3 are involved in stem cell maintenance and self-renewal. 54,55,58,69,70 Activation of Notch1 and STAT3 signaling pathways is also required for efficient muscle regeneration, 51,57 and their activation in SASCs from injured muscle may verify the highly regenerative potential and important function of this specific cell population in repairing injured muscle. In addition, the finding of activated Notch1 signaling in SASCs may suggest a promising contribution of the cells in therapeutic applications for regeneration of aged skeletal muscle.…”

Section: Discussionmentioning

confidence: 99%

Slow-Adhering Stem Cells Derived from Injured Skeletal Muscle Have Improved Regenerative Capacity

Xiang

Rathbone

et al. 2011

The American Journal of Pathology

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A wide variety of myogenic cell sources have been used for repair of injured and diseased muscle including muscle stem cells, which can be isolated from skeletal muscle as a group of slow-adhering cells on a collagen-coated surface. The therapeutic use of muscle stem cells for improving muscle regeneration is promising; however, the effect of injury on their characteristics and engraftment potential has yet to be described. In the present study, slow-adhering stem cells (SASCs) from both laceration-injured and control noninjured skeletal muscles in mice were isolated and studied. Migration and proliferation rates, multidifferentiation potentials, and differences in gene expression in both groups of cells were compared in vitro. Results demonstrated that a larger population of SASCs could be isolated from injured muscle than from control noninjured muscle. In addition, SASCs derived from injured muscle demonstrated improved migration, a higher rate of proliferation and multidifferentiation, and increased expression of Notch1, STAT3, Msx1, and MMP2. Moreover, when transplanted into dystrophic muscle in MDX/SCID mice, SASCs from injured muscle generated greater engraftments with a higher capillary density than did SASCs from control noninjured muscle. These data suggest that traumatic injury may modify stem cell characteristics through trophic factors and improve the transplantation potential of SASCs in alleviating skeletal muscle injuries and diseases.

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Notch1 activation increases hematopoietic stem cell self-renewal in vivo and favors lymphoid over myeloid lineage outcome

Cited by 352 publications

References 53 publications

Notch1 regulates progenitor cell proliferation and differentiation during mouse yolk sac hematopoiesis

Notch1 regulates progenitor cell proliferation and differentiation during mouse yolk sac hematopoiesis

Somatic stem cells and the origin of cancer

Slow-Adhering Stem Cells Derived from Injured Skeletal Muscle Have Improved Regenerative Capacity

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