Notch signaling and the bone marrow hematopoietic stem cell niche. Bone 46:281

University of Rochester, Rochester, New York, United States
Bone (Impact Factor: 3.97). 09/2009; 46(2):281-5. DOI: 10.1016/j.bone.2009.08.007
Source: PubMed


Recently there has been increased interest in the regulatory interactions between osteoblasts and cells in the surrounding bone marrow microenvironment. The proximity of hematopoietic stem cells (HSCs) with osteoblastic cells first suggested regulatory interactions, and recent data have highlighted the role of osteoblastic cells in providing a HSC niche. Reports have indicated that direct contact is necessary to mediate the osteoblastic effects and that these effects could be mediated through Notch activation. Notch signaling is important throughout development and also appears to play a critical role in cellular maturation and differentiation of osteoblastic cells and hematopoietic cells as disregulation can lead to bone loss and leukemias, respectively. In this review we discuss the current understanding of Notch signaling and how it functions in hematopoiesis, osteoblastic cells, and the interactions between HSC and their osteoblastic niche.

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    • "Recent studies have also shown that these two signaling pathways act directly on stem cell niches to regulate stem cells. For example, both IGF and Notch signaling maintain the hematopoietic stem cell niche to regulate hematopoiesis in mice (Mayack et al., 2010; Weber and Calvi, 2010). Therefore, an understanding of the mechanism by which systemic insulin signals are integrated with niche-local Notch signaling is central to stem cell biology. "
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    ABSTRACT: The stem cell niche houses and regulates stem cells by providing both physical contact and local factors that regulate stem cell identity. The stem cell niche also plays a role in integrating niche-local and systemic signals, thereby ensuring that the balance of stem cells meets the needs of the organism. However, it is not clear how these signals are merged within the niche. Nutrient-sensing insulin/FOXO signaling has been previously shown to directly control Notch activation in the Drosophila female germline stem cell (GSC) niche, which maintains the niche and GSC identity. Here, we demonstrate that FOXO directly activates transcription of fringe, a gene encoding a glycosyltransferase that modulates Notch glycosylation. Fringe facilitates Notch inactivation in the GSC niche when insulin signaling is low. We also show that the Notch ligand predominantly involved is GSC niche-derived Delta. These results reveal that FOXO-mediated regulation of fringe links the insulin and Notch signaling pathways in the GSC niche in response to nutrition, and emphasize that stem cells are regulated by complex interactions between niche-local and systemic signals.
    Developmental Biology 07/2013; 382(1). DOI:10.1016/j.ydbio.2013.07.018 · 3.55 Impact Factor
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    • "GEP analysis revealed also the up-regulation of genes taking part in HSC adhesion to the BM niche, such as N-cadherin (N-CAD) [14], [15] and LAYN, a newly identified hyaluronan receptor [16]. Moreover, co-culture with OBs induces the up-regulation of Jagged1 (JAG1) [17], GAS6 and its receptor Axl [18], which are involved in the maintenance of HSCs in a quiescent state. Among up-regulated genes were also found several chemokines and pro-inflammatory cytokines, such as CCL4, IL1A, IL1B and CCL20, that, as already reported by Majka M. et al. [19], can be secreted by hematopoietic precursors and regulate with an autocrine and/or paracrin mechanism the various stages of hematopoiesis. "
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    ABSTRACT: Hematopoietic stem cells (HSCs) are located in the bone marrow in a specific microenvironment referred as the hematopoietic stem cell niche, where HSCs interact with a variety of stromal cells. Though several components of the stem cell niche have been identified, the regulatory mechanisms through which such components regulate the stem cell fate are still unknown. In order to address this issue, we investigated how osteoblasts (OBs) can affect the molecular and functional phenotype of Hematopoietic Stem/Progenitor Cells (HSPCs) and vice versa. For this purpose, human CD34+ cells were cultured in direct contact with primary human OBs. Our data showed that CD34+ cells cultured with OBs give rise to higher total cell numbers, produce more CFUs and maintain a higher percentage of CD34+CD38- cells compared to control culture. Moreover, clonogenic assay and long-term culture results showed that co-culture with OBs induces a strong increase in mono/macrophage precursors coupled to a decrease in the erythroid ones. Finally, gene expression profiling (GEP) allowed us to study which signalling pathways were activated in the hematopoietic cell fraction and in the stromal cell compartment after coculture. Such analysis allowed us to identify several cytokine-receptor networks, such as WNT pathway, and transcription factors, as TWIST1 and FOXC1, that could be activated by co-culture with OBs and could be responsible for the biological effects reported above. Altogether our results indicate that OBs are able to affect HPSCs on 2 different levels: on one side, they increase the immature progenitor pool in vitro, on the other side, they favor the expansion of the mono/macrophage precursors at the expense of the erythroid lineage.
    PLoS ONE 01/2013; 8(1):e53496. DOI:10.1371/journal.pone.0053496 · 3.23 Impact Factor
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    • "The preferential induction of Notch1 ICD by Jagged1-Fc stimulation and that of Notch2 ICD by Dll1-Fc stimulation supported this notion. Although we could not directly indicate the preferential Dll1/Notch2 and Jagged1/Notch1 interactions due to a lack of appropriate blocking mAbs against Notch1 and Notch2, such a preferential Notch2/Dll1 interaction also plays a key role in the development of marginal zone B cells in the spleen [25] and a preferential Notch1/Jagged1 interaction has been implicated in the maintenance of hematopoietic stem cells in the BM [26,27]. It has been known that interaction of Notch receptors with Dll versus Jagged ligands is affected by glycosylation of Notch extracellular domain by Fringe [28,29]. "
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    ABSTRACT: Osteoclastogenesis plays an important role in the bone erosion of rheumatoid arthritis (RA). Recently, Notch receptors have been implicated in the development of osteoclasts. However, the responsible Notch ligands have not been identified yet. This study was undertaken to determine the role of individual Notch receptors and ligands in osteoclastogenesis. Mouse bone marrow-derived macrophages or human peripheral blood monocytes were used as osteoclast precursors and cultured with receptor activator of nuclear factor-kappaB ligand (RANKL) and macrophage-colony stimulating factor (M-CSF) to induce osteoclasts. Osteoclasts were detected by tartrate-resistant acid phosphatase (TRAP) staining. K/BxN serum-induced arthritic mice and ovariectomized mice were treated with anti-mouse Delta-like 1 (Dll1) blocking monoclonal antibody (mAb). Blockade of a Notch ligand Dll1 with mAb inhibited osteoclastogenesis and, conversely, immobilized Dll1-Fc fusion protein enhanced it in both mice and humans. In contrast, blockade of a Notch ligand Jagged1 enhanced osteoclastogenesis and immobilized Jagged1-Fc suppressed it. Enhancement of osteoclastogenesis by agonistic anti-Notch2 mAb suggested that Dll1 promoted osteoclastogenesis via Notch2, while suppression by agonistic anti-Notch1 mAb suggested that Jagged1 suppressed osteoclastogenesis via Notch1. Inhibition of Notch signaling by a gamma-secretase inhibitor suppressed osteoclastogenesis, implying that Notch2/Dll1-mediated enhancement was dominant. Actually, blockade of Dll1 ameliorated arthritis induced by K/BxN serum transfer, reduced the number of osteoclasts in the affected joints and suppressed ovariectomy-induced bone loss. The differential regulation of osteoclastogenesis by Notch2/Dll1 and Notch1/Jagged1 axes may be a novel target for amelioration of bone erosion in RA patients.
    Arthritis research & therapy 03/2012; 14(2):R45. DOI:10.1186/ar3758 · 3.75 Impact Factor
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