The Notch Ligand Jagged-1 Represents a Novel Growth Factor of Human Hematopoietic Stem Cells

Karanu, Frances N.; Murdoch, Barbara; Gallacher, Lisa; Wu, Dongmei; Koremoto, Masahide; Sakano, Seiji; Bhatia, Mickie

doi:10.1084/jem.192.9.1365

Cited by 391 publications

(295 citation statements)

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“…Therefore, pharmacological activation of PPR increased HSC, but appeared to do so without a broad haematopoietic cell expansion. These data are consistent with HSC expansion by enhanced self-renewal, a phenomenon known to result from Notch activation [13][14][15][16][17] .To assess whether PPR stimulation could have a meaningful physiological effect, we chose a model relevant to the clinical use of stem cells in humans. PTH was administered to animals undergoing myeloablative bone marrow transplantation using limiting numbers of donor cells to mimic a setting of therapeutic need.…”

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confidence: 51%

“…The procedure for BrdU pulse labeling, LTR and subsequent detection has been reported 16 . The mice were fed BrdU (0.8 mg ml 21 in water) for 10 days, during which time 40% of LT-HSCs would divide at least once 31 .…”

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“…3). Therefore, membrane-or matrix-bound cytokines were necessary for the stromal effect on HSCs.The Notch signalling pathway involves membrane-bound ligands and regulates cell-fate specification in a wide variety of systems, including HSC self-renewal [13][14][15][16][17] . By changing the balance of daughter cell self-renewal versus differentiation, Notch signalling has been shown to increase stem cell numbers without expanding mature cells in a manner reminiscent of the phenotype observed here 13,16 .…”

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Osteoblastic cells regulate the haematopoietic stem cell niche

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Weibrecht

et al. 2003

Nature

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The procedures for bone and bone marrow section preparation, immunostaining conditions and antibodies are described in Supplementary Methods. The procedure for BrdU pulse labeling, LTR and subsequent detection has been reported 16 . The mice were fed BrdU (0.8 mg ml 21 in water) for 10 days, during which time 40% of LT-HSCs would divide at least once 31 . Seventy days after BrdU labelling, sections were stained with anti-BrdU antibody. N-cadherin 1 cell countFor quantitative analysis of N-cadherin þ cells, the sections were developed with AEC after being incubated with rabbit anti-N-cadherin antibody for 1 h and horseradish peroxidase (HRP)-conjugated goat anti-rabbit second antibody for 1 h. Three people counted the SNO cells in these sections, blind to the source of the sections. X-ray imageHigh-resolution X-rays (Faxitron MX-20) of bone and bone histomorphometry (OsteoMetrics, Inc.) were performed at the University of Missouri-Kansas City School of Dentistry. 1965-1972 (1996). 193-197 (2000). 10. Simmons, P., Gronthos, S. & Zannettino, A. C. Stem cell fate is influenced by specialized microenvironments that remain poorly defined in mammals 1-3 . To explore the possibility that haematopoietic stem cells derive regulatory information from bone, accounting for the localization of haematopoiesis in bone marrow, we assessed mice that were genetically altered to produce osteoblast-specific, activated PTH/PTHrP receptors (PPRs) 4 . Here we show that PPRstimulated osteoblastic cells that are increased in number produce high levels of the Notch ligand jagged 1 and support an increase in the number of haematopoietic stem cells with evidence of Notch1 activation in vivo. Furthermore, liganddependent activation of PPR with parathyroid hormone (PTH) increased the number of osteoblasts in stromal cultures, and augmented ex vivo primitive haematopoietic cell growth that was abrogated by g-secretase inhibition of Notch activation. An increase in the number of stem cells was observed in wild-type animals after PTH injection, and survival after bone marrow transplantation was markedly improved. Therefore, osteoblastic cells are a regulatory component of the haematopoietic stem cell niche in vivo that influences stem cell function through Notch activation. Niche constituent cells or signalling pathways provide pharmacological targets with therapeutic potential for stem-cell-based therapies.Mammalian bone marrow architecture involves haematopoietic stem cells (HSCs) in close proximity to the endosteal surfaces 5,6 , with more differentiated cells arranged in a loosely graduated fashion as the central longitudinal axis of the bone is approached 5,7,8 . This nonrandom organization of the marrow suggests a possible relationship between HSCs and osteoblasts-osteogenic cells lining the endosteal surface. Osteoblasts produce haematopoietic growth factors [9][10][11] and are activated by parathyroid hormone (PTH) or the locally produced PTH-related protein (PTHrP), through the PTH/ PTHrP receptor (PPR). We tested whether osteoblast...

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Osteoblastic cells regulate the haematopoietic stem cell niche

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Weibrecht

et al. 2003

Nature

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

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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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“…7 In humans, a critical role for Notch signaling, through the Notch ligand Jagged1, has been demonstrated in the proliferation and differentiation of normal primitive human hematopoietic progenitors. [12][13][14] However, these studies were mostly performed using adult hematopoietic cells or established hematopoietic cell lines. Although the effect of Notch signaling in human embryos or embryonic stem cells (hESCs) has been investigated previously, 15,16 the role of Notch signaling in cellular specification and hematopoietic or endothelial commitment during early human development remains largely unknown.…”

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confidence: 99%