Angiocrine factors from Akt-activated endothelial cells balance self-renewal and differentiation of haematopoietic stem cells. Nature - Cell Biology

Howard Hughes Medical Institute, Ansary Stem Cell Institute, Department of Genetic Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
Nature Cell Biology (Impact Factor: 20.06). 10/2010; 12(11):1046-56. DOI: 10.1038/ncb2108
Source: PubMed

ABSTRACT Endothelial cells establish an instructive vascular niche that reconstitutes haematopoietic stem and progenitor cells (HSPCs) through release of specific paracrine growth factors, known as angiocrine factors. However, the mechanism by which endothelial cells balance the rate of proliferation and lineage-specific differentiation of HSPCs is unknown. Here, we demonstrate that Akt activation in endothelial cells, through recruitment of mTOR, but not the FoxO pathway, upregulates specific angiocrine factors that support expansion of CD34(-)Flt3(-) KLS HSPCs with long-term haematopoietic stem cell (LT-HSC) repopulation capacity. Conversely, co-activation of Akt-stimulated endothelial cells with p42/44 MAPK shifts the balance towards maintenance and differentiation of the HSPCs. Selective activation of Akt1 in the endothelial cells of adult mice increased the number of colony forming units in the spleen and CD34(-)Flt3(-) KLS HSPCs with LT-HSC activity in the bone marrow, accelerating haematopoietic recovery. Therefore, the activation state of endothelial cells modulates reconstitution of HSPCs through the modulation of angiocrine factors, with Akt-mTOR-activated endothelial cells supporting the self-renewal of LT-HSCs and expansion of HSPCs, whereas MAPK co-activation favours maintenance and lineage-specific differentiation of HSPCs.

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Available from: Laura Elaine Benjamin, Sep 19, 2014
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    • "Study by a group of Salter shows a consistent observation that endothelial progenitor cells injected in total body irradiated mice can stimulate HSC reconstitution and hematologic recovery [72]. Furthermore, selective activation of Akt in endothelial cells produced angiocrine factors mediated in the reconstitution, expansion, and maintenance of HSCs [73]. Nonetheless, constitutively activation of Akt, a binding ligand of phosphoinositide 3 in the phosphoinositide 3-kinase pathway, impaired engraftment ability and preferable generated leukemia in mice [74]. "
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    ABSTRACT: Hematopoietic stem cells (HSCs) play a key role in hematopoietic system that functions mainly in homeostasis and immune response. HSCs transplantation has been applied for the treatment of several diseases. However, HSCs persist in the small quantity within the body, mostly in the quiescent state. Understanding the basic knowledge of HSCs is useful for stem cell biology research and therapeutic medicine development. Thus, this paper emphasizes on HSC origin, source, development, the niche, and signaling pathways which support HSC maintenance and balance between self-renewal and proliferation which will be useful for the advancement of HSC expansion and transplantation in the future.
    07/2012; 2012:270425. DOI:10.1155/2012/270425
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    • "In addition, the mTORC1 signaling pathway is important in the nervous system (Li et al., 2010; Neasta et al., 2010), ageing (Selman et al., 2009; Kapahi et al., 2010), and immune cells (Powell and Delgoffe, 2010). It can balance self-renewal and differentiation of hematopoietic stem cells (Kobayashi et al., 2010) and induce differentiation of pluripotent human embryonic stem cells (Easley et al., 2010). mTORC1 signaling plays an evolutionarily conserved role in the regulation of cell growth, proliferation , survival, and metabolism via different cellular processes. "
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    ABSTRACT: The mammalian target of rapamycin (mTOR) is a Ser/Thr kinase. It plays an evolutionarily conserved role in regulating cell growth, proliferation, survival, and metabolism via different cellular processes. The purpose of this study was to explore the inhibitory effects of CCI-779 (temsirolimus), a specific mTOR inhibitor, on mTOR signaling, and examine the mechanism of cell growth suppression by CCI-779 in Cashmere goat fetal fibroblasts (GFb cells). GFb cells were sensitive to CCI-779 and the survival rate of cells treated with >3.0 μM of CCI-779 was significantly reduced compared with the control (p<0.01). CCI-779 inhibited the phosphorylation of mTOR (at Ser2448) and S6 (at Ser240/244), and the expression of mTOR, p70S6K, and S6. Thus, CCI-779 was toxic to GFb cells, and it induced a dose-dependent decrease in cell proliferation and caused G1/S cell cycle arrest. Taken together, these data show that CCI-779 can inhibit mTOR signaling and proliferation in GFb cells in vitro. Therefore, mTOR is an important regulator for GFb cell growth and proliferation.
    DNA and cell biology 02/2012; 31(6):1095-9. DOI:10.1089/dna.2011.1559 · 1.99 Impact Factor
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    • "Overall, our results support the idea of an informative transference between endothelial cells and GSCs, whereby endothelial-secreted factors could retain GSC properties. Our findings are similar to angiocrine factors that are shown to regulate hematopoietic stem-cell fate (Kobayashi et al, 2010). We next explored whether endothelial cell secretome might modulate the mTOR signalling nexus in GSCs. "
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    ABSTRACT: Glioma stem-cells are associated with the brain vasculature. However, the way in which this vascular niche regulates stem-cell renewal and fate remains unclear. Here, we show that factors emanating from brain endothelial cells positively control the expansion of long-term glioblastoma stem-like cells. We find that both pharmacological inhibition of and RNA interference with the mammalian target of rapamycin (mTOR) pathway reduce their spheroid growth. Conversely, the endothelial secretome is sufficient to promote this mTOR-dependent survival. Thus, interfering with endothelial signals might present opportunities to identify treatments that selectively target malignant stem-cell niches.
    EMBO Reports 04/2011; 12(5):470-6. DOI:10.1038/embor.2011.39 · 7.86 Impact Factor
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