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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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    • "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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    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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    • "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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