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The AKT pathway plays an important role in various aspects of stem cell biology. However, the consequences of constitutive activation of AKT in mesenchymal stromal cells (MSCs) on the fate of hematopoietic stem cells (HSCs) were unknown. Here, we show that bone marrow-derived MSCs expressing a constitutively active AKT1 expand HSCs, but severely affect their functionality. Conversely, stromal cells with silenced AKT1 limit HSC proliferation, but boost their functionality. These effects were related to differential modulation of several important regulatory genes, in both, the cocultured HSCs and in the stromal cells themselves. The detrimental effect of stromal cells with constitutively activated AKT1 involved dynamin-dependent endocytosis, whereas the salutary effect of stromal cells devoid of AKT1 was mediated via GAP junctions. Constitutive activation of AKT1 led to deregulated formation of GAP junctions in the stromal cells, which consequently exhibited strikingly increased intercellular transfer of molecular cargo to the HSCs. Conversely, stromal cells with silenced AKT1 exhibited normal intercellular arrangement of GAP junctions at appositional membrane areas, and did not show aberrant intercellular transfer. Micro-vesicles isolated from conditioned media of the stromal cells not only mimicked the effect of these cells, but also showed stronger effects. This is perhaps the first report demonstrating that AKT1 signaling prevailing in the MSCs regulates HSC functionality through various intercellular communication mechanisms. These findings could have important implications in the use of MSCs in regenerative medicine. Stem Cells 2016;34:2354-2367., (© 2016 AlphaMed Press.)