AKT Signaling Prevailing in Mesenchymal Stromal Cells Modulates the Functionality of Hematopoietic Stem Cells via Intercellular Communication

Abstract

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 SIGNIFICANCE STATEMENTThis study demonstrates that AKT1 signaling prevailing in the mesenchymal stromal cells regulates HSC functionality through various intercellular communication mechanisms. These findings may also have implications in the use of mesenchymal stromal cells in regenerative medicine.

Intercellular Transfer of Microvesicles from Young Mesenchymal Stromal Cells Rejuvenates Aged Murine Hematopoietic Stem Cells

“…Taking clue from our previous study , we examined whether the rejuvenating factors are present in the EVs secreted by the MSCs. CM were subjected to ultra‐centrifugation (100,000 g ) and the pellets containing EVs were suspended in sterile medium.…”

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Oestrogen retains human periodontal ligament stem cells stemness in long‐term culture

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Histological and Immunohistochemical Study on the Possible Effect of Mangosteen and Mesenchymal Stem Cells on Isoproterenol Induced Myocardial Infarction in Adult Male Albino Rats

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