Introduction: Despite having a proven immunosuppressive potential in vitro, human mesenchymal stromal cells\r\n(MSCs) are reported to display variable efficacy in vivo and, in fact, their proven benefit in the clinical practice is still\r\nlimited and controversial.\r\nMethods: The interplay between clinical grade MSCs and pre-activated donor lymphocytes or selected lymphocyte\r\nsubsets was studied in vitro. The kinetics of MSC growth and viability was evaluated by adhesion-dependent\r\nchanges of culture plate impedance and biochemically by a colorimetric assay. Activation of natural killer (NK) cells\r\nwas assessed as well, using a flow cytometry assay.\r\nResults: A strong inhibition of MSC growth was rapidly induced by the addition of pre-activated lymphocytes\r\nbut not of resting lymphocytes. Inhibition seems not to be attributable to a single cell population, as similar\r\nresults can be obtained by depleting NK cells or by using either selected CD4+ or CD8+ lymphocytes. In addition,\r\nconditioned medium (CM) from activated lymphocytes was able to inhibit MSC growth in a dose-dependent\r\nmanner. Furthermore, licensing with IFN-? partially protected MSCs from pre-activated lymphocytes but not from\r\ntheir CM. These results suggest an inhibitory role of lymphocyte-activation-derived substances. However, the\r\nidentification of a single molecule responsible for MSC inhibition remained elusive, even if preliminary experiments\r\nshowed that ATP and, to a lesser extent, TNF-a might play a role.\r\nConclusions: These results suggest that survival of MSCs can be affected by soluble mediators released by\r\nactivated lymphocytes. Thus it can be hypothesized that MSC immunosuppressive action in vivo could be impaired\r\nby ongoing immune activation through the release of inflammatory mediators
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