386 The Adaptive Response of Old ABCB5+ MSCs is Changed Upon Exposure to LPS

Abstract

Mesenchymal stem cells (MSCs) are endowed with the unique capacity to raise an adaptive response to environmental cues. This allows MSCs to control their direct neighbourhood and endogenous tissue niche. Upon exposure of MSCs with infection mimicking lipopolysaccharide (LPS), MSCs completely shift their transcriptome with the release of neutrophil activating chemokines. The LPS induced transcriptomic shift resulted in a significant increase in neutrophil expulsed DNA traps (NETs) and proteolytic enzymes. This adaptive response guarantees the defense from bacterial attack. Wound healing decreases with age and propensity for infection increases. Therefore, we addressed the question whether MSCs from old healthy donors (> 65 years) unlike young healthy donors (< 30 years) may change their adaptive response upon LPS exposure towards a reduced microbicidal response. Cultured ABCB5+ MSCs from young and old donors treated with LPS revealed differences in the time kinetic of NF-κB translocation from the cytoplasm to the nucleus. By contrast to ABCB5+ MSCs from young donors, ABCB5+ MSCs from old donors depicted a significantly delayed back regulation of nuclear NF-κB translocation, supported by an overshooting increase of p-p65. This correlates with a higher and longer persisting expression of NF-κB target genes like IL-6 in MSCs of elderly individuals compared to young individuals. Notably, ABCB5+ MSCs from young donors depict higher expression levels of IL-8 and IL-10 compared to old donors. Of note, LPS primed ABCB5+ MSCs from young donors can activate neutrophils by producing NETs to a higher level in comparison to old donors. NE activity indicative for microbicidal NET formation from co-cultures of LPS primed ABCB5+ MSC from young donors with PMA stimulated neutrophils is significantly higher and LPS-concentration-dependent compared to old donors. Collectively, MSCs from old individuals reveal a dysregulated anti-bacterial response which is supported by an impressively reduced killing ability of gram negative bacteria and at least in part explained higher susceptibility for severe bacterial infections in elderly.