Donor variability among anti-inflammatory pre-activated mesenchymal stromal cells

Therapeutic mesenchymal stromal cells (MSCs) are attractive in part due to their immunomodulatory properties, achieved by their paracrine secretion of factors including prostaglandin E2 (PGE2). Despite promising pre-clinical data, demonstrating clinical efficacy has proven difficult. The current studies were designed to develop approaches to pre-induce desired functions from naive MSCs and examine MSC donor variability, two factors contributing to this disconnect. MSCs from six human donors were pre-activated with interleukin 1 beta (IL-1 beta) at a concentration and duration identified as optimal or interferon gamma (IFN-gamma) as a comparator. Their secretion of PGE2 after pre-activation and secondary exposure to pro-inflammatory molecules was measured. Modulation of tumor necrosis factor alpha (TNF-alpha) secretion from M1 pro-inflammatory macrophages by co-cultured pre-activated MSCs was also measured. Our results indicated that pre-activation of MSCs with IL-1 beta resulted in upregulated PGE2 secretion post exposure. Pre-activation with IL-1 beta or IFN-gamma resulted in higher sensitivity to induction by secondary stimuli compared to no pre-activation. While IL-1 beta pre-activation led to enhanced MSC-mediated attenuation of macrophage TNF-alpha secretion, IFN-gamma pre-activation resulted in enhanced TNF-alpha secretion. Donor variability was noted in PGE2 secretion and upregulation and the level of improved or impaired macrophage modulation.