Gray Andrea, Schloss Rene S, Yarmush Martin
Department of Biomedical Engineering, Rutgers, the State University of New Jersey, New Jersey, USA.
Center for Engineering in Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
Technology (Singap World Sci). 2016 Sep;4(3):201-215. doi: 10.1142/S2339547816500084.
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 naïve 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-1β) at a concentration and duration identified as optimal or interferon gamma (IFN-γ) 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-α) 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-1β resulted in upregulated PGE2 secretion post exposure. Pre-activation with IL-1β or IFN-γ resulted in higher sensitivity to induction by secondary stimuli compared to no pre-activation. While IL-1β pre-activation led to enhanced MSC-mediated attenuation of macrophage TNF-α secretion, IFN-γ pre-activation resulted in enhanced TNF-α secretion. Donor variability was noted in PGE2 secretion and upregulation and the level of improved or impaired macrophage modulation.
治疗性间充质基质细胞（MSC）具有吸引力，部分原因在于其免疫调节特性，这是通过其旁分泌包括前列腺素E2（PGE2）在内的因子来实现的。尽管临床前数据很有前景，但证明其临床疗效却很困难。当前的研究旨在开发方法，从原始MSC中预先诱导出所需功能，并研究MSC供体变异性，这是导致这种脱节的两个因素。来自六名人类供体的MSC用白细胞介素1β（IL-1β）以确定为最佳的浓度和持续时间进行预激活，或用干扰素γ（IFN-γ）作为对照。测量它们在预激活和再次暴露于促炎分子后的PGE2分泌。还测量了共培养的预激活MSC对M1促炎巨噬细胞肿瘤坏死因子α（TNF-α）分泌的调节作用。我们的结果表明，用IL-1β预激活MSC会导致暴露后PGE2分泌上调。与未预激活相比，用IL-1β或IFN-γ预激活导致对二次刺激诱导的敏感性更高。虽然IL-1β预激活导致MSC介导的巨噬细胞TNF-α分泌减弱增强，但IFN-γ预激活导致TNF-α分泌增强。在PGE2分泌、上调以及巨噬细胞调节改善或受损的水平方面存在供体变异性。
