Mesenchymal stromal cells (MSCs) were first used as a source for cell therapy in 1995; however, despite their versatility and unambiguous demonstration of efficacy and safety in preclinical/phase I studies, the positive effect of MSCs in human phase III studies did not resemble the success obtained in mouse models of disease. This dissonance highlights the need to more thoroughly study the immunobiology of MSCs to make better use of these cells. Thus, we aimed to study the immunobiology of MSCs by using chip array analysis as a method for general screening to obtain a global picture in our model study and found IFNy and IL-17 signaling as the first two “top canonical pathways” involved in MSCs immunomodulation. The role of IFNy in triggering the immunosuppressive properties of MSCs is well recognized by many groups; however, the role of IL-17 in this process remains uncertain. Interestingly, in contrast to IFNy, which actively improved the MSCs-mediated immunosuppression, IL-17 did not improve directly the MSCs-mediated immunosuppression. Instead, IL-17 signaling induced the migration of MSCs and inflammatory cells, bringing these cell types together and increasing the likelihood of the lymphocytes sensing the immunosuppressive molecules produced by the MSCs. These effects also correlated with high levels of cytokine/chemokine production and metalloprotease activation by MSCs. Importantly, this treatment maintained the MSCs safety profile by not inducing the expression of molecules related to antigen presentation. In this way, our findings highlight the possibility of using IL-17, in combination with IFNy, to prime MSCs for cell therapy to improve their biological properties and thus their therapeutic efficacy. Finally, the use of preactivated MSCs may also minimize variations among MSCs to produce more uniform therapeutic products. In the not-so-distant future, we envisage a portfolio of MSCs activated by different cocktails specifically designed to target and treat specific diseases.

间充质基质细胞 (MSC) 于 1995 年首次用作细胞治疗的来源；然而，尽管 MSCs 在临床前/I 期研究中的多功能性和有效性和安全性的明确证明，在人类 III 期研究中的积极作用与在小鼠疾病模型中获得的成功并不相似。这种不协调突出表明需要更彻底地研究 MSC 的免疫生物学，以更好地利用这些细胞。因此，我们旨在通过使用芯片阵列分析作为一般筛选方法来研究 MSCs 的免疫生物学，从而在我们的模型研究中获得全局图片，并发现 IFNy 和 IL-17 信号传导是参与 MSCs 的前两个“顶级经典途径”免疫调节。IFNy 在触发 MSCs 免疫抑制特性中的作用已为许多团体所公认；然而，IL-17 在这个过程中的作用仍然不确定。有趣的是，与积极改善 MSCs 介导的免疫抑制的 IFNy 相比，IL-17 并没有直接改善 MSCs 介导的免疫抑制。相反，IL-17 信号传导诱导了 MSCs 和炎症细胞的迁移，将这些细胞类型聚集在一起并增加了淋巴细胞感知由 MSCs 产生的免疫抑制分子的可能性。这些作用还与高水平的细胞因子/趋化因子产生和 MSC 激活金属蛋白酶相关。重要的是，这种治疗不会诱导与抗原呈递相关的分子表达，从而保持了 MSC 的安全性。通过这种方式，我们的研究结果强调了使用 IL-17 与 IFNy 结合的可能性，为细胞治疗准备 MSC，以改善其生物学特性，从而改善其治疗效果。最后，使用预活化的 MSCs 还可以最大限度地减少 MSCs 之间的差异，以生产更均匀的治疗产品。在不久的将来，我们设想了一系列由专门设计用于靶向和治疗特定疾病的不同鸡尾酒激活的 MSC。