Department of Chemical and Biomolecular Engineering, Tulane University, Lindy Boggs Center Room 300, New Orleans, LA 70118, USA.
In Vitro Cell Dev Biol Anim. 2010 Jun;46(6):566-72. doi: 10.1007/s11626-010-9279-1. Epub 2010 Mar 3.
Therapeutic administration of mesenchymal stem cells (MSCs) by systemic delivery utilizes the innate ability of the cells to home to damaged tissues, but it can be an inefficient process due to a limited knowledge of cellular cues that regulate migration and homing. Our lab recently discovered that a potent pro-inflammatory cytokine, macrophage migration inhibitory factor (MIF), inhibits MSC migration. Because MIF may act on multiple cellular targets, an activating antibody (CD74Ab) was employed in this study to examine the effect of one MIF receptor, CD74 (major histocompatibility complex class II-associated invariant chain), on MSC motility. CD74 activation inhibits in a dose-dependent manner up to 90% of in vitro migration of MSCs at 40 mug/ml CD74Ab (p < 0.001), with consistent effects observed among three MSC donor preparations. A blocking peptide from the C-terminus of CD74 eliminates the effect of CD74Ab on MSCs. This suggests that MIF may act on MSCs, at least in part, through CD74. Late-passage MSCs exhibit less chemokinesis than those at passage 2. However, MSCs remain responsive to CD74 activation during ex vivo expansion: MSC migration is inhibited approximately 2-fold in the presence of 5 microg/ml CD74Ab at passage 9 vs. approximately 3-fold at passage 2 (p < 0.001). Consistent with this result, there were no significant differences in CD74 expression at all tested passages or after CD74Ab exposure. Targeting CD74 to regulate migration and homing potentially may be a useful strategy to improve the efficacy of a variety of MSC therapies, including those that require ex vivo expansion.
间质干细胞（MSCs）的全身给药治疗利用了细胞向受损组织归巢的固有能力，但由于对调节迁移和归巢的细胞信号了解有限，这种方法可能效率低下。我们实验室最近发现，一种强效的促炎细胞因子巨噬细胞移动抑制因子（MIF）抑制 MSC 的迁移。由于 MIF 可能作用于多个细胞靶点，因此在这项研究中使用了一种激活抗体（CD74Ab）来研究 MIF 受体 CD74（主要组织相容性复合体 II 相关不变链）对 MSC 迁移的影响。CD74 的激活以剂量依赖性方式抑制高达 40ug/ml CD74Ab 时 MSC 的体外迁移 90%（p<0.001），在三种 MSC 供体制剂中观察到一致的效果。CD74 的 C 末端阻断肽消除了 CD74Ab 对 MSC 的作用。这表明 MIF 可能至少部分通过 CD74 作用于 MSC。晚期传代 MSC 的趋化性比第 2 代 MSC 差。然而，MSC 在体外扩增过程中仍然对 CD74 激活有反应：在第 9 代时，在存在 5ug/ml CD74Ab 的情况下，MSC 迁移被抑制约 2 倍，而在第 2 代时被抑制约 3 倍（p<0.001）。与这一结果一致的是，在所有测试的传代或 CD74Ab 暴露后，CD74 的表达均无显著差异。靶向 CD74 以调节迁移和归巢可能是一种有用的策略，可以提高各种 MSC 疗法的疗效，包括需要体外扩增的疗法。
