Mesenchymal stromal cells (MSCs) are widely used in clinical trials because of their ability to modulate inflammation. The success of MSCs has been variable over 25 years, most likely due to an incomplete understanding of their mechanism. After MSCs are injected, they traffic to the lungs and other tissues where they are rapidly cleared. Despite being cleared, MSCs suppress the inflammatory response in the long term. Using human cord tissue‐derived MSCs (hCT‐MSCs), we demonstrated that hCT‐MSCs directly interact and reprogram monocytes and macrophages. After engaging hCT‐MSCs, monocytes and macrophages engulfed cytoplasmic components of live hCT‐MSCs, then downregulated gene programs for antigen presentation and costimulation, and functionally suppressed the activation of helper T cells. We determined that low‐density lipoprotein receptor‐related proteins on monocytes and macrophages mediated the engulfment of hCT‐MSCs. Since a large amount of cellular information can be packaged in cytoplasmic RNA processing bodies (p‐bodies), we generated p‐body deficient hCT‐MSCs and confirmed that they failed to reprogram monocytes and macrophages in vitro and in vivo. hCT‐MSCs suppressed an inflammatory response caused by a nasal lipopolysaccharide challenge. Although both control and p‐body deficient hCT‐MSCs were engulfed by infiltrating lung monocytes and macrophages, p‐body deficient hCT‐MSCs failed to suppress inflammation and downregulate MHC‐II. Overall, we identified a novel mechanism by which hCT‐MSCs indirectly suppressed a T‐cell response by directly interacting and reprogramming monocytes and macrophages via p‐bodies. The results of this study suggest a novel mechanism for how MSCs can reprogram the inflammatory response and have long‐term effects to suppress inflammation.

中文翻译：

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间充质基质细胞用加工体重新编程单核细胞和巨噬细胞

间充质基质细胞 (MSC) 因其调节炎症的能力而被广泛用于临床试验。MSCs 的成功在 25 年间一直变化无常，很可能是由于对其机制的不完全了解。注射 MSC 后，它们会进入肺部和其他组织，在那里它们会被迅速清除。尽管被清除，MSCs 仍能长期抑制炎症反应。使用人脐带组织来源的 MSCs (hCT-MSCs)，我们证明了 hCT-MSCs 直接相互作用并重编程单核细胞和巨噬细胞。在与 hCT-MSCs 结合后，单核细胞和巨噬细胞吞噬了活 hCT-MSCs 的细胞质成分，然后下调了抗原呈递和共刺激的基因程序，并在功能上抑制了辅助 T 细胞的激活。我们确定单核细胞和巨噬细胞上的低密度脂蛋白受体相关蛋白介导了 hCT-MSCs 的吞噬。由于大量细胞信息可以封装在细胞质 RNA 加工体（p-bodies）中，我们生成了 p-body 缺陷的 hCT-MSCs，并证实它们无法在体外和体内重编程单核细胞和巨噬细胞。hCT-MSCs 抑制了鼻脂多糖激发引起的炎症反应。尽管对照和 p-body 缺陷 hCT-MSCs 都被肺单核细胞和巨噬细胞吞噬，但 p-body 缺陷 hCT-MSCs 未能抑制炎症和下调 MHC-II。总体而言，我们确定了一种新机制，通过该机制，hCT-MSCs 通过 p 体直接相互作用和重编程单核细胞和巨噬细胞，从而间接抑制 T 细胞反应。