Mesenchymal stromal cells (MSCs) modulate immune cells to ameliorate multiple inflammatory pathologies. Biophysical signals that regulate this process are poorly defined. By engineering hydrogels with tunable biophysical parameters relevant to bone marrow where MSCs naturally reside, we show that soft extracellular matrix maximizes the ability of MSCs to produce paracrine factors that have been implicated in monocyte production and chemotaxis upon inflammatory stimulation by tumor necrosis factor–α (TNFα). Soft matrix increases clustering of TNF receptors, thereby enhancing NF-κB activation and downstream gene expression. Actin polymerization and lipid rafts, but not myosin-II contractility, regulate mechanosensitive activation of MSCs by TNFα. We functionally demonstrate that human MSCs primed with TNFα in soft matrix enhance production of human monocytes in marrow of xenografted mice and increase trafficking of monocytes via CCL2. The results suggest the importance of biophysical signaling in tuning inflammatory activation of stromal cells to control the innate immune system.

间充质基质细胞 (MSC) 调节免疫细胞以改善多种炎症病理。调节这一过程的生物物理信号尚不清楚。通过设计具有与间充质干细胞自然驻留的骨髓相关的可调节生物物理参数的水凝胶，我们发现软细胞外基质最大限度地提高了间充质干细胞产生旁分泌因子的能力，这些旁分泌因子与肿瘤坏死因子-α炎症刺激下的单核细胞生成和趋化性有关。肿瘤坏死因子α）。软基质增加 TNF 受体的聚集，从而增强 NF-κB 激活和下游基因表达。肌动蛋白聚合和脂筏，但不是肌球蛋白-II 收缩性，调节 TNFα 对 MSC 的机械敏感性激活。我们在功能上证明，在软基质中用 TNFα 引发的人 MSC 可以增强异种移植小鼠骨髓中人单核细胞的产生，并增加单核细胞通过 CCL2 的运输。结果表明生物物理信号在调节基质细胞炎症激活以控制先天免疫系统中的重要性。