Substrate stiffness modulates bone marrow-derived macrophage polarization through NF-κB signaling pathway
Substrate stiffness modulates bone marrow-derived macrophage polarization through NF-κB signaling pathway
复制标题
基质硬度通过 NF-κB 信号通路调节骨髓源性巨噬细胞极化
DOI：
10.1016/j.bioactmat.2020.05.004
复制
发表时间：
2020-12-01
影响因子：
18.9
通讯作者：
Shi, Qin
中科院分区：
文献类型：
--
作者：
Chen, Mimi;Zhang, Yu;Shi, Qin
细胞外基质（extracellular matrix，ECM）的硬度在调节细胞程序化中起着重要作用。然而，ECM影响细胞分化的力学特性仍在研究中。本文旨在研究ECM底物硬度对巨噬细胞极化的影响。分别制备了不同基质刚度的聚丙烯酰胺水凝胶。在证实水凝胶具有良好的生物相容性后，将来自小鼠的骨髓源性巨噬细胞（BMSCs）在水凝胶上孵育。在低底物硬度的刺激下，Bcells细胞表面CD 86的表达和细胞内活性氧（ROS）的产生增加，并在上清液中分泌更多的IL-1 β和TNF-α。相反，在中等硬度的胁迫下，BMPs表达更多的CD 206，产生更少的ROS，并分泌更多的IL-4和TGF-β。在小鼠皮下注射的研究中，低硬度水凝胶周围的CD 68（+）CD 86（+）细胞较多，中硬度水凝胶周围的CD 68（+）CD 206（+）细胞较多。此外，低硬度刺激后，BcV 6细胞NIK、磷酸化p65（pi-p65）和磷酸化I κ B（pi-I κ B）的表达明显增加。综上所述，这些发现表明基质硬度可能影响巨噬细胞极化。低底物硬度通过调节ROS启动的NF-κ B B通路，促进BclA向经典活化的巨噬细胞（M1）和中间活化的巨噬细胞（M2）转化。因此，我们预计，如有必要，将在临床应用中考虑基于ECM的基质刚度和免疫调节。
The stiffness of the extracellular matrix (ECM) plays an important role in regulating the cellular programming. However, the mechanical characteristics of ECM affecting cell differentiation are still under investigated. Herein, we aimed to study the effect of ECM substrate stiffness on macrophage polarization. We prepared polyacrylamide hydrogels with different substrate stiffness, respectively. After the hydrogels were confirmed to have a good biocompatibility, the bone marrow-derived macrophages (BMMs) from mice were incubated on the hydrogels. With simulated by the low substrate stiffness, BMMs displayed an enhanced expression of CD86 on the cell surface and production of reactive oxygen species (ROS) in cells, and secreted more IL-1 beta and TNF-alpha in the supernatant. On the contrary, stressed by the medium stiffness, BMMs expressed more CD206, produced less ROS, and secreted more IL-4 and TGF-beta. In vivo study by delivered the hydrogels subcutaneously in mice, more CD68(+)CD86(+) cells around the hydrogels with the low substrate stiffness were observed while more CD68(+)CD206(+) cells near by the middle stiffness hydrogels. In addition, the expressions of NIK, phosphorylated p65 (pi-p65) and phosphorylated I kappa B (pi-I kappa B) were significantly increased after stimulation with low stiffness in BMMs. Taken together, these findings demonstrated that substrate stiffness could affect macrophages polarization. Low substrate stiffness promoted BMMs to shift to classically activated macrophages (M1) and the middle one to alternatively activated macrophages (M2), through modulating ROS-initiated NF-kappa B pathway. Therefore, we anticipated ECM-based substrate stiffness with immune modulation would be under consideration in the clinical applications if necessary.