Wnt signaling modulates macrophage polarization and is regulated by biomaterial surface properties
Wnt signaling modulates macrophage polarization and is regulated by biomaterial surface properties
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DOI：
10.1016/j.biomaterials.2020.119920
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发表时间：
2020-06-01
期刊：
影响因子：
14
通讯作者：
Olivares-Navarrete, Rene
中科院分区：
文献类型：
--
作者：
Abaricia, Jefferson O.;Shah, Arth H.;Olivares-Navarrete, Rene
巨噬细胞是最早与生物材料相互作用的细胞之一，并最终决定了它们的整合命运。生物材料的表面特性，如粗糙度和亲水性，可以激活巨噬细胞以抗炎表型。WNT信号是细胞增殖和分化的关键途径，与疾病中巨噬细胞活性失调有关。然而，Wnt信号在巨噬细胞激活和对生物材料的反应中所起的作用尚不清楚。本研究的目的是研究在经典的促炎和抗炎极化过程中巨噬细胞中Wnt信号的调节，以及巨噬细胞对光滑、粗糙和粗糙亲水性钛表面的反应。与未经治疗的对照组相比，髓内钛棒内固定的巨噬细胞消融(MAFIA)小鼠的种植体周围Wnt信号显著减弱。在C57B1/6小鼠体内，从钛表面分离的巨噬细胞中，WNT配体mRNA以表面修饰依赖的方式上调。在体外，原代培养的小鼠骨髓巨噬细胞以表面修饰依赖的方式调节Wnt mRNAs。当巨噬细胞分泌Wnt被抑制时，巨噬细胞对物理和生物刺激的敏感性都被消除。体内巨噬细胞来源的WNTs的丢失也损害了骨髓间充质干细胞和T细胞在钛种植体上的募集。最后，抑制整合素信号减少了WRIT基因表面依赖的上调。这些结果表明，Wnt信号调节巨噬细胞对生物材料的反应，巨噬细胞是炎症和愈合过程中Wnt配体的重要来源。
Macrophages are among the first cells to interact with biomaterials and ultimately determine their integrative fate. Biomaterial surface characteristics like roughness and hydrophilicity can activate macrophages to an anti-inflammatory phenotype. Wnt signaling, a key cell proliferation and differentiation pathway, has been associated with dysregulated macrophage activity in disease. However, the role Wnt signaling plays in macrophage activation and response to biomaterials is unknown. The aim of this study was to characterize the regulation of Wnt signaling in macrophages during classical pro- and anti-inflammatory polarization and in their response to smooth, rough, and rough-hydrophilic titanium (Ti) surfaces. Peri-implant Wnt signaling in macrophage-ablated (MaFIA) mice instrumented with intramedullary Ti rods was significantly attenuated compared to untreated controls. Wnt ligand mRNA were upregulated in a surface modification-dependent manner in macrophages isolated from the surface of Ti implanted in C57B1/6 mice. In vitro, Wnt mRNAs were regulated in primary murine bone-marrow-derived macrophages cultured on Ti in a surface modification-dependent manner. When macrophageal Wnt secretion was inhibited, macrophage sensitivity to both physical and biological stimuli was abrogated. Loss of macrophage-derived Wnts also impaired recruitment of mesenchymal stem cells and T-cells to Ti implants in vivo. Finally, inhibition of integrin signaling decreased surface-dependent upregulation of Writ genes. These results suggest that Wnt signaling regulates macrophage response to biomaterials and that macrophages are an important source of Wnt ligands during inflammation and healing.