Swartzlander Mark D, Blakney Anna K, Amer Luke D, Hankenson Kurt D, Kyriakides Themis R, Bryant Stephanie J
Department of Chemical & Biological Engineering, University of Colorado, Boulder, CO 80309, USA; Biofrontiers Institute, University of Colorado, Boulder, CO 80309, USA.
Department of Chemical & Biological Engineering, University of Colorado, Boulder, CO 80309, USA.
Biomaterials. 2015 Feb;41:79-88. doi: 10.1016/j.biomaterials.2014.11.020. Epub 2014 Dec 5.
The implantation of non-biological materials, including scaffolds for tissue engineering, ubiquitously leads to a foreign body response (FBR). We recently reported that this response negatively impacts fibroblasts encapsulated within a synthetic hydrogel and in turn leads to a more severe FBR, suggesting a cross-talk between encapsulated cells and inflammatory cells. Given the promise of mesenchymal stem cells (MSCs) in tissue engineering and recent evidence of their immunomodulatory properties, we hypothesized that MSCs encapsulated within poly(ethylene glycol) (PEG) hydrogels will attenuate the FBR. In vitro, murine MSCs encapsulated within PEG hydrogels attenuated classically activated primary murine macrophages by reducing gene expression and protein secretion of pro-inflammatory cytokines, most notably tumor necrosis factor-α. Using a COX2 inhibitor, prostaglandin E2 (PGE2) was identified as a mediator of MSC immunomodulation of macrophages. In vivo, hydrogels laden with MSCs, osteogenically differentiating MSCs, or no cells were implanted subcutaneously into C57BL/6 mice for 28 days to assess the impact of MSCs on the fibrotic response of the FBR. The presence of encapsulated MSCs reduced fibrous capsule thickness compared to acellular hydrogels, but this effect diminished with osteogenic differentiation. The use of MSCs prior to differentiation in tissue engineering may therefore serve as a dynamic approach, through continuous cross-talk between MSCs and the inflammatory cells, to modulate macrophage activation and attenuate the FBR to implanted synthetic scaffolds thus improving the long-term tissue engineering outcome.
植入非生物材料，包括用于组织工程的支架，普遍会引发异物反应（FBR）。我们最近报道，这种反应会对包裹在合成水凝胶中的成纤维细胞产生负面影响，进而导致更严重的FBR，这表明包裹的细胞与炎症细胞之间存在相互作用。鉴于间充质干细胞（MSC）在组织工程中的前景以及它们免疫调节特性的最新证据，我们推测包裹在聚乙二醇（PEG）水凝胶中的MSC将减轻FBR。在体外，包裹在PEG水凝胶中的小鼠MSC通过降低促炎细胞因子（最显著的是肿瘤坏死因子-α）的基因表达和蛋白质分泌，减弱了经典活化的原代小鼠巨噬细胞的活性。使用COX2抑制剂，前列腺素E2（PGE2）被确定为MSC对巨噬细胞进行免疫调节的介质。在体内，将负载有MSC、成骨分化的MSC或无细胞的水凝胶皮下植入C57BL/6小鼠体内28天，以评估MSC对FBR纤维化反应的影响。与无细胞水凝胶相比，包裹的MSC的存在降低了纤维囊的厚度，但这种效果随着成骨分化而减弱。因此，在组织工程中分化前使用MSC可能是一种动态方法，通过MSC与炎症细胞之间的持续相互作用，调节巨噬细胞活化并减轻对植入合成支架的FBR，从而改善长期组织工程结果。
