The School of Materials Science and Engineering, South China University of Technology, Guangzhou 510641, PR China; National Engineering Research Center for Tissue Restoration and Reconstruction, Guangzhou 510006, PR China; Guangdong Province Key Laboratory of Biomedical Engineering, South China University of Technology, Guangzhou 510006, PR China.
The School of Materials Science and Engineering, South China University of Technology, Guangzhou 510641, PR China; National Engineering Research Center for Tissue Restoration and Reconstruction, Guangzhou 510006, PR China; Guangdong Province Key Laboratory of Biomedical Engineering, South China University of Technology, Guangzhou 510006, PR China.
Biomaterials. 2018 Jul;171:107-117. doi: 10.1016/j.biomaterials.2018.04.035. Epub 2018 Apr 16.
Adipose-derived mesenchymal stem cells (ASCs) represent an excellent candidate for tissue engineering due to their multipotency and paracrine functions. Physical cues provided by the scaffolds have been shown to direct a variety of cellular behaviors of ASCs; however, their effects on the paracrine functions of ASCs, especially immunomodulatory functions, remain largely unexplored. Thus, PLLA electrospun fibrous scaffolds, with fibers oriented either randomly or aligned, were used as a model to investigate the effects of fiber orientation on the immunomodulatory paracrine secretion of ASCs. ASCs cultured on aligned fibers produced significantly higher levels of immunomodulatory factors than those cultured on random fibers. By using the conditioned media from ASCs cultured on aligned fibers, the enhanced immunomodulatory functions of ASCs were confirmed by the M2 phenotypic change seen in macrophages. The enhanced immunomodulation of ASCs correlated with the activation of FAK signaling, as evidenced by a decreased production of immunomodulatory factors in ASCs after treatment with inhibitors of the FAK pathway. In addition, aligned fibers promoted the activation of YAP signaling in ASCs. The inhibited immunomodulatory properties of ASCs by a YAP inhibitor indicated that YAP signaling was also involved in mediating the increased immunomodulatory functions of ASCs on aligned fibers. Our findings identify both FAK and YAP/TAZ signaling as required mechanotransduction pathways through which aligned fibers stimulate the immunomodulatory function of ASCs and highlight fiber orientation as a key design parameter for immunomodulatory fibrous engineered scaffolds.
脂肪间充质干细胞（ASCs）由于其多能性和旁分泌功能，是组织工程的理想候选细胞。支架提供的物理线索已被证明可以指导 ASCs 的多种细胞行为；然而，它们对 ASCs 的旁分泌功能（尤其是免疫调节功能）的影响在很大程度上仍未得到探索。因此，我们使用 PLLA 静电纺丝纤维支架作为模型，研究纤维取向对 ASCs 免疫调节旁分泌分泌的影响，其中纤维分别呈现随机取向或定向排列。与培养在随机纤维上的 ASCs 相比，培养在定向纤维上的 ASCs 产生的免疫调节因子水平显著更高。通过使用培养在定向纤维上的 ASCs 的条件培养基，我们观察到巨噬细胞中 M2 表型的变化，证实了 ASCs 的增强免疫调节功能。ASCs 的增强免疫调节作用与 FAK 信号通路的激活相关，FAK 通路抑制剂处理后 ASCs 中免疫调节因子的产生减少证实了这一点。此外，定向纤维还促进了 ASCs 中 YAP 信号通路的激活。YAP 抑制剂抑制了 ASCs 的免疫调节特性，表明 YAP 信号通路也参与介导 ASCs 在定向纤维上增强的免疫调节功能。我们的研究结果确定了 FAK 和 YAP/TAZ 信号通路都是必需的机械转导通路，通过这些通路，定向纤维刺激 ASCs 的免疫调节功能，并强调纤维取向是免疫调节纤维工程支架的关键设计参数。
