FAK- and YAP/TAZ dependent mechanotransduction pathways are required for enhanced immunomodulatory properties of adipose-derived mesenchymal stem cells induced by aligned fibrous scaffolds.

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.