Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA, USA; Petit Institute for Bioengineering and Biosciences, Georgia Institute of Technology, Atlanta, GA, USA.
Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
Biomaterials. 2019 Nov;220:119403. doi: 10.1016/j.biomaterials.2019.119403. Epub 2019 Aug 2.
Because of their immunomodulatory activities, human mesenchymal stem cells (hMSCs) are being explored to treat a variety of chronic conditions such as inflammatory bowel disorders and graft-vs-host disease. Treating hMSCs with IFN-γ prior to administration augments these immunomodulatory properties; however, this ex vivo treatment limits the broad applicability of this therapy due to technical and regulatory issues. In this study, we engineered an injectable synthetic hydrogel with tethered recombinant IFN-γ that activates encapsulated hMSCs to increase their immunomodulatory functions and avoids the need for ex vivo manipulation. Tethering IFN-γ to the hydrogel increases retention of IFN-γ within the biomaterial while preserving its biological activity. hMSCs encapsulated within hydrogels with tethered IFN-γ exhibited significant differences in cytokine secretion and showed a potent ability to halt activated T-cell proliferation and monocyte-derived dendritic cell differentiation compared to hMSCs that were pre-treated with IFN-γ and untreated hMSCs. Importantly, hMSCs encapsulated within hydrogels with tethered IFN-γ accelerated healing of colonic mucosal wounds in both immunocompromised and immunocompetent mice. This novel approach for licensing hMSCs with IFN-γ may enhance the clinical translation and efficacy of hMSC-based therapies.
由于其免疫调节活性，人类间充质干细胞（hMSCs）正在被探索用于治疗多种慢性疾病，如炎症性肠病和移植物抗宿主病。在给予 hMSCs 之前用 IFN-γ 处理可增强这些免疫调节特性；然而，这种体外处理由于技术和监管问题限制了这种治疗的广泛适用性。在这项研究中，我们设计了一种带有固定化重组 IFN-γ 的可注射合成水凝胶，该水凝胶可激活封装的 hMSCs 以增加其免疫调节功能，同时避免体外操作的需要。将 IFN-γ 固定在水凝胶上可以增加生物材料内 IFN-γ 的保留，同时保持其生物活性。与用 IFN-γ 预处理和未处理的 hMSCs 相比，封装在带有固定化 IFN-γ 的水凝胶中的 hMSCs 在细胞因子分泌方面表现出显著差异，并显示出有效阻止活化 T 细胞增殖和单核细胞衍生树突状细胞分化的能力。重要的是，封装在带有固定化 IFN-γ 的水凝胶中的 hMSCs 可加速免疫功能低下和免疫功能正常的小鼠结肠黏膜创伤的愈合。这种用 IFN-γ 许可 hMSCs 的新方法可能会增强基于 hMSC 的治疗的临床转化和疗效。
