John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, and NIHR Biomedical Research Centre, University of Cambridge, CB2 0PY Cambridge, UK; Wellcome Trust-Medical Research Council Stem Cell Institute, Cambridge, UK.
Institute for Molecular Bioscience, University of Queensland, St Lucia QLD 4072, Australia.
Mol Cell. 2014 Oct 23;56(2):193-204. doi: 10.1016/j.molcel.2014.08.020. Epub 2014 Sep 18.
The idea that stem cell therapies work only via cell replacement is challenged by the observation of consistent intercellular molecule exchange between the graft and the host. Here we defined a mechanism of cellular signaling by which neural stem/precursor cells (NPCs) communicate with the microenvironment via extracellular vesicles (EVs), and we elucidated its molecular signature and function. We observed cytokine-regulated pathways that sort proteins and mRNAs into EVs. We described induction of interferon gamma (IFN-γ) pathway in NPCs exposed to proinflammatory cytokines that is mirrored in EVs. We showed that IFN-γ bound to EVs through Ifngr1 activates Stat1 in target cells. Finally, we demonstrated that endogenous Stat1 and Ifngr1 in target cells are indispensable to sustain the activation of Stat1 signaling by EV-associated IFN-γ/Ifngr1 complexes. Our study identifies a mechanism of cellular signaling regulated by EV-associated IFN-γ/Ifngr1 complexes, which grafted stem cells may use to communicate with the host immune system.
干细胞疗法仅通过细胞替代起作用的观点受到了挑战，因为人们观察到移植物和宿主之间存在持续的细胞间分子交换。在这里，我们定义了一种通过细胞外囊泡 (EV) 进行神经干细胞/前体细胞 (NPC) 与微环境之间细胞信号传递的机制，并阐明了其分子特征和功能。我们观察到细胞因子调节的途径将蛋白质和 mRNA 分选到 EV 中。我们描述了暴露于促炎细胞因子的 NPC 中干扰素 γ (IFN-γ) 途径的诱导，该途径在 EV 中得到了反映。我们表明，EV 中与 IFN-γ 结合的 Ifngr1 通过激活靶细胞中的 Stat1。最后，我们证明了靶细胞中内源性 Stat1 和 Ifngr1 对于维持 EV 相关 IFN-γ/Ifngr1 复合物对 Stat1 信号的激活是不可或缺的。我们的研究确定了一种由 EV 相关 IFN-γ/Ifngr1 复合物调节的细胞信号传递机制，移植的干细胞可能会利用这种机制与宿主免疫系统进行通信。
