Extracellular vesicles from neural stem cells transfer the IFN-γ/IFNGR1 complex to activate Stat1-dependent signalling in target cells

Abstract

Advances in stem cell biology have raised great expectations that diseases of the central nervous system may be ameliorated by the development of nonhaematopoietic stem cell medicines. Yet, the application of stem cells as therapeutics is challenging and the interpretation of some of the outcomes ambiguous. The initial idea that stem cell transplants work only via structural cell replacement has been challenged by the observation of consistent intercellular information exchange between the graft and the host. Here, we focused on defining whether the form of cellular signalling mediated by extracellular membrane vesicles (EVs) exists for neural stem/precursor cells (NPCs), and on its molecular signature and functional relevance on target cells. We also investigated whether the EV cargo molecules are modulated by extracellular pro- or anti-inflammatory cytokines, and determined the key elements responsible for this novel mechanism of EV-mediated intercellular communication. We show that NPC EVs primarily consist of exosomes and observe novel cytokine-regulated pathways that sort specific proteins and mRNAs into EVs. We describe a highly specific induction of IFN-gamma pathways in parental NPCs exposed to Th1 pro-inflammatory cytokines that is mirrored in EVs and exosomes. We finally demonstrate the activation of Stat1-dependent signalling in target cells through intercellular transfer of IFN-gamma bound to IFNGR1-enriched EVs. While confirming the intrinsic signalling properties of EVs, our study identifies a novel mechanism of intercellular communication regulated by IFN-gamma/IFNGR1 complex, which stem cell grafts may use to signal to the host immune system.