Exosomes derived from human neural stem cells stimulated by interferon gamma improve therapeutic ability in ischemic stroke model

Guilong Zhang; Zhihan Zhu; Hong Wang; Yongbo Yu; Wanghao Chen; Ahmed Waqas; Yezhong Wang; Lukui Chen

doi:10.1016/j.jare.2020.05.017

Exosomes derived from human neural stem cells stimulated by interferon gamma improve therapeutic ability in ischemic stroke model

J Adv Res. 2020 May 25:24:435-445. doi: 10.1016/j.jare.2020.05.017. eCollection 2020 Jul.

Authors

Guilong Zhang¹, Zhihan Zhu², Hong Wang², Yongbo Yu², Wanghao Chen², Ahmed Waqas², Yezhong Wang¹, Lukui Chen³

Affiliations

¹ Department of Neurosurgery, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, China.
² School of Medicine, Southeast University, Nanjing 210009, China.
³ Department of Neurosurgery, Neuroscience Center, Cancer Center, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510310, China.

Abstract

Transplanted neural stem cells promote neural tissue regeneration and functional recovery primarily by releasing paracrine factors. Exosomes act as important secreted paracrine molecules to deliver therapeutic agents involved in cellular functions. Here, we focused on the role of exosomes (hNSC-Exo) derived from human neural stem cells (hNSCs). We utilized the pro-inflammatory factor interferon gamma (IFN-γ) to induce the generation of altered exosomes (IFN-γ-hNSC-Exo), and compared their roles with those of hNSC-Exo and explored the potential mechanism. Importantly, IFN-γ preconditioning did not affect the secretion, but significantly altered the ability of exosomes derived from hNSCs. Moreover, IFN-γ-hNSC-Exo was functionally superior to hNSC-Exo; showed increased cell proliferation and cell survival and decreased cell apoptosis in vitro. Furthermore, IFN-γ-hNSC-Exo further exerted therapeutic effects (showed better behavioral and structural outcomes) compared to those of hNSCs-Exo in an ischemic stroke rat model. Next-generation sequencing (NGS) revealed specific exosomal miRNAs (hsa-miR-206, hsa-miR-133a-3p and hsa-miR-3656) in IFN-γ-hNSC-Exo with important roles in cell survival. Thus, our findings demonstrate that the inflammatory factor IFN-γ can regulate the functions of exosomes and highlight its role in regulating the application of neural stem cell-derived exosomes.

Keywords: Exosomes; Interferon gamma; Ischemic stroke; MicroRNA; Neural stem cells.