Extracellular vesicles from neural stem cells safeguard neurons in intracerebral hemorrhage by suppressing reactive astrocyte neurotoxicity

Tianwen Li; Liansheng Zhang; Peng Wang; Jingyu Yu; Junjie Zhong; Qisheng Tang; Tongming Zhu; Kezhu Chen; Fengshi Li; Pengjie Hong; Jiachen Wei; Xicai Sun; Guangchao Ji; Bin Song; Jianhong Zhu

doi:10.1016/j.celrep.2024.114854

Extracellular vesicles from neural stem cells safeguard neurons in intracerebral hemorrhage by suppressing reactive astrocyte neurotoxicity

Cell Rep. 2024 Oct 11;43(10):114854. doi: 10.1016/j.celrep.2024.114854. Online ahead of print.

Authors

Tianwen Li¹, Liansheng Zhang², Peng Wang¹, Jingyu Yu¹, Junjie Zhong¹, Qisheng Tang¹, Tongming Zhu¹, Kezhu Chen¹, Fengshi Li¹, Pengjie Hong¹, Jiachen Wei², Xicai Sun³, Guangchao Ji³, Bin Song⁴, Jianhong Zhu⁵

Affiliations

¹ Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, National Center for Neurological Disorders, National Clinical Center for Geriatric Disorders, National Key Laboratory for Medical Neurobiology, Institutes of Brain Science, Shanghai Key Laboratory of Brain Function and Regeneration, Institute of Neurosurgery, MOE Frontiers Center for Brain Science, Fudan University, Shanghai 200041, China.
² Institute of Neuroscience, State Key Laboratory of Neuroscience, Key Laboratory of Primate Neurobiology, Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai 200031, China.
³ Shanghai Angecon Biotechnology Co., Ltd, Shanghai 201318, China.
⁴ Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. Electronic address: bsong@mgh.harvard.edu.
⁵ Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, National Center for Neurological Disorders, National Clinical Center for Geriatric Disorders, National Key Laboratory for Medical Neurobiology, Institutes of Brain Science, Shanghai Key Laboratory of Brain Function and Regeneration, Institute of Neurosurgery, MOE Frontiers Center for Brain Science, Fudan University, Shanghai 200041, China. Electronic address: jzhu@fudan.edu.cn.

PMID: 39395173
DOI: 10.1016/j.celrep.2024.114854

Abstract

Extracellular vesicles (EVs) derived from stem cells have shown therapeutic potential in various diseases, but their use in treating neurological disorders remains limited. In this study, we observed neurotoxic activation of reactive astrocytes and lipoapoptosis pathways in both mice and patients with intracerebral hemorrhage (ICH) and found that EVs derived from neural stem cells (EVs-NSC) could suppress this activation. Using loss- and gain-of-function approaches, we identified interferon-β (IFNβ) as a key regulator in neurotoxic activation of astrocytes. In addition, we demonstrated that the microRNA (miRNA) miR-124-3p within EVs-NSC degrades IFNβ mRNA and inhibits ELOVL1 expression via miRNA-coding sequence (CDS) and miRNA-3' UTR binding mechanisms, respectively. This dual action likely reduces astrocyte neurotoxicity by lowering saturated lipid secretion. These mechanisms enable EVs-NSC or miR-124-3p overexpression to inhibit astrocyte neurotoxicity, reduce neural damage, and promote recovery in ICH models, offering strategies for treating neurological disorders by targeting neurotoxic reactive astrocytes.

Keywords: CP: Neuroscience.