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NSC-derived exosomes enhance therapeutic effects of NSC transplantation on cerebral ischemia in mice.

ABSTRACT: Transplantation of neural stem cells (NSCs) has been proved to promote functional rehabilitation of brain lesions including ischemic stroke. However, the therapeutic effects of NSC transplantation are limited by the low survival and differentiation rates of NSCs due to the harsh environment in the brain after ischemic stroke. Here, we employed NSCs derived from human induced pluripotent stem cells together with exosomes extracted from NSCs to treat cerebral ischemia induced by middle cerebral artery occlusion/reperfusion in mice. The results showed that NSC-derived exosomes significantly reduced the inflammatory response, alleviated oxidative stress after NSC transplantation, and facilitated NSCs differentiation in vivo. The combination of NSCs with exosomes ameliorated the injury of brain tissue including cerebral infarction, neuronal death, and glial scarring, and promoted the recovery of motor function. To explore the underlying mechanisms, we analyzed the miRNA profiles of NSC-derived exosomes and the potential downstream genes. Our study provided the rationale for the clinical application of NSC-derived exosomes as a supportive adjuvant for NSC transplantation after stroke.

SUBMITTER: Zhang R

PROVIDER: S-EPMC10139690 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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NSC-derived exosomes enhance therapeutic effects of NSC transplantation on cerebral ischemia in mice.

Zhang Ruolin R Mao Weibing W Niu Lumeng L Bao Wendai W Wang Yiqi Y Wang Ying Y Zhu Yasha Y Yang Zhihao Z Chen Jincao J Dong Jiawen J Cai Meng M Yuan Zilong Z Song Haikun H Li Guangqiang G Zhang Min M Xiong Nanxiang N Wei Jun J Dong Zhiqiang Z

eLife 20230427

Transplantation of neural stem cells (NSCs) has been proved to promote functional rehabilitation of brain lesions including ischemic stroke. However, the therapeutic effects of NSC transplantation are limited by the low survival and differentiation rates of NSCs due to the harsh environment in the brain after ischemic stroke. Here, we employed NSCs derived from human induced pluripotent stem cells together with exosomes extracted from NSCs to treat cerebral ischemia induced by middle cerebral ar ...[more]

PMID: 37104115

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Project description:Macrophages play a critical role in the development of acute ischemic stroke (AIS). Cerebral ischemia-reperfusion injury (CIRI) is a pivotal pathological process that exacerbates AIS, with exosomes act as crucial mediators. However, the effects and mechanisms of action of macrophage-derived exosomes on CIRI remain unclear. This study demonstrated that macrophage-derived exosomes induce endothelial ferroptosis and barrier disruption during CIRI. Through proteomic sequencing and the reanalysis of transcriptomic and single-cell sequencing data, thrombospondin-1 (THBS1) was identified as a key exosomal molecule. Elevated THBS1 was observed in exosomes and monocytes from the peripheral blood of patients with AIS in oxygen-glucose deprivation/reoxygenation (OGD/R)-stimulated THP-1 and RAW264.7, in their secreted exosomes, and in macrophages within the brains of transient middle cerebral artery occlusion (tMCAO) mice. Additionally, THBS1 expression in exosomes was positively correlated with vascular barrier injury biomarkers, including MMP-9 and S100B. Modulation of THBS1 in macrophage-derived exosomes affected exosome-induced ferroptosis in endothelial cells. The mechanism by which THBS1 binds directly to OTUD5 and promotes GPX4 ubiquitination was elucidated using RNA interference, adeno-associated virus transfection, and endothelial-specific Gpx4 knockout mice. High-throughput screening of small-molecule compounds targeting THBS1 was performed. Molecular docking, molecular dynamics simulations, and cellular thermal shift assays further confirmed that salvianolic acid B (SAB) has a potent binding affinity for THBS1. SAB treatment inhibited the interaction between THBS1 and OTUD5, leading to reduced GPX4 ubiquitination. Further research revealed that SAB treatment enhanced the cerebral protective effects of THBS1 inhibition. In conclusion, this study explored the role of exosome-mediated signaling between macrophages and cerebral vascular endothelial cells in CIRI, highlighting the THBS1-OTUD5-GPX4 axis as a driver of endothelial ferroptosis and brain injury. Targeting this signaling axis represents a potential therapeutic strategy for treating CIRI.

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NSC-derived exosomes enhance therapeutic effects of NSC transplantation on cerebral ischemia in mice.

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NSC-derived exosomes enhance therapeutic effects of NSC transplantation on cerebral ischemia in mice.

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