Infarct-preconditioning exosomes of umbilical cord mesenchymal stem cells promoted vascular remodeling and neurological recovery after stroke in rats

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Abstract

Background

Stroke is the leading cause of disability worldwide, resulting in severe damage to the central nervous system and disrupting neurological functions. There is no effective therapy for promoting neurological recovery. Growing evidence suggests that the composition of exosomes from different microenvironments may benefit stroke. Therefore, it is reasonable to assume that exosomes secreted in response to infarction microenvironment could have further therapeutic effects.

Methods

In our study, cerebral infarct tissue extracts were used to pretreat umbilical cord mesenchymal stem cells (UCMSC). Infarct-preconditioned exosomes were injected into rats via tail vein after middle cerebral artery occlusion (MCAO). The effect of infarct-preconditioned exosomes on the neurological recovery of rats was examined using Tunel assay, 2,3,5-triphenyltetrazolium chloride (TTC) assay, magnetic resonance imaging (MRI) analyses, modified Neurological Severity Score (mNSS), Morris water maze (MWM), and vascular remodeling analysis. Mi-RNA sequencing and functional enrichment analysis were used to validate the signal pathway involved in the effect of infarct-preconditioned exosomes. Human umbilical vein endothelial cells (HUVECs) were co-cultured with the isolated exosomes. Cell Counting Kit-8 (CCK-8) assay, scratch healing, and Western blot analysis were used to detect the biological behavior of HUVECs.

Results

The results showed that compared with normal exosomes, infarct-preconditioned exosomes further promoted vascular remodeling and recovery of neurological function after stroke. The function of upregulated miRNAs and their target genes which is beneficial to vascular smooth muscle cells verified the importance of vascular remodeling in improving stroke. Better resistance to oxygen–glucose deprivation/reoxygenation (OGD/R), reduced apoptosis, and enhanced migration were observed in infarct-preconditioned exosomes-treated umbilical vein endothelial cells.

Conclusions

Our results demonstrated that infarct-preconditioned exosomes promoted neurological recovery after stroke by enhancing vascular endothelial remodeling, suggested that infarct-preconditioned exosomes could be a novel way to alleviate brain damage following a stroke.

Supplementary Information

The online version contains supplementary material available at 10.1186/s13287-022-03083-9.

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Most cited references 47

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Exosome secreted by MSC reduces myocardial ischemia/reperfusion injury.

Ruenn Chai Lai, Fatih Arslan, May Lee … (2010)

Human ESC-derived mesenchymal stem cell (MSC)-conditioned medium (CM) was previously shown to mediate cardioprotection during myocardial ischemia/reperfusion injury through large complexes of 50-100 nm. Here we show that these MSCs secreted 50- to 100-nm particles. These particles could be visualized by electron microscopy and were shown to be phospholipid vesicles consisting of cholesterol, sphingomyelin, and phosphatidylcholine. They contained coimmunoprecipitating exosome-associated proteins, e.g., CD81, CD9, and Alix. These particles were purified as a homogeneous population of particles with a hydrodynamic radius of 55-65 nm by size-exclusion fractionation on a HPLC. Together these observations indicated that these particles are exosomes. These purified exosomes reduced infarct size in a mouse model of myocardial ischemia/reperfusion injury. Therefore, MSC mediated its cardioprotective paracrine effect by secreting exosomes. This novel role of exosomes highlights a new perspective into intercellular mediation of tissue injury and repair, and engenders novel approaches to the development of biologics for tissue repair. Copyright 2009 Elsevier B.V. All rights reserved.

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Neuroprotection in acute stroke: targeting excitotoxicity, oxidative and nitrosative stress, and inflammation.

Angel Chamorro, Ulrich Dirnagl, Xabier Urra … (2016)

Treatments for acute ischaemic stroke continue to evolve after the superior value of endovascular thrombectomy was confirmed over systemic thrombolysis. Unfortunately, numerous neuroprotective drugs have failed to show benefit in the treatment of acute ischaemic stroke, making the search for new treatments imperative. Increased awareness of the relevance of rigorous preclinical testing, and appropriate selection of study participants, might overcome the barriers to progress in stroke research. Relevant areas of interest include the search for safe and effective treatment strategies that combine neuroprotection reperfusion, better use of advanced brain imaging for patient selection, and wider implementation of prehospital conducted clinical trials. Randomised controlled trials of combination treatments completed within the past 5 years have included growth factors, hypothermia, minocycline, natalizumab, fingolimod, and uric acid; the latter two drugs with alteplase produced encouraging results. Blocking of excitotoxicity is also being reassessed in clinical trials with new approaches, such as the postsynaptic density-95 inhibitor NA-1, or peritoneal dialysis to remove excess glutamate. The findings of these randomised trials are anticipated to improve treatment options and clinical outcomes in of patients with acute stroke.

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Mesenchymal stem cell exosomes.

Ruenn Chai Lai, Ronne Yeo, Sai Lim (2015)

MSCs are an extensively used cell type in clinical trials today. The initial rationale for their clinical testing was based on their differentiation potential. However, the lack of correlation between functional improvement and cell engraftment or differentiation at the site of injury has led to the proposal that MSCs exert their effects not through their differentiation potential but through their secreted product, more specifically, exosomes, a type of extracellular vesicle. We propose here that MSC exosomes function as an extension of MSC's biological role as tissue stromal support cells. Like their cell source, MSC exosomes help maintain tissue homeostasis for optimal tissue function. They target housekeeping biological processes that operate ubiquitously in all tissues and are critical in maintaining tissue homeostasis, enabling cells to recover critical cellular functions and begin repair and regeneration. This hypothesis provides a rationale for the therapeutic efficacy of MSCs and their secreted exosomes in a wide spectrum of diseases. Here, we give a brief introduction of the biogenesis of MSC exosomes, review their physiological functions and highlight some of their biochemical potential to illustrate how MSC exosomes could restore tissue homeostasis leading to tissue recovery and repair.

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Author and article information

Contributors

Yi Wang: wangyils2005@126.com

Xiao-Hong Li:

ORCID: http://orcid.org/0000-0002-5342-5358

xhli18@tju.edu.cn

Journal

Journal ID (nlm-ta): Stem Cell Res Ther

Journal ID (iso-abbrev): Stem Cell Res Ther

Title: Stem Cell Research & Therapy

Publisher: BioMed Central (London )

ISSN (Electronic): 1757-6512

Publication date (Electronic): 28 July 2022

Publication date PMC-release: 28 July 2022

Publication date Collection: 2022

Volume: 13

Electronic Location Identifier: 378

Affiliations

[1 ]GRID grid.33763.32, ISNI 0000 0004 1761 2484, Academy of Medical Engineering and Translational Medicine, , Tianjin University, ; Tianjin, 300072 China

[2 ]Tianjin Key Laboratory of Neurotrauma Repair, Characteristic Medical Center of People’s Armed Police Forces, Tianjin, 300162 China

[3 ]GRID grid.33763.32, ISNI 0000 0004 1761 2484, Health Management Department, Tianjin Hospital, , Tianjin University, ; Tianjin, 300299 China

[4 ]GRID grid.33763.32, ISNI 0000 0004 1761 2484, Neurology Department, Tianjin Hospital, , Tianjin University, ; Tianjin, 300299 China

Author information

Xiao-Hong Li http://orcid.org/0000-0002-5342-5358

Article

Publisher ID: 3083

DOI: 10.1186/s13287-022-03083-9

PMC ID: 9330700

PubMed ID: 35902882

SO-VID: c4224374-4b63-4f28-9e44-f715ecd8d07c

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 13 April 2022

Date accepted : 21 July 2022

Funding

Funded by: National Key Research and Development Plan of China

Award ID: 2021YFF1200800

Award Recipient : Xiao-Hong Li

Funded by: National Nature Scientific Fund of China

Award ID: 82171861

Award ID: 81971782

Award ID: 82101448

Award Recipient : Xiao-Hong Li

Funded by: Nature Scientific Fund of Tianjin

Award ID: 18JCJQJC48500

Award ID: 19JCYBJC27900

Award Recipient : Xiao-Hong Li

Custom metadata

ScienceOpen disciplines: Molecular medicine

Keywords: preconditioning,brain extract,exosomes,stroke,umbilical cord mesenchymal stem cells,vascular remodeling

Data availability:

ScienceOpen disciplines: Molecular medicine

Keywords: preconditioning, brain extract, exosomes, stroke, umbilical cord mesenchymal stem cells, vascular remodeling

Infarct-preconditioning exosomes of umbilical cord mesenchymal stem cells promoted vascular remodeling and neurological recovery after stroke in rats

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Abstract

Background

Methods

Results

Conclusions

Supplementary Information

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Stroke MRI

Most cited references 47

Exosome secreted by MSC reduces myocardial ischemia/reperfusion injury.

Neuroprotection in acute stroke: targeting excitotoxicity, oxidative and nitrosative stress, and inflammation.

Mesenchymal stem cell exosomes.

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