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Oxygen–Glucose Deprived Peripheral Blood Mononuclear Cells Protect Against Ischemic Stroke

  • Original Article
  • Published:
Neurotherapeutics

Abstract

Stroke is the leading cause of severe long-term disability. Cell therapy has recently emerged as an approach to facilitate functional recovery in stroke. Although administration of peripheral blood mononuclear cells preconditioned by oxygen–glucose deprivation (OGD-PBMCs) has been shown to be a therapeutic strategy for ischemic stroke, the recovery mechanisms remain largely unknown. We hypothesised that cell–cell communications within PBMCs and between PBMCs and resident cells are necessary for a polarising protective phenotype. Here, we investigated the therapeutic mechanisms underlying the effects of OGD-PBMCs through the secretome. We compared levels of transcriptomes, cytokines, and exosomal microRNA in human PBMCs by RNA sequences, Luminex assay, flow cytometric analysis, and western blotting under normoxic and OGD conditions. We also performed microscopic analyses to assess the identification of remodelling factor-positive cells and evaluate angiogenesis, axonal outgrowth, and functional recovery by blinded examination by administration of OGD-PBMCs after ischemic stroke in Sprague–Dawley rats. We found that the therapeutic potential of OGD-PBMCs was mediated by a polarised protective state through decreased levels of exosomal miR-155-5p, and upregulation of vascular endothelial growth factor and a pluripotent stem cell marker stage-specific embryonic antigen-3 through the hypoxia-inducible factor-1α axis. After administration of OGD-PBMCs, microenvironment changes in resident microglia by the secretome promoted angiogenesis and axonal outgrowth, resulting in functional recovery after cerebral ischemia. Our findings revealed the mechanisms underlying the refinement of the neurovascular unit by secretome-mediated cell–cell communications through reduction of miR-155-5p from OGD-PBMCs, highlighting the therapeutic potential carrier of this approach against ischemic stroke.

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Availability of Data and Materials

All miRNA microarray data were deposited in the Gene Expression Omnibus (GEO) (https://www.ncbi.nlm.nih.gov/geo/) database (accession number: miRNA data, GSE190407). All other relevant data and materials are available within the article file or Supplementary Information or are available from the authors on reasonable request.

Abbreviations

ANOVA:

Analysis of variance

CD:

Cluster of differentiation

CNS:

Central nervous system

DAPI:

4′,6′-Diamidino-2-phenylindole

GAP43:

Growth associated protein 43

GO:

Gene ontology

HIF-1α:

Hypoxia-inducible factor-1alpha

IL:

Interleukin

KEGG:

Kyoto Encyclopaedia of Genes and Genomes

MAP2:

Microtubule-associated protein 2

miRNA:

MicroRNA

NF-kB:

Nuclear factor-kappa B

OGD:

Oxygen–glucose deprivation

OGD-PBMC:

Peripheral blood mononuclear cell preconditioned by oxygen–glucose deprivation

PBMC:

Peripheral blood mononuclear cell

pNF-kB:

Phospho-NF-kB

RNAseq:

RNA sequencing

ROI:

Regions of interest

rRNA:

Ribosomal RNA

PPARγ:

Proliferator-activated receptor gamma

SD:

Standard deviation

SSEA-3:

Stage-specific embryonic antigen 3

TGF-β:

Transforming growth factor-beta

TNF-α:

Tumour necrosis factor-alpha

TMEM119:

Transmembrane protein 119

VEGF:

Vascular endothelial growth factor

vWF:

Von Willebrand factor

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Funding

This work was supported by a Grant-in-Aid for Scientific Research (Research Project Number: 18K07493, 21K19441, 22H03183), the Translational Research program, Strategic Promotion for practical application of Innovative Medical Technology (TR-SPRINT) supported by the Japan Agency for Medical Research and Development (AMED) under Grant Number JP19lm0203023, a grant from Takeda Science Foundation and SENSHIN Medical Research Foundation, and Moriyama Award of Japan Brain Foundation (Dr. Kanazawa). This work was also supported by a Grant-in-Aid for Scientific Research (Research Project Number: 20K16485) (Dr. Hatakeyama) and a grant from the Tsubaki Memorial Foundation (Dr. Otsu).

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Author notes

  1. Yutaka Otsu and Masahiro Hatakeyama have equally contributed to this work.

Authors and Affiliations

  1. Department of Neurology, Brain Research Institute, Niigata University, 1-757 Asahimachi-Dori, Chuoku, Niigata, 951-8585, Japan

    Yutaka Otsu, Masahiro Hatakeyama, Takeshi Kanayama, Natsuki Akiyama, Itaru Ninomiya, Osamu Onodera & Masato Kanazawa

  2. Translational Research Center for Medical Innovation, Foundation for Biomedical Research and Innovation at Kobe, 1-5-4 Minatojima-Minamimachi, Kobe, 650-0047, Japan

    Kaoru Omae

  3. Department of System Pathology for Neurological Disorders, Brain Science Branch, Brain Research Institute, Niigata University, 1-757 Asahimachi-Dori, Chuoku, Niigata, 951-8585, Japan

    Taisuke Kato

  4. Foundation of Learning Health Society Institute, 8F, Nagoya Mitsui Bussan Bldg. 1-16-21 Meiekiminami, Nakamura-ku, Nagoya, 450-003, Japan

    Masanori Fukushima

  5. Department of Neurology, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu, 501-1194, Japan

    Takayoshi Shimohata

Authors
  1. Yutaka Otsu
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Contributions

Y.O. and M. H. performed the experiments, analysed the data, and drafted the manuscript. T.K., N. A., and I.N. performed the experiments and analysed the data. T.K. and O.O. advised experiments. K.O., M.F., and T.S. analysed the data and supervised all aspects of this project. M. K. performed the experiments, analysed the data, developed the concept, designed the experiments, wrote the manuscript, and supervised all aspects of this project. All authors have read and approved the final manuscript.

Corresponding author

Correspondence to Masato Kanazawa.

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Ethical Approval and Consent to Participate

This study was conducted in strict accordance with the recommendations of the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health (Bethesda, MD). The protocol (#SA00706) was approved by the Niigata University Administrative Panel on Laboratory Animal Care and the Ethical Committee of Niigata University. Ethical approval for the present study (#2019–0374) was provided by the Institutional Ethics Committee of Niigata University Medical and Dental Hospital. Informed consent was obtained healthy donors.

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We have obtained consent to publish from the participant to report individual data.

Conflict of Interests

Prof. Shimohata is an academic advisor, Shimojani LLC. The authors declare no financial interests related to the materials in this manuscript. Drs. Otsu, Hatakeyama, Kanayama, Akiyama, Ninomiya, Omae, Kato, Onodera, Fukushima, and Kanazawa declare no competing interests.

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Otsu, Y., Hatakeyama, M., Kanayama, T. et al. Oxygen–Glucose Deprived Peripheral Blood Mononuclear Cells Protect Against Ischemic Stroke. Neurotherapeutics 20, 1369–1387 (2023). https://doi.org/10.1007/s13311-023-01398-w

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