Skip to main content

Advertisement

SpringerLink
Log in

Induced Mesenchymal Stem Cells-Small Extracellular Vesicles Alleviate Post-stroke Cognitive Impairment by Rejuvenating Senescence of Neural Stem Cells

  • Research
  • Published:
Journal of Molecular Neuroscience Aims and scope Submit manuscript

Abstract

Ischemic stroke is typified by hypoxia and a cascade of pathophysiological events, including metabolic dysfunction, ionic dysregulation, excitotoxicity, inflammatory infiltration, and oxidative stress. These ultimately result in neuronal apoptosis or necrosis with constrained neuroregenerative capabilities. In this study, neural stem cells (NSCs) under conditions of oxygen–glucose deprivation (OGD) in vitro and following middle cerebral artery occlusion (MCAO) in vivo were explored. Transcriptome sequencing revealed a decline in NSC differentiation and neurogenesis after OGD exposure, which was related to cellular senescence. This observation was corroborated by increased senescence markers in the MCAO mouse model, reduction in NSC numbers, and decline in neurogenesis. Importantly, iMSC-sEVs (induced mesenchymal stem cells-small extracellular vesicles) have the therapeutic potential to alleviate NSC senescence and rejuvenate their regenerative capacities both in vitro and in vivo. Moreover, iMSC-sEVs contribute to the recovery of cognitive function and synapse loss caused by MCAO.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Availability of Data and Materials

The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

References

  • Anacker C, Luna VM, Stevens GS, Millette A, Shores R, Jimenez JC et al (2018) Hippocampal neurogenesis confers stress resilience by inhibiting the ventral dentate gyrus. Nature 559:98–102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Andrzejewska A, Dabrowska S, Lukomska B, Janowski M (2021) Mesenchymal stem cells for neurological disorders. Adv Sci (weinh) 8:2002944

    Article  CAS  PubMed  Google Scholar 

  • Ayata C, Dunn AK, Gursoy OY, Huang Z, Boas DA, Moskowitz MA (2004) Laser speckle flowmetry for the study of cerebrovascular physiology in normal and ischemic mouse cortex. J Cereb Blood Flow Metab 24:744–755

    Article  PubMed  Google Scholar 

  • Calcinotto A, Kohli J, Zagato E, Pellegrini L, Demaria M, Alimonti A (2019) Cellular senescence: aging, cancer, and injury. Physiol Rev 99:1047–1078

    Article  CAS  PubMed  Google Scholar 

  • Childs BG, Durik M, Baker DJ, van Deursen JM (2015) Cellular senescence in aging and age-related disease: from mechanisms to therapy. Nat Med 21:1424–1435

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cloonan N, Wani S, Xu Q, Gu J, Lea K, Heater S et al (2011) MicroRNAs and their isomiRs function cooperatively to target common biological pathways. Genome Biol 12:R126

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Djavadian RL (2004) Serotonin and neurogenesis in the hippocampal dentate gyrus of adult mammals. Acta Neurobiol Exp (wars) 64:189–200

    Article  PubMed  Google Scholar 

  • Drew WG, Miller LL, Baugh EL (1973) Effects of delta9-THC, LSD-25 and scopolamine on continuous, spontaneous alternation in the Y-maze. Psychopharmacologia 32:171–182

    Article  CAS  PubMed  Google Scholar 

  • Fischer UM, Harting MT, Jimenez F, Monzon-Posadas WO, Xue H, Savitz SI et al (2009) Pulmonary passage is a major obstacle for intravenous stem cell delivery: the pulmonary first-pass effect. Stem Cells Dev 18:683–692

    Article  CAS  PubMed  Google Scholar 

  • Giovannelli L, Bari E, Jommi C, Tartara F, Armocida D, Garbossa D et al (2023) Mesenchymal stem cell secretome and extracellular vesicles for neurodegenerative diseases: risk-benefit profile and next steps for the market access. Bioact Mater 29:16–35

    CAS  PubMed  PubMed Central  Google Scholar 

  • Gould E, Tanapat P, Rydel T, Hastings N (2000) Regulation of hippocampal neurogenesis in adulthood. Biol Psychiatry 48:715–720

    Article  CAS  PubMed  Google Scholar 

  • Hong L, Lai M, Chen M, Xie C, Liao R, Kang YJ et al (2010) The miR-17-92 cluster of microRNAs confers tumorigenicity by inhibiting oncogene-induced senescence. Cancer Res 70:8547–8557

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jin K, Wang X, Xie L, Mao XO, Zhu W, Wang Y et al (2006) Evidence for stroke-induced neurogenesis in the human brain. Proc Natl Acad Sci U S A 103:13198–13202

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kim HY, Kim TJ, Kang L, Kim YJ, Kang MK, Kim J et al (2020) Mesenchymal stem cell-derived magnetic extracellular nanovesicles for targeting and treatment of ischemic stroke. Biomaterials 243:119942

    Article  CAS  PubMed  Google Scholar 

  • Kokaia Z, Lindvall O (2003) Neurogenesis after ischaemic brain insults. Curr Opin Neurobiol 13:127–132

    Article  CAS  PubMed  Google Scholar 

  • Krupinski J, Kaluza J, Kumar P, Kumar S, Wang JM (1994) Role of angiogenesis in patients with cerebral ischemic stroke. Stroke 25:1794–1798

    Article  CAS  PubMed  Google Scholar 

  • Lang HL, Zhao YZ, Xiao RJ, Sun J, Chen Y, Hu GW et al (2023) Small extracellular vesicles secreted by induced pluripotent stem cell-derived mesenchymal stem cells improve postoperative cognitive dysfunction in mice with diabetes. Neural Regen Res 18:609–617

    Article  CAS  PubMed  Google Scholar 

  • Li W, Shi L, Hu B, Hong Y, Zhang H, Li X et al (2021) Mesenchymal stem cell-based therapy for stroke: current understanding and challenges. Front Cell Neurosci 15:628940

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Marques BL, Carvalho GA, Freitas EMM, Chiareli RA, Barbosa TG, Di Araújo AGP et al (2019) The role of neurogenesis in neurorepair after ischemic stroke. Semin Cell Dev Biol 95:98–110

    Article  CAS  PubMed  Google Scholar 

  • Molofsky AV, Slutsky SG, Joseph NM, He S, Pardal R, Krishnamurthy J et al (2006) Increasing p16INK4a expression decreases forebrain progenitors and neurogenesis during ageing. Nature 443:448–452

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mousavinejad M, Andrews PW, Shoraki EK (2016) Current biosafety considerations in stem cell therapy. Cell J 18:281–287

    PubMed  PubMed Central  Google Scholar 

  • Péron S, Berninger B (2015) Imported stem cells strike against stroke. Cell Stem Cell 17:501–502

    Article  PubMed  Google Scholar 

  • Phipps MS, Cronin CA (2020) Management of Acute Ischemic Stroke Bmj 368:l6983

    PubMed  Google Scholar 

  • Rahmani A, Saleki K, Javanmehr N, Khodaparast J, Saadat P, Nouri HR (2020) Mesenchymal stem cell-derived extracellular vesicle-based therapies protect against coupled degeneration of the central nervous and vascular systems in stroke. Ageing Res Rev 62:101106

    Article  CAS  PubMed  Google Scholar 

  • Rost NS, Brodtmann A, Pase MP, van Veluw SJ, Biffi A, Duering M et al (2022) Post-stroke cognitive impairment and dementia. Circ Res 130:1252–1271

    Article  CAS  PubMed  Google Scholar 

  • Sahay A, Scobie KN, Hill AS, O’Carroll CM, Kheirbek MA, Burghardt NS et al (2011) Increasing adult hippocampal neurogenesis is sufficient to improve pattern separation. Nature 472:466–470

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, Dulawa S et al (2003) Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science 301:805–809

    Article  CAS  PubMed  Google Scholar 

  • Sarter M, Bodewitz G, Stephens DN (1988) Attenuation of scopolamine-induced impairment of spontaneous alteration behaviour by antagonist but not inverse agonist and agonist beta-carbolines. Psychopharmacology 94:491–495

    Article  CAS  PubMed  Google Scholar 

  • Schmidt A, Minnerup J (2016) Promoting recovery from ischemic stroke. Expert Rev Neurother 16:173–186

    Article  CAS  PubMed  Google Scholar 

  • Théry C, Witwer KW, Aikawa E, Alcaraz MJ, Anderson JD, Andriantsitohaina R et al (2018) Minimal information for studies of extracellular vesicles 2018 (MISEV2018): a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines. J Extracell Vesicles 7:1535750

    Article  PubMed  PubMed Central  Google Scholar 

  • Ullah I, Subbarao RB, Rho GJ (2015) Human mesenchymal stem cells - current trends and future prospective. Biosci Rep 35:e00191

  • van Praag H, Schinder AF, Christie BR, Toni N, Palmer TD, Gage FH (2002) Functional neurogenesis in the adult hippocampus. Nature 415:1030–1034

    Article  PubMed  PubMed Central  Google Scholar 

  • Villeda SA, Luo J, Mosher KI, Zou B, Britschgi M, Bieri G et al (2011) The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature 477:90–94

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wu S, Wu B, Liu M, Chen Z, Wang W, Anderson CS et al (2019) Stroke in China: advances and challenges in epidemiology, prevention, and management. Lancet Neurol 18:394–405

    Article  PubMed  Google Scholar 

  • Xekardaki A, Santos M, Hof P, Kövari E, Bouras C, Giannakopoulos P (2012) Neuropathological substrates and structural changes in late-life depression: the impact of vascular burden. Acta Neuropathol 124:453–464

    Article  PubMed  Google Scholar 

  • Xin H, Li Y, Buller B, Katakowski M, Zhang Y, Wang X et al (2012) Exosome-mediated transfer of miR-133b from multipotent mesenchymal stromal cells to neural cells contributes to neurite outgrowth. Stem Cells 30:1556–1564

    Article  CAS  PubMed  Google Scholar 

  • Xin H, Katakowski M, Wang F, Qian JY, Liu XS, Ali MM et al (2017a) MicroRNA cluster miR-17-92 cluster in exosomes enhance neuroplasticity and functional recovery after stroke in rats. Stroke 48:747–753

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xin H, Wang F, Li Y, Lu QE, Cheung WL, Zhang Y et al (2017b) Secondary release of exosomes from astrocytes contributes to the increase in neural plasticity and improvement of functional recovery after stroke in rats treated with exosomes harvested from microRNA 133b-overexpressing multipotent mesenchymal stromal cells. Cell Transplant 26:243–257

    Article  PubMed  PubMed Central  Google Scholar 

  • Zhang ZG, Chopp M (2016) Exosomes in stroke pathogenesis and therapy. J Clin Invest 126:1190–1197

    Article  PubMed  PubMed Central  Google Scholar 

  • Zhang M, Lin YH, Sun YJ, Zhu S, Zheng J, Liu K et al (2016) Pharmacological reprogramming of fibroblasts into neural stem cells by signaling-directed transcriptional activation. Cell Stem Cell 18:653–667

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang H, Wu J, Wu J, Fan Q, Zhou J, Wu J et al (2019a) Exosome-mediated targeted delivery of miR-210 for angiogenic therapy after cerebral ischemia in mice. J Nanobiotechnology 17:29

    Article  PubMed  PubMed Central  Google Scholar 

  • Zhang ZG, Buller B, Chopp M (2019b) Exosomes - beyond stem cells for restorative therapy in stroke and neurological injury. Nat Rev Neurol 15:193–203

    Article  PubMed  Google Scholar 

  • Zhou X, Deng X, Liu M, He M, Long W, Xu Z et al (2023) Intranasal delivery of BDNF-loaded small extracellular vesicles for cerebral ischemia therapy. J Control Release 357:1–19

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by the National Natural Science Foundation of China (82272225, 81860249).

Funding

This study was funded by the National Natural Science Foundation of China (82272225, 81860249) and the Wujieping Medical Foundation (320.6750.2021–03-1).

Author information

Authors and Affiliations

  1. Department of Anesthesiology, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, Anhui, China

    Jiayuan Liu, Li Peng, Lingwei He, Tianyue Yin, Yuhao Du, Mengmeng Yang, Ping Wu, Jun Li, Jiangbing Cao, Hongrui Zhu & Sheng Wang

  2. Core Facility Center, The First Affiliated Hospital of USTC (Anhui Provincial Hospital), Hefei, 230001, Anhui, China

    Jiayuan Liu, Li Peng, Lingwei He & Tianyue Yin

  3. Department of Anesthesiology, Anhui Provincial Hospital Affiliated to Anhui Medical University, Hefei, 230001, Anhui, China

    Yuhao Du & Ping Wu

Authors
  1. Jiayuan Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Li Peng
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lingwei He
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tianyue Yin
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yuhao Du
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Mengmeng Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ping Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jun Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jiangbing Cao
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Hongrui Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Sheng Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

SW, H-RZ, and J-YL designed the research. J-YL drafted the manuscript. J-YL, LP, L-WH, T-YY, M-MY, PW, Y-HD, JL, and J-BC performed all experiments. J-YL, H-RZ, and SW participated in discussions, data analysis, and manuscript editing. All authors have read and approved the final version of the manuscript.

Corresponding authors

Correspondence to Hongrui Zhu or Sheng Wang.

Ethics declarations

Ethics Approval

All animal experiments were carried out in strict accordance with the requirements of the Animal Care and Use Committee of USTC. Male C57/BL6 mice were provided by the Experimental Animal Center of First Affiliated Hospital of USTC, China.

Competing interests

The authors declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Liu, J., Peng, L., He, L. et al. Induced Mesenchymal Stem Cells-Small Extracellular Vesicles Alleviate Post-stroke Cognitive Impairment by Rejuvenating Senescence of Neural Stem Cells. J Mol Neurosci 74, 29 (2024). https://doi.org/10.1007/s12031-024-02191-w

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s12031-024-02191-w

Keywords

Search

Navigation