Cited by 101Mesenchymal stem cell researchNeuroinflammation and Neurodegeneration MechanismsAcute Ischemic Stroke Management

Increasing tPA activity in astrocytes induced by multipotent mesenchymal stromal cells facilitate neurite outgrowth after stroke in the mouse

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Xin, Hongqi, Li, Yi, Shen, Li Hong, Liu, Xianshuang, Wang, Xinli, Zhang, Jing, Pourabdollah-Nejad D, Siamak, Zhang, Chunling +4 more·2010·PLoS ONE

Abstract

We demonstrate that tissue plasminogen activator (tPA) and its inhibitors contribute to neurite outgrowth in the central nervous system (CNS) after treatment of stroke with multipotent mesenchymal stromal cells (MSCs). In vivo, administration of MSCs to mice subjected to middle cerebral artery occlusion (MCAo) significantly increased activation of tPA and downregulated PAI-1 levels in the ischemic boundary zone (IBZ) compared with control PBS treated mice, concurrently with increases of myelinated axons and synaptophysin. In vitro, MSCs significantly increased tPA levels and concomitantly reduced plasminogen activator inhibitor 1 (PAI-1) expression in astrocytes under normal and oxygen and glucose deprivation (OGD) conditions. ELISA analysis of conditioned medium revealed that MSCs stimulated astrocytes to secrete tPA. When primary cortical neurons were cultured in the conditioned medium from MSC co-cultured astrocytes, these neurons exhibited a significant increase in neurite outgrowth compared to conditioned medium from astrocytes alone. Blockage of tPA with a neutralizing antibody or knock-down of tPA with siRNA significantly attenuated the effect of the conditioned medium on neurite outgrowth. Addition of recombinant human tPA into cortical neuronal cultures also substantially enhanced neurite outgrowth. Collectively, these in vivo and in vitro data suggest that the MSC mediated increased activation of tPA in astrocytes promotes neurite outgrowth after stroke.

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Authors
Xin, H., Li, Y., Shen, L. H., Liu, X., Wang, X., Zhang, J., Pourabdollah-Nejad D, S., Zhang, C., Zhang, L., Jiang, H., Zhang, Z. G., & Chopp, M.
Affiliations
Henry Ford Health (US)
Corresponding author
Chopp, Michael
Venue
PLoS ONE
Published
2010-02-03
Volume
5
Issue
2
Pages
e9027
ISSN
1932-6203 (ISSN-L)
OpenAlex
W2016357728
Cited by
101
References
104
Citations by year
2026: 1 · 2025: 2 · 2024: 3 · 2023: 6 · 2022: 2 · 2021: 2 · 2020: 3 · 2019: 2 · 2018: 5 · 2017: 4 · 2016: 9 · 2015: 3 · 2014: 16 · 2013: 19 · 2012: 8
FWCI
6.12
Type
journal article
Language
en
Open access
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Institute of Neurological Disorders and Stroke (NS 042345, R01NS066041, P01NS042345)
Topics
  • Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Epidemiology › Acute Ischemic Stroke Management
Keywords
tissue plasminogen activator, astrocytes, multipotent mesenchymal stromal cells, neurite outgrowth, stroke, plasminogen activator inhibitor-1, middle cerebral artery occlusion, oxygen-glucose deprivation, cortical neurons, axon regeneration, cell therapy
MeSH terms
Animals, Astrocytes, Brain, Cells, Cultured, Glucose, Humans, Mesoderm, Mice, Inbred C57BL, Neurons, Tissue Plasminogen Activator, Blotting, Western, Gene Expression, Neurites, Synaptophysin, Culture Media, Conditioned, Stromal Cells, Apoptosis, Plasminogen Activator Inhibitor 1, Coculture Techniques, Reverse Transcriptase Polymerase Chain Reaction, In Situ Nick-End Labeling, Stroke, RNA Interference, Multipotent Stem Cells, Mice

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