Increasing tPA activity in astrocytes induced by multipotent mesenchymal stromal cells facilitate neurite outgrowth after stroke in the mouse
Open accessAbstract
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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Delivery of bone-marrow-derived stromal cells or mesenchymal stromal cells further increases levels of GDNF and tPA and reduces levels of tPA inhibitor PAI-1.
“Delivery of bone-marrow-derived stromal cells or mesenchymal stromal cells was shown to further increase levels of GDNF66 and tPA68,69 and reduce levels of the tPA inhibitor plasminogen activator inhibitor 1.70”
From Promoting brain remodelling and plasticity for stroke recovery: therapeutic promise and potential pitfalls of clinical translation (2012) · cites this paper as [68]
After focal cerebral ischaemia, astrocytes de novo express neurotrophic factors such as GDNF and VEGF, and serine proteases such as tPA, in parallel with downregulation of growth-repulsive proteoglycans.
“Subsequent to focal cerebral ischaemia, and in parallel to the downregulation of growth-repulsive proteoglycans, astrocytes de novo express neurotrophic factors, such as glial-cell-line-derived neurotrophic factor (GDNF)66 and VEGF,67 and serine proteases, namely tissue plasminogen activator (tPA).68”
From Promoting brain remodelling and plasticity for stroke recovery: therapeutic promise and potential pitfalls of clinical translation (2012) · cites this paper as [68]
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Buller, B., Chopp, M., & Zhang, Z. G. (2017) · Springer series in translational stroke research · doi:10.1007/978-3-319-66679-2_16 · Cited by 1 · see citing works
Self-citationOn the Regulation of the Serine Protease t-PA and its Inhibitor PAI-1 in the Brain
Hultman, K. (2010) · Gothenburg University Publications Electronic Archive (Gothenburg University)
Molecular Biology of Brain Injury: 2012
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Stem cells application for the treatment of traumatic brain injury
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Emerging Mechanism of Cell Death Caused by Stroke: A Role of Neurovascular Unit
Ohtomo, R., & Arai, K. (2020) · Stroke revisited · doi:10.1007/978-981-10-1430-7_17
- 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
- ORCID
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2010-02-03
- Volume
- 5
- Issue
- 2
- Pages
- e9027
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC2815778
- 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
- gold
- doi.org
- 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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