Multipotent Mesenchymal Stromal Cells Increase tPA Expression and Concomitantly Decrease PAI-1 Expression in Astrocytes through the Sonic Hedgehog Signaling Pathway after Stroke ( in vitro Study)
Open accessAbstract
Multipotent mesenchymal stromal cells (MSCs) increase tissue plasminogen activator (tPA) activity in astrocytes of the ischemic boundary zone, leading to increased neurite outgrowth in the brain. To probe the mechanisms that underlie MSC-mediated activation of tPA, we investigated the morphogenetic gene, sonic hedgehog (Shh) pathway. In vitro oxygen and glucose deprivation and coculture of astrocytes and MSCs were used to mimic an in vivo ischemic condition. Both real-time-PCR and western blot showed that MSC coculture significantly increased the Shh level and concomitantly increased tPA and decreased plasminogen activator inhibitor 1 (PAI-1) levels in astrocytes. Inhibiting the Shh signaling pathway with cyclopamine blocked the increase of tPA and the decrease of PAI-1 expression in astrocytes subjected to MSC coculture or recombinant mouse Shh (rm-Shh) treatment. Both MSCs and rm-Shh decreased the transforming growth factor- β1 level in astrocytes, and the Shh pathway inhibitor cyclopamine reversed these decreases. Both Shh-small-interfering RNA (siRNA) and Glil-siRNA downregulated Shh and Gli1 (a key mediator of the Shh transduction pathway) expression in cultured astrocytes and concomitantly decreased tPA expression and increased PAI-1 expression in these astrocytes after MSC or rm-Shh treatment. Our data indicate that MSCs increase astrocytic Shh, which subsequently increases tPA expression and decreases PAI-1 expression after ischemia.
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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 [70]
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- Authors
- Xin, H., Li, Y., Shen, L. H., Liu, X., Hozeska-Solgot, A., Zhang, R. L., Zhang, Z. G., & Chopp, M.
- Affiliations
- Henry Ford Health (US)
- Department of Neurology, Henry Ford Hospital, Detroit, Michigan, USA
- Corresponding author
- Chopp, Michael
- Venue
- Journal of Cerebral Blood Flow & Metabolism
- Publisher
- SAGE Publications
- Published
- 2011-08-10
- Volume
- 31
- Issue
- 11
- Pages
- 2181-2188
- ISSN
- 0271-678X (ISSN-L)
- 1559-7016
- PMC
- PMC3210339
- OpenAlex
- W1972753549
- Cited by
- 40
- References
- 40
- Citations by year
- 2024: 1 · 2023: 2 · 2021: 1 · 2019: 1 · 2018: 2 · 2017: 4 · 2016: 4 · 2015: 6 · 2014: 5 · 2013: 10 · 2012: 3
- FWCI
- 3.07
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Cerebral Blood Flow & Metabolism (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (R01AG037506)
- National Institute of Neurological Disorders and Stroke (R01NS066041)
- Topics
- Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Hedgehog Signaling Pathway Studies
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- multipotent mesenchymal stromal cells, tissue plasminogen activator, plasminogen activator inhibitor-1, Sonic hedgehog signaling, astrocytes, ischemic stroke, cyclopamine, Gli1, TGF-β1, oxygen-glucose deprivation, neurite outgrowth, co-culture
- MeSH terms
- Animals, Astrocytes, Culture Media, Glucose, Mice, Inbred C57BL, Oxygen, Tissue Plasminogen Activator, Signal Transduction, Down-Regulation, Cell Hypoxia, Up-Regulation, Coculture Techniques, Cell Culture Techniques, Receptor Cross-Talk, Stroke, Multipotent Stem Cells, Mice, Hedgehog Proteins, Serpin E2, Mesenchymal Stem Cells
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