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)
| Autor: | Hongqi Xin, Xianshuang Liu, Ann Hozeska-Solgot, Yi Li, Li Hong Shen, Zheng Gang Zhang, Michael Chopp, Rui Lan Zhang |
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| Rok vydání: | 2011 |
| Předmět: |
animal structures
Cyclopamine Cell Culture Techniques Down-Regulation Tissue plasminogen activator Mice chemistry.chemical_compound Downregulation and upregulation GLI1 Serpin E2 medicine Animals Hedgehog Proteins Sonic hedgehog biology Multipotent Stem Cells Mesenchymal stem cell Mesenchymal Stem Cells Receptor Cross-Talk Molecular biology Cell Hypoxia Coculture Techniques Culture Media Up-Regulation Cell biology Mice Inbred C57BL Oxygen Stroke Glucose Neurology chemistry Astrocytes Tissue Plasminogen Activator Plasminogen activator inhibitor-1 embryonic structures biology.protein Original Article Neurology (clinical) Signal transduction Cardiology and Cardiovascular Medicine Signal Transduction medicine.drug |
| Zdroj: | Journal of Cerebral Blood Flow & Metabolism. 31:2181-2188 |
| ISSN: | 1559-7016 0271-678X |
| DOI: | 10.1038/jcbfm.2011.116 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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