Thrombin is a potent mitogen for rat astroblasts but not for oligodendroblasts and neuroblasts in primary culture

Perraud, Frédéric; Besnard, François; Sensenbrenner, M.; Labourdette, G.

doi:10.1016/0736-5748(87)90028-1

Cited by 90 publications

(59 citation statements)

References 41 publications

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“…11 Thrombin also can stimulate cell proliferation. [12][13][14] In addition, vascular endothelial growth factor (VEGF) plays an important role in neurogenesis, 15,16 and thrombin can upregulate cell VEGF levels. 17 The present study examined whether neurogenesis takes place in the rat blood injection ICH model and the effects thrombin on ICH-related neurogenesis.…”

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confidence: 99%

Effects of Thrombin on Neurogenesis After Intracerebral Hemorrhage

Yang

Song

Hua

et al. 2008

Stroke

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Background and Purposes-Neurogenesis in intracerebral hemorrhage (ICH) has not been investigated. Thrombin formation causes acute brain injury after ICH, but thrombin also can stimulate cell proliferation. The present study examined whether neurogenesis takes place in ICH and the role of thrombin in ICH-related neurogenesis. Methods-This study was divided into four parts. (1) Rats received either an ICH or a needle insertion (sham). The rats were killed for doublecortin (DCX) Western blot analysis and immunohistochemistry. (2) Rats had an ICH or a sham operation, and then received intraperitoneal injections of 5-bromo-2Ј-deoxyuridine (BrdU) at day-7 and day-9 later. Brains were perfused to identify BrdU-positive cells. (3) Rats had an intracaudate injection of thrombin (1 U) and brains were sampled for Western blots. (4) Rats had an ICH with or without a thrombin inhibitor, hirudin. The brains were sampled for DCX quantitation. Results-DCX levels in the ipsilateral basal ganglia started to increase as early as 7 days after ICH, peaked at 14 days, and then gradually decreased at 1 month. Immunohistochemistry also demonstrated that DCX immunoreactivity was increased in the ipsilateral subventricular zone and basal ganglia at 2 weeks after ICH. Some DCX-positive cells were BrdU-positive. One unit thrombin, which does not cause marked brain injury, was injected into the caudate. Thrombin increased DCX levels in the ipsilateral basal ganglia and hirudin blocked ICH-induced upregulation of DCX. Conclusions-Our results demonstrated that neurogenesis occurs in the brain after ICH and that thrombin may play a role in ICH-induced neurogenesis.

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confidence: 99%

Effects of Thrombin on Neurogenesis After Intracerebral Hemorrhage

Yang

Song

Hua

et al. 2008

Stroke

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“…They can be modulated by two regulators of this protease that are synthesized by astrocytes: protease nexin 1 (glial-derived nexin), which is upregulated in reactive astrocytes (Nitsch et al, 1993) ; and thrombomodulin, an integral-membrane chondroitin sulfate proteoglycan that is a functionally active in astrocytes (Pindon et al, 1997). In addition to its effect on astrocyte shape, thrombin has other actions on astrocytes, including stimulation of mitogenesis (Grabham and Cunningham, 1995;Cavanaugh et al, 1990;Perraud et al, 1987), and induction of endothelin-1 (Ehrenreich et al, 1993) and nerve-growth factor secretion (Neveu et al, 1993). Astrocyte responses to thrombin are not due to a general proteolytic effect but involve an intracellular signal transduction since the morphological changes and mitogenic effects are mediated by the tethered ligand receptor PAR-1 (Jalink and Moolenaar, 1992;Beecher et al, 1994;Grabham and Cunningham, 1995).…”

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Thrombin‐induced reversal of astrocyte stellation is mediated by activation of protein kinase C β‐1

Pindon

Festoff

Hantaı̈

1998

European Journal of Biochemistry

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Exogenous or endogenous injuries of the central nervous system trigger astrogliosis characterized by proliferation of astrocytes and changes in their morphology from stellate to flat polygonal. Astrocytes in culture are very sensitive to thrombin, a serine protease, which through its proteolytically activated receptor (PAR-1) induces proliferation and morphological changes comparable to astrogliosis. Evaluation of the thrombin signal-transduction pathway in the reversal of astrocyte stellation might help to understand astrogliosis. For this purpose, primary cultured murine cortical astrocytes were treated with H7, a proteinkinase inhibitor, and thrombin, which resulted in an inhibition of stellation reversal. Treatments with phorbol 12-myristate 13-acetate (PMA), a protein kinase C (PKC) activator, mimicked the action of thrombin. Subsequently, direct assay of astrocyte PKC activity after thrombin or PMA treatment demonstrated involvement of PKC in thrombin signaling associated with shape change. Western blotting showed that PKC isoform β-1 was involved in this pathway, while PKC A was only weakly activated and PKC β-2 was not activated by thrombin. PKC β-1 translocation was also elicited by a thrombin-receptor active peptide (SFLLRN), demonstrating the involvement of PAR-1 in this process. PKC δ and ε were located constitutively in the membrane fraction in stellate astrocytes. Isoforms γ, η, θ, and ζ were absent from astrocytes. These results suggest that astrogliosis in vivo might be regulated by modulating the activity of thrombin, PAR-1, or specific PKC isoforms.

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“…In the extravasculature thrombin is mitogenic for fibroblasts, smooth muscle cells, and astroglia cells (1)(2)(3). In addition, thrombin causes neurite retraction in neurons (4) and promotes cell death in certain cell types (5,6).…”

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Thrombin Causes a Marked Delay in Skeletal Myogenesis That Correlates with the Delayed Expression of Myogenin and p21

Guttridge¹,

Lau

Tran

et al. 1997

Journal of Biological Chemistry

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Thrombin is a multifunctional serine protease whose activity is regulated in the extravasculature by an extracellular inhibitor, protease nexin-1. Because protease nexin-1 expression has been shown to be regulated during skeletal muscle cell differentiation, we reasoned that thrombin inactivation may be an important requirement for this developmental process. To test this hypothesis, we examined the effects of thrombin on differentiating C2C12 myoblasts. We report here that myogenesis, as scored by myotube formation, is considerably delayed by thrombin. This regulation correlated with delayed expression of myogenin and p21 CIP1/WAF1 , both considered critical components of the skeletal muscle cell differentiation program. Regulation occurred at the RNA level, indicating that the effect of thrombin is either transcriptional or post-transcriptional. Furthermore, we present evidence suggesting that this regulation is mediated by the thrombin receptor. Although thrombin is mitogenic for certain cell types, we found that delay of myogenesis in C2C12 cells did not involve a mitogenic signal. Taken together, these results imply that inhibition of the serine protease thrombin may be required for proper progression through the myogenic differentiation program. The data point to potentially important roles that thrombin and protease nexin-1 may play during skeletal muscle development.Thrombin is a multifunctional serine protease that regulates both vascular and extravascular cellular processes. In the extravasculature thrombin is mitogenic for fibroblasts, smooth muscle cells, and astroglia cells (1-3). In addition, thrombin causes neurite retraction in neurons (4) and promotes cell death in certain cell types (5, 6). Most if not all of the actions of thrombin are mediated by a seven-transmembrane domain, G-protein-coupled receptor that is activated by a thrombin cleavage event in the extracellular domain of the receptor (7,8). Proteolysis generates a new N terminus that acts as a tethered peptide ligand, binding to a site in the receptor, and activating a signal transduction cascade (9).Thrombin activity is tightly regulated in the extravasculature by the serine protease inhibitor protease nexin-1 (PN-1), 1 also referred to as glia-derived nexin (10, 11). PN-1 expression is relatively high in brain, and because it is regulated during injury it is thought to protect neuronal cells from the potentially harmful effects of serine proteases (12-14). PN-1 may also play a role in synapse formation in skeletal muscle because it is secreted from muscle fibers at the neuromuscular junction where acetylcholine receptors are expressed, and PN-1 blocks the proteolytic action of thrombin, which mediates activitydependent synapse reduction (15, 16).Formation of the neuromuscular junction is preceded by the differentiation of skeletal muscle cells, an event morphologically characterized as the fusion of mononucleated myoblasts into multinucleated myotubes. Differentiation is largely controlled by the myogenic basic helix-loop-helix fami...

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Thrombin is a potent mitogen for rat astroblasts but not for oligodendroblasts and neuroblasts in primary culture

Cited by 90 publications

References 41 publications

Effects of Thrombin on Neurogenesis After Intracerebral Hemorrhage

Effects of Thrombin on Neurogenesis After Intracerebral Hemorrhage

Thrombin‐induced reversal of astrocyte stellation is mediated by activation of protein kinase C β‐1

Thrombin Causes a Marked Delay in Skeletal Myogenesis That Correlates with the Delayed Expression of Myogenin and p21

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