Expression of plasminogen activator inhibitor-1 by olfactory ensheathing glia promotes axonal regeneration

Simón, Diana; Martín‐Bermejo, María Jesús; Gallego-Hernández, M. Teresa; Pastrana, Érika; García-Escudero, Vega; García-Gómez, Ana; Lim, Filip; Díaz‐Nido, Javier; Ávila, Jesús; Moreno-Flores, María Teresa

doi:10.1002/glia.21189

Cited by 21 publications

(27 citation statements)

References 63 publications

(73 reference statements)

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“…Our data suggest that microglia can also be a source of PAI-1 in the CNS. A recent study indicates that PAI-1 is also expressed in olfactory ensheathing glia [44]. In the current study, PAI-1 mRNA expression was detected in primary astrocytes, primary microglia cultures, and cell lines of microglia or astrocyte origin (Figure 1C,D).…”

Section: Discussionsupporting

confidence: 67%

“…PAI-1 reduced brain edema and axonal degeneration after ischemic brain injury [42]. PAI-1 produced by astrocytes protected neurons against N-methyl-D-aspartate receptor-mediated excitotoxicity [43], and PAI-1 expressed in olfactory ensheathing glia was shown to promote axonal regeneration [44]. However, the role of PAI-1 in the regulation of microglial functions has not been investigated.…”

Section: Introductionmentioning

confidence: 99%

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Plasminogen activator inhibitor type 1 regulates microglial motility and phagocytic activity

Jeon

Kim

et al. 2012

J Neuroinflammation

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BackgroundPlasminogen activator inhibitor type 1 (PAI-1) is the primary inhibitor of urokinase type plasminogen activators (uPA) and tissue type plasminogen activators (tPA), which mediate fibrinolysis. PAI-1 is also involved in the innate immunity by regulating cell migration and phagocytosis. However, little is known about the role of PAI-1 in the central nervous system.MethodsIn this study, we identified PAI-1 in the culture medium of mouse mixed glial cells by liquid chromatography and tandem mass spectrometry. Secretion of PAI-1 from glial cultures was detected by ELISA and western blotting analysis. Cell migration was evaluated by in vitro scratch-wound healing assay or Boyden chamber assay and an in vivo stab wound injury model. Phagocytic activity was measured by uptake of zymosan particles.ResultsThe levels of PAI-1 mRNA and protein expression were increased by lipopolysaccharide and interferon-γ stimulation in both microglia and astrocytes. PAI-1 promoted the migration of microglial cells in culture via the low-density lipoprotein receptor-related protein (LRP) 1/Janus kinase (JAK)/signal transducer and activator of transcription (STAT)1 axis. PAI-1 also increased microglial migration in vivo when injected into mouse brain. PAI-1-mediated microglial migration was independent of protease inhibition, because an R346A mutant of PAI-1 with impaired PA inhibitory activity also promoted microglial migration. Moreover, PAI-1 was able to modulate microglial phagocytic activity. PAI-1 inhibited microglial engulfment of zymosan particles in a vitronectin- and Toll-like receptor 2/6-dependent manner.ConclusionOur results indicate that glia-derived PAI-1 may regulate microglial migration and phagocytosis in an autocrine or paracrine manner. This may have important implications in the regulation of brain microglial activities in health and disease.

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Section: Discussionsupporting

confidence: 67%

Section: Introductionmentioning

confidence: 99%

Plasminogen activator inhibitor type 1 regulates microglial motility and phagocytic activity

Jeon

Kim

et al. 2012

J Neuroinflammation

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“…Since we wanted to investigate their impact on NSCs, it was critical to have one, specific OEC cell type. Therefore, we chose a line that has been shown to be pure and to have phenotypes identical to primary cell lines in a number of models 54–56 .…”

Section: Resultsmentioning

confidence: 99%

Olfactory Ensheathing Cells Promote Differentiation of Neural Stem Cells and Robust Neurite Extension

Sethi

Redmond

et al. 2014

Stem Cell Rev and Rep

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Aims The goal of this study was to gain insight into the signaling between olfactory ensheathing cells (OECs) and neural stem cells (NSCs). We sought to understand the impact of OECs on NSC differentiation and neurite extension and to begin to elucidate the factors involved in these interactions to provide new targets for therapeutic interventions. Materials and Methods We utilized lines of OECs that have been extremely well characterized in vitro and in vivo along with well studied NSCs in gels to determine the impact of the coculture in three dimensions. To further elucidate the signaling, we used conditioned media from the OECs as well as fractioned components on NSCs to determine the molecular weight range of the soluble factors that was most responsible for the NSC behavior. Results We found that the coculture of NSCs and OECs led to robust NSC differentiation and extremely long neural processes not usually seen with NSCs in three dimensional gels in vitro. Through culture of NSCs with fractioned OEC media, we determined that molecules larger than 30 kDa have the greatest impact on the NSC behavior. Conclusions Overall, our findings suggest that cocultures of NSCs and OECs may be a novel combination therapy for neural injuries including spinal cord injury (SCI). Furthermore, we have identified a class of molecules which plays a substantial role in the behavior that provides new targets for investigating pharmacological therapies.

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“…The glial cells from the olfactory system have a number of attributes that make them particularly favorable and place them at the upper end of potentially useful cells. OECs have been shown to reduce inflammation [1], promote axon regeneration [2]–[5], phagocytose cellular debris [6]–[8] and bacteria [9], [10], as well as integrate with astrocytes to potentially allow them to penetrate astrocytic glial scar tissue [11], [12]. When transplanted into the injured spinal cord in rodents [13]–[17] and dogs [18], OECs have been shown to promote axonal regeneration and improve functional restoration.…”

Section: Introductionmentioning

confidence: 99%

Low-Dose Curcumin Stimulates Proliferation, Migration and Phagocytic Activity of Olfactory Ensheathing Cells

et al. 2014

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One of the promising strategies for neural repair therapies is the transplantation of olfactory ensheathing cells (OECs) which are the glial cells of the olfactory system. We evaluated the effects of curcumin on the behaviour of mouse OECs to determine if it could be of use to further enhance the therapeutic potential of OECs. Curcumin, a natural polyphenol compound found in the spice turmeric, is known for its anti-cancer properties at doses over 10 µM, and often at 50 µM, and it exerts its effects on cancer cells in part by activation of MAP kinases. In contrast, we found that low-dose curcumin (0.5 µM) applied to OECs strikingly modulated the dynamic morphology, increased the rate of migration by up to 4-fold, and promoted significant proliferation of the OECs. Most dramatically, low-dose curcumin stimulated a 10-fold increase in the phagocytic activity of OECs. All of these potently stimulated behavioural characteristics of OECs are favourable for neural repair therapies. Importantly, low-dose curcumin gave a transient activation of p38 kinases, which is in contrast to the high dose curcumin effects on cancer cells in which these MAP kinases tend to undergo prolonged activation. Low-dose curcumin mediated effects on OECs demonstrate cell-type specific stimulation of p38 and ERK kinases. These results constitute the first evidence that low-dose curcumin can modulate the behaviour of olfactory glia into a phenotype potentially more favourable for neural repair and thereby improve the therapeutic use of OECs for neural repair therapies.

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Expression of plasminogen activator inhibitor-1 by olfactory ensheathing glia promotes axonal regeneration

Cited by 21 publications

References 63 publications

Plasminogen activator inhibitor type 1 regulates microglial motility and phagocytic activity

Plasminogen activator inhibitor type 1 regulates microglial motility and phagocytic activity

Olfactory Ensheathing Cells Promote Differentiation of Neural Stem Cells and Robust Neurite Extension

Low-Dose Curcumin Stimulates Proliferation, Migration and Phagocytic Activity of Olfactory Ensheathing Cells

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