Neuroinflammation in Sepsis: Molecular Pathways of Microglia Activation

Frequently underestimated, encephalopathy or delirium are common neurological manifestations associated with sepsis. Brain dysfunction occurs in up to 80% of cases and is directly associated with increased mortality and long-term neurocognitive consequences. Although the central nervous system (CNS) has been classically viewed as an immune-privileged system, neuroinflammation is emerging as a central mechanism of brain dysfunction in sepsis. Microglial cells are major players in this setting. Here, we aimed to discuss the current knowledge on how the brain is affected by peripheral immune activation in sepsis and the role of microglia in these processes. This review focused on the molecular pathways of microglial activity in sepsis, its regulatory mechanisms, and their interaction with other CNS cells, especially with neuronal cells and circuits

Bone marrow-derived cells as a therapeutic approach to optic nerve diseases

Submitted by Janaína Nascimento ([email protected]) on 2019-02-21T11:54:08Z No. of bitstreams: 1 ve_Mesentier-Louro_Louise_etal_INI_2016.pdf: 1312382 bytes, checksum: 24a4c20038aa767b1874623fee10dc72 (MD5)Approved for entry into archive by Janaína Nascimento ([email protected]) on 2019-02-22T13:53:00Z (GMT) No. of bitstreams: 1 ve_Mesentier-Louro_Louise_etal_INI_2016.pdf: 1312382 bytes, checksum: 24a4c20038aa767b1874623fee10dc72 (MD5)Made available in DSpace on 2019-02-22T13:53:00Z (GMT). No. of bitstreams: 1 ve_Mesentier-Louro_Louise_etal_INI_2016.pdf: 1312382 bytes, checksum: 24a4c20038aa767b1874623fee10dc72 (MD5) Previous issue date: 2016Universidade Federal do Rio de Janeiro. Instituto de Biofísica Carlos Chagas Filho. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Nacional de Infectologia Evandro Chagas. Rio de Janeiro, RJ, Brasil.Universidade Federal do Rio de Janeiro. Instituto de Ciências Biomédicas. Rio de Janeiro, RJ, Brasil.Universidade Federal do Rio de Janeiro. Instituto de Biofísica Carlos Chagas Filho. Rio de Janeiro, RJ, Brasil.Universidade Federal do Rio de Janeiro. Instituto de Biofísica Carlos Chagas Filho. Rio de Janeiro, RJ, Brasil.Universidade Federal do Rio de Janeiro. Instituto de Biofísica Carlos Chagas Filho. Rio de Janeiro, RJ, Brasil.Universidade Federal do Rio de Janeiro. Instituto de Biofísica Carlos Chagas Filho. Rio de Janeiro, RJ, Brasil.Following optic nerve injury associated with acute or progressive diseases, retinal ganglion cells (RGCs) of adult mammals degenerate and undergo apoptosis. These diseases have limited therapeutic options, due to the low inherent capacity of RGCs to regenerate and due to the inhibitory milieu of the central nervous system. Among the numerous treatment approaches investigated to stimulate neuronal survival and axonal extension, cell transplantation emerges as a promising option. This review focuses on cell therapies with bone marrow mononuclear cells and bone marrow-derived mesenchymal stem cells, which have shown positive therapeutic effects in animal models of optic neuropathies. Different aspects of available preclinical studies are analyzed, including cell distribution, potential doses, routes of administration, and mechanisms of action. Finally, published and ongoing clinical trials are summarized

CD60b: Enriching Neural Stem/Progenitor Cells from Rat Development into Adulthood

CD60b antigens are highly expressed during development in the rat nervous system, while in the adult their expression is restricted to a few regions, including the subventricular zone (SVZ) around the lateral ventricles—a neurogenic niche in the adult brain. For this reason, we investigated whether the expression of C60b is associated with neural stem/progenitor cells in the SVZ, from development into adulthood. We performed in vitro and in vivo analyses of CD60b expression at different stages and identified the presence of these antigens in neural stem/progenitor cells. We also observed that CD60b could be used to purify and enrich a population of neurosphere-forming cells from the developing and adult brain. We showed that CD60b antigens (mainly corresponding to ganglioside 9-O-acetyl GD3, a well-known molecule expressed during central nervous system development and mainly associated with neuronal migration) are also present in less mature cells and could be used to identify and isolate neural stem/progenitor cells during development and in the adult brain. A better understanding of molecules associated with neurogenesis may contribute not only to improve the knowledge about the physiology of the mammalian central nervous system, but also to find new treatments for regenerating tissue after disease or brain injury

Intraspinal bone-marrow cell therapy at pre- and symptomatic phases in a mouse model of amyotrophic lateral sclerosis

Background: Amyotrophic lateral sclerosis (ALS) is a progressive neurological disease that selectively affects the motor neurons. The details of the mechanisms of selective motor-neuron death remain unknown and no effective therapy has been developed. We investigated the therapy with bone-marrow mononuclear cells (BMMC) in a mouse model of ALS (SOD1(G93A) mice).Methods: We injected 10(6) BMMC into the lumbar portion of the spinal cord of SOD1(G93A) mice in presymptomatic (9 weeks old) and symptomatic (14 weeks old) phases. In each condition, we analyzed the progression of disease and the lifespan of the animals.Results: We observed a mild transitory delay in the disease progression in the animals injected with BMMC in the presymptomatic phase. However, we observed no increase in the lifespan. When we injected BMMC in the symptomatic phase, we observed no difference in the animals' lifespan or in the disease progression. Immunohistochemistry for NeuN showed a decrease in the number of motor neurons during the course of the disease, and this decrease was not affected by either treatment. Using different strategies to track the BMMC, we noted that few cells remained in the spinal cord after transplantation. This observation could explain why the BMMC therapy had only a transitory effect.Conclusion: This is the first report of intraspinal BMMC therapy in a mouse model of ALS. We conclude this cellular therapy has only a mild transitory effect when performed in the presymptomatic phase of the disease

Additional file 1: Figure S1. of Intraspinal bone-marrow cell therapy at pre- and symptomatic phases in a mouse model of amyotrophic lateral sclerosis

Quantification of neurons in the anterior horn of the spinal cord. The number of interneurons (NeuN-positive cells with cross-sectional area ≤250 μm2) was analyzed in week 12 in the presymptomatic injected animals a and in week 15 in the symptomatic injected animals b. There was no difference in the number of interneurons in the SOD1G93A mice compared with the wild-type animals. The number of motor neurons was analyzed in the end stage of the disease in the presymptomatic injected animals c and in the symptomatic injected animals d. Both saline-injected and BMMC-injected mice showed a decrease in the number of motor neurons compared with the wild-type mice at the time point analyzed. ***p <0.001. (TIF 745 kb

Distribution of Mesenchymal Stem Cells and Effects on Neuronal Survival and Axon Regeneration after Optic Nerve Crush and Cell Therapy

<div><p>Bone marrow-derived cells have been used in different animal models of neurological diseases. We investigated the therapeutic potential of mesenchymal stem cells (MSC) injected into the vitreous body in a model of optic nerve injury. Adult (3–5 months old) Lister Hooded rats underwent unilateral optic nerve crush followed by injection of MSC or the vehicle into the vitreous body. Before they were injected, MSC were labeled with a fluorescent dye or with superparamagnetic iron oxide nanoparticles, which allowed us to track the cells <i>in vivo</i> by magnetic resonance imaging. Sixteen and 28 days after injury, the survival of retinal ganglion cells was evaluated by assessing the number of Tuj1- or Brn3a-positive cells in flat-mounted retinas, and optic nerve regeneration was investigated after anterograde labeling of the optic axons with cholera toxin B conjugated to Alexa 488. Transplanted MSC remained in the vitreous body and were found in the eye for several weeks. Cell therapy significantly increased the number of Tuj1- and Brn3a-positive cells in the retina and the number of axons distal to the crush site at 16 and 28 days after optic nerve crush, although the RGC number decreased over time. MSC therapy was associated with an increase in the FGF-2 expression in the retinal ganglion cells layer, suggesting a beneficial outcome mediated by trophic factors. Interleukin-1β expression was also increased by MSC transplantation. In summary, MSC protected RGC and stimulated axon regeneration after optic nerve crush. The long period when the transplanted cells remained in the eye may account for the effect observed. However, further studies are needed to overcome eventually undesirable consequences of MSC transplantation and to potentiate the beneficial ones in order to sustain the neuroprotective effect overtime.</p></div

MSC transplantation increased RGC survival 28 days after optic nerve crush.

<p>A-C: Confocal images of flat-mounted retinas labeled with Tuj1 antibody (A-C). D-F: Photomontage of confocal images of flat-mounted retinas labeled with Brn3a antibody. A, D: Control retina (contralateral eye). B, E: Twenty-eight days after optic nerve injury, there was a large reduction in the number of RGCs, and axon bundles were thinner (arrows in B) in the vehicle-treated group compared to control. C, F: In MSC-injected animals, the number of surviving RGCs increased compared to vehicle-injected animals, and axon bundles were similar to control (arrows in C). G-J: Quantification of RGC survival 28 days after nerve crush at 1.0 mm or 3.5 mm from the optic disc, using Tuj1 (G, H) or Brn3a labeling (I, J). Results are displayed as mean ± SEM of the percentage of Tuj1+ or Brn3a+ cells relative to the control retina (contralateral ye). *P<0.05; **P<0.01; ***P<0.001. Scale bar: 50 µm (A-C); 500 µm (D-F).</p

MSC transplantation increased RGC axon regeneration 16 and 28 days after optic nerve crush.

<p>A-D: Photomontage of confocal images of optic nerve sections to illustrate axonal outgrowth. CTB-488 was injected into the vitreous body 2 days prior to euthanasia to label the axons. Sixteen days after nerve crush (A,B,E) only a few axons had crossed the lesion site (asterisk) in the vehicle-injected animals (A) and this number was larger in the MSC-injected animals (B). Twenty-eight days after optic nerve injury (C,D,F), the MSC-injected group had an even larger number of axons regenerating beyond the crush site, compared to the vehicle-injected group. E, F: Quantification of CTB-488⁺ axons per nerve at different distances from the crush site (from 0.25 to 2.0 mm). Results are displayed as mean ± SEM. *P<0.05; **P<0.01. Scale bar: 200 µm.</p