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Thermo-mechanical behaviour of a new fire resistant steel: experimental and numerical results
No full textModulation of proliferation and differentiative potential of adult brain subventricular zone cells by purinergic signaling in vitro and in vivo: contribution of reactive astrocytes
No full textThe subventricular zone (SVZ) of the lateral ventricles is one of the two neurogenic regions persisting in the adult brain. Here, GFAP+ precursors (Type B cells) give raise to transit-amplifying Mash1+ Type C cells, which eventually further differentiate to doublecortin+ neuroblasts (Type A cells). It is now emerging that brain injuries boost neurogenesis in the adult SVZ, also through action on surrounding parenchyma or niche cells. Nevertheless, very few newborn neurons survive and integrate in the damaged areas, suggesting a non-permissive environment. Thus, understanding the pro- or anti-neurogenic activity of the various molecules composing the extracellular milieu of the neurogenic niche would greatly help designing appropriate pharmacological approaches to promote neurogenesis while reducing inhibitory signals.
In pathological conditions, the concentrations of extracellular nucleotides (eNTs) raise several folds, and contribute to reactive astrogliosis [Abbracchio & Ceruti, PUSI 2:595, 2006]. Among their multiple functions in brain parenchima, astrocytes are also key components of the neurogenic niche, and regulate neural stem cells (NSC) proliferation and differentiation. Moreover, also eNTs could directly modulate SVZ cells, possibly through the G protein-coupled P2Y1 nucleotide receptor [Mishra et al., Development, 33:675, 2006; Grimm et al., J Cell Sci 122:2524, 2009], although very few data are available especially in vivo.
In the present study, we tested the ability of the stable P2Y1 agonist ADPβS to control adult NSC activities, with a focus on the possible effects exerted by reactive astrocytes. ADPβS administration in the lateral ventricle of adult mice caused both reactive astrogliosis in the brain parenchyma and activation of SVZ progenitors. Indeed, proliferation of GFAP+ NSCs increased, leading to a significant expansion of the population of transit-amplifying Mash1+ progenitors and doublecortin+ neuroblasts in the SVZ. Lineage tracing experiments further demonstrated that ADPβS promoted GLAST+ progenitor proliferation, and sustained their progression towards the generation of rapidly dividing progenitors. Data were fully confirmed in vitro by the neurosphere assay, where ADPβS stimulated the differentiation of undissociated NS towards GFAP+ astrocytes, and β-IIITub+ neurons. To test whether ADPβS was acting directly on NSCs only or whether reactive astrocytes were involved, we grew NS in the conditioned media derived from Control astrocytic cultures or from astrocytes cultured in presence of ADPβS. Both astrocyte-conditioned medium reduced the number and size of primary NS with respect to control neurosphere medium. Notably, a significant enhancement in SVZ progenitor proliferation was observed when SVZ cells, initially grown in the supernatant of astrocytes exposed to ADPβS, were then shifted to normal medium. This suggests that ADPβS stimulates the release of yet-to-be identified mediator(s) whose removal boosted proliferation of SVZ cells. Our preliminary results from an ELISA assay suggest that IL-10 could likely play a role in this effect.
Taken together our results strengthen evidence that purinergic system crucially regulates SVZ progenitors, both directly and through the involvement of reactive astrocytes. The pharmacological modulation of the purinergic system could therefore represent a promising and innovative approach to exploit the intrinsic ability of the adult brain to regenerate in acute and chronic neurodegenerative disorders
Purinergic signaling modulates adult neurogenesis in the subventricular zone: role of parenchymal astrocytes
No full textBackground and Purpose - The subventricular zone (SVZ) of the lateral ventricles is one of the two neurogenic regions persisting in the adult brain [1]. Evidence is accumulating that neurogenesis in the SVZ is boosted following trauma or ischemia, also through the interaction with surrounding parenchyma or niche cells. Astrocytes are key components of the neurogenic niche, and play a vital role in regulating neural stem cells (NSC) proliferation and differentiation. However, the exact molecular mechanisms by which astrocytes modulate NSC functions have not been identified. Besides significantly contributing to reactive astrogliosis, increasing evidence suggests that extracellular nucleotides play a role in controlling adult neurogenesis; these functions become prominent especially under pathological conditions where nucleotides concentrations raise several folds. From the few data published so far, a primary role for the P2Y1 G protein-coupled receptor subtype is clearly emerging in controlling the proliferation and differentiative potential of SVZ cells [2]. Therefore, we tested the ability of ADP-beta-S, a stable P2Y1 receptor agonist, to modulate stem cell properties in the adult brain in vitro and in vivo, with a particular focus on the possible modulatory effects exerted by reactive astrocytes
Methods and Results – In vitro results: neurospheres (NS; floating aggregates of SVZ precursor cells, maintaining the ability to proliferate and self-renew in culture) were obtained by mouse SVZ [3] and grown in the absence or presence of ADPβS. When cells derived from the dissociation of SVZ were plated in the presence of ADPβS, an increased number of NS was generated with respect to cultures grown under control conditions. Moreover, ADPβS stimulated the differentiation of undissociated NS towards GFAP+ astrocytes, and β-IIITub+ neurons. Interestingly, a significant enhancement in secondary NS generation was detected when SVZ cells were initially grown as primary NS in the supernatant of astrocytic culture exposed to ADP-beta-S, and then shifted to normal medium. This suggests that extracellular nucleotide stimulate the release of yet-to-be identified astrocytic mediator(s) whose removal from the culture medium boosted the self-renewal capability of SVZ cells. Preliminary results reveal that ADPβS influence the release from astrocytes of several pro- and anti-inflammatory cytokines that could likely play a role in this effect.
In vivo results: a 7-day long intracerebroventricular (i.c.v.) administration of 100 μM ADPβS stimulated reactive astrogliosis in the brain parenchima surrounding the SVZ, and induced a massive reaction of GFAP-expressing precursors and astrocytes in the SVZ, which became hypertrophic. Moreover, ADPβS promoted BrdU incorporation, indicating a proliferative effect. Confirming in vitro data, ADPβS administration induced also a significant expansion of the population of Mash1+ transit-amplifying cells and of doublecortin+ neuroblasts. By taking advantage of a conditional GLAST::CreERT2 Rosa YFP mouse model, we also demonstrated that ADPβS promoted the proliferation of GLAST-expressing progenitors in the neurogenic niche, and sustained their progression towards the generation of rapidly dividing transit-amplifying cells.
Conclusions - Taken together, our data suggest that nucleotides can be used to increase the pool of NSCs and their differentiation towards neuroblasts, either directly or through the activation of parenchymal astrocytes. This effect could be exploited to restore brain functions following acute and chronic neurodegenerative disorders, by stimulating the self-repair intrinsic ability of the brain.
References
[1] Doetsch F, Garcia-Verdugo JM, Alvarez-Buylla A (1997) Cellular composition and three-dimensional organization of the subventricular germinal zone in the adult mammalian brain. J Neurosci 17:5046-5061.
[2] Suyama S, Sunabori T, Kanki H, Sawamoto K , Gachet C, Koizumi S, Okano H (2012) Purinergic signaling promotes proliferation of adult mouse subventricular zone cells. J Neurosci 32:9238-9247.
[2] Johansson C.B. et al., 1999. Exp.Cell Res. 253:733-736
Purines regulate adult brain subventricular zone cell functions: Contribution of reactive astrocytes
No full textBrain injuries modulate activation of neural stem cells (NSCs) in the adult brain. In pathological conditions, the concentrations of extracellular nucleotides (eNTs) raise several folds, contribute to reactive gliosis, and possibly directly affect subventricular zone (SVZ) cell functioning. Among eNTs and derived metabolites, the P2Y1 receptor agonist ADP strongly promotes astrogliosis and might also influence SVZ progenitor activity. Here, we tested the ability of the stable P2Y1 agonist adenosine 5'-O-(2-thiodiphosphate) (ADPβS) to control adult NSC functions both in vitro and in vivo, with a focus on the possible effects exerted by reactive astrocytes. In the absence of growth factors, ADPβS promoted proliferation and differentiation of SVZ progenitors. Moreover, ADPβS-activated astrocytes markedly changed the pattern of released cytokines and chemokines, and strongly modulated neurosphere-forming capacity of SVZ progenitors. Notably, a significant enhancement in proliferation was observed when SVZ cells, initially grown in the supernatant of astrocytes exposed to ADPβS, were shifted to normal medium. In vivo, ADPβS administration in the lateral ventricle of adult mice by osmotic minipumps caused diffused reactive astrogliosis, and a strong response of SVZ progenitors. Indeed, proliferation of glial fibrillary acidic protein-positive NSCs increased and led to a significant expansion of SVZ transit-amplifying progenitors and neuroblasts. Lineage tracing experiments performed in the GLAST::CreERT2;Rosa-YFP transgenic mice further demonstrated that ADPβS promoted proliferation of glutamate/aspartate transporter-positive progenitors and sustained their progression toward the generation of rapidly dividing progenitors. Altogether, our results show that the purinergic system crucially affects SVZ progenitor activities both directly and through the involvement of reactive astrocytes
MODULATION OF THE PROLIFERATION AND DIFFERENTIATIVE POTENTIAL OF ADULT BRAIN SUBVENTRICULAR ZONE CELLS BY PURINERGIC SIGNALING IN VITRO AND IN VIVO : CONTRIBUTION OF REACTIVE ASTROCYTES
No full textAstrocytes in the damaged brain : molecular and cellular insights into their reactive response and healing potential
No full textLong considered merely a trophic and mechanical support to neurons, astrocytes have progressively taken the center stage as their ability to react to acute and chronic neurodegenerative situations became increasingly clear. Reactive astrogliosis starts when trigger molecules produced at the injury site drive astrocytes to leave their quiescent state and become activated. Distinctive morphological and biochemical features characterize this process (cell hypertrophy, upregulation of intermediate filaments, and increased cell proliferation). Moreover, reactive astrocytes migrate towards the injured area to constitute the glial scar, and release factors mediating the tissue inflammatory response and remodeling after lesion. A novel view of astrogliosis derives from the finding that subsets of reactive astrocytes can recapitulate stem cell/progenitor features after damage, fostering the concept of astroglia as a promising target for reparative therapies. But which biochemical/signaling pathways modulate astrogliosis with respect to both the time after injury and the type of damage? Are reactive astrocytes overall beneficial or detrimental for neuroprotection and tissue regeneration? This debate has been animating this research field for several years now, and an integrated view on the results obtained and the possible future perspectives is needed. With this Commentary article we have attempted to answer the above-mentioned questions by reviewing the current knowledge on the molecular mechanisms controlling and sustaining the reaction of astroglia to injury and its stem cell-like properties. Moreover, the cellular/molecular mechanisms supporting the detrimental or beneficial features of astrogliosis have been scrutinized to gain insights on possible pharmacological approaches to enhance astrocyte neuroprotective activities
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
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