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Master's Dissertation
DOI
10.11606/D.46.2013.tde-22102013-134022
Document
Author
Full name
Rodrigo La Banca de Oliveira
E-mail
Institute/School/College
Knowledge Area
Date of Defense
Published
São Paulo, 2013
Supervisor
Committee
Ulrich, Alexander Henning (President)
Bassères, Daniela Sanchez
Souza, Diogo Onofre Gomes de
Title in Portuguese
Sinergia entre os receptores purinérgicos e o fator de crescimento de nervos (NGF) na diferenciação e proliferação de células tronco neurais
Keywords in Portuguese
Diferenciação celular
Diferenciação neural
NGF
Proliferação
Receptores purinérgicos
Abstract in Portuguese
Os receptores purinérgicos são divididos em receptores P1 e P2 de acordo com o seu agonista endógeno, os receptores metabotrópicos P1 são ativados por adenosina, enquanto os metabotrópicos P2Y e ionotrópicos P2X são estimulados através do ATP e outros nucleotídeos. Além de sua função bem estabelecida na neurotransmissão, a sinalização purinérgica tem despertado crescente interesse científico devido à sua importância nas funções no metabolismo celular, incluindo os processos de desenvolvimento embrionário e reparação de tecidos. Isso ocorre especialmente no sistema nervoso central, onde eles controlam a proliferação, diferenciação, apoptose e a liberação de fatores neurotróficos. Nesse trabalho nós focamos nas ações sinérgicas entre a sinalização purinérgica e o fator de crescimento de nervos (NGF), tendo em vista três formas conhecidas de interação entre o NGF e os receptores purinérgicos, a potencialização dos efeitos do NGF através de uma ligação cruzada entre as vias, a regulação da expressão dos receptores purinérgicos pelo NGF e regulação da liberação de NGF pela adenosina. Com o objetivo de investigar estes processos sinérgicos na regulação da proliferação, migração e determinação fenotípica, células precursoras neurais foram obtidas do telencéfalo de embriões de rato e cultivadas na forma de neuroesferas, sendo então submetidas a tratamentos com agonistas e antagonistas dos receptores purinérgicos, em associação com o NGF, ao longo da diferenciação. Os efeitos desses tratamentos foram analisados por citometria de fluxo. Nós mostramos que o NGF age sobre as células aumentando a proliferação, migração e população de células indiferenciadas e diminuindo a apoptose. A ativação dos receptores P1 levou à diminuição da gliogênese e ao aumento da proliferação e da migração. A estimulação de receptores P2 resultou em aumento da proliferação e redução da taxa de apoptose. Os receptores purinérgicos potenciaram a proliferação mediada por NGF, resultando assim num aumento da população de células indiferenciadas. Neste último efeito percebemos a participação do receptor P2Y2 na sinergia. Os resultados aqui apresentados revelam novos mecanismos para a interação entre o NGF e a sinalização purinérgica na biologia de células tronco neurais
Title in English
Synergy between purinergic receptors and nerve growth factor (NGF) in the differentiation and proliferation of neural stem cells
Keywords in English
Cellular differentiation
Neural differentiation
NGF
Proliferation
Purinergic receptors
Abstract in English
Purinergic receptors are divided into P1 and P2 receptors according to agonist selectivity, G-protein- coupled P1 receptors are activated by adenosine, while metabotropic P2Y and ionotropic P2X subtypes are stimulated by ATP and other nucleotides. In addition to its well-established function in neurotransmission, purinergic signaling has raised increasing scientific interest due to its importance in essential cellular functions and metabolism including embryonic developmental processes and tissue repair, specially in the central nervous system, where they control proliferation, differentiation, apoptosis and the release of neurotrophic factors. Here we focus on synergistic actions between purinergic P1 and P2 receptor-mediated signaling and the nerve growth factor (NGF), in view of three recognized forms of interaction between NGF and purinergic signaling, the potencialization of NGF-mediated effects through a crosstalk, the regulation of purinergic receptor expression by NGF and the regulation of NGF release by adenosine. With the objective to investigate such synergistic processes in regulating proliferation, neural migration and phenotype determination, neurospheres obtained as proliferating neural stem and progenitor from rat embryonic telencephalon were subjected to treatments with purinergic receptor agonists and antagonists in association with NGF along differentiation. Effects of these treatments were analyzed by flow cytometry. We show that NGF acted on cells by increasing the population of undifferentiated cells, proliferation, migration and reducing apoptosis. P1 receptor activation led to decreased gliogenesis, increased proliferation and migration. Stimulation of P2 receptors resulted in increased proliferation and decreased apoptosis rates. Purinergic receptors potentiated NGF-mediated proliferation, thereby resulting in increased population of undifferentiated cells, in this latter effect, the P2Y2 receptor subtype participated in synergistic processes. The herein presented results reveal novel mechanisms for the interaction of NGF and purinergic signaling in neural stem cell biology
 
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Publishing Date
2013-11-13
 
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