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Diferenciação in vitro de células-tronco mesenquimais de ratos wistar em células neuron-like catecolaminérgicasCélulas-tronco mesenquimais.Diferenciação neuronal.Doença de Parkinson.Terapia celular.Doenças neurodegenerativas.Mesenchymal stem cells.Neuronal differentiation.Parkinson's disease.Cell therapy.Neurodegenerative diseases.FisiologiaCélulas-tronco mesenquimais (MSCs) são células-tronco adultas encontradas em diferentes tecidos e capazes de secretar moléculas bioativas, migrar para locais de injúria tecidual e se diferenciar em células de diversas linhagens. Tais características embasaram anos de pesquisa empregando MSCs em modelos experimentais de doença de Parkinson, uma doença neurodegenerativa caracterizada pela perda de neurônios dopaminérgicos da via nigro-estriatal (entre a substância negra, parte compacta e o corpo estriado). Inúmeros trabalhos demonstraram o efeito neurorregenerador das MSCs sobre essas vias dopaminérgicas perdidas, levando à melhoria nos sintomas. Apesar de todo esse potencial terapêutico, há de se encontrar meios de tornar essas células mais eficientes para um tratamento curativo da doença. Nesse intuito, um passo importante é buscar um protocolo para aumentar a eficiência terapêutica de MSCs de rato por meio de diferenciação prévia, uma vez que esse animal é um dos principais modelos de experimentação e estudo da doença de Parkinson. Por isso, o presente trabalho testou um protocolo de diferenciação prévia de MSCs em células neuron-like dopaminérgicas usando CoCl2 – que ativa o fator transcricional induzido por hipóxia -1 (HIF-1) - e Y-27632, o qual inibe a enzima Rho quinase (ROCK). Para tanto, foram utilizadas células-tronco mesenquimais de medula óssea (bmMSCs) de ratos Wistar cultivadas até entre a quarta passagem e a sétima passagem.As bmMSCs foram separadas em três grupos: G1, no qual elas foram mantidas em meio de cultura; G2, onde elas foram tratadas com CoCl2 por 72 horas; e G3, no qual as bmMSCs foram incubadas com CoCl2 e Y-27632 pelo mesmo tempo. Ao longo de três dias (72 horas) as células foram analisadas à microscopia de contraste de fase. Em seguida, as células foram submetidas à marcação por imunofluorescência para a enzima tirosina hidroxilase (TH) e para a proteína 2 associada à microtúbulo (MAP-2). Algumas células foram separadas para ensaio com ácido glioxílico a fim de detectar catecolamina intracitoplasmática. Na análise microscópica depois de 72 horas, as células do G1 se apresentaram inalteradas, G2 apresentaram aspecto de neuroblastos e as do G3 características neuron-like, com várias ramificações partindo do corpo celular. Na imunofluorescência, as células do G1 não apresentaram marcação, G2 expressou positividade para MAP-2 e G3 para TH e MAP-2. O ensaio com ácido glioxílico revelou que as células do G3 possuíam catecolamina em seu citoplasma. Os resultados indicam que bmMSCs de ratos também são suscetíveis a diferenciação in vitro em células neuron-like catecolaminérgicas após tratadas com CoCl2 e Y-27632. Portanto, considerando esses resultados juntamente com o que é descrito pela literatura é provável que a catecolamina presente no citoplasma das células neuron – like diferenciadas seja a dopamina.Mesenchymal stem cells (MSCs) are adult stem cells found in different tissues and capable of secreting bioactive molecules, migrate to sites of tissue injury and differentiate into cells of different lineages. These characteristics supported years of research using MSCs in experimental models of Parkinson's disease, a neurodegenerative disease characterized by the loss of dopaminergic neurons from the nigro striatal pathway (between the substantia nigra pars compacta and in the striatum). Numerous studies have demonstrated the neurorregenerating effect of MSCs on these lost dopaminergic pathways, leading to improvement in symptoms. Despite all this therapeutic potential, is necessary to find ways of making these cells more efficient for a curative treatment of the disease. To this end, an important step is to seek a protocol to increase the therapeutic efficiency of rat’s MSCs by prior differentiation, since this animal is one of the best models of experimentation and study of Parkinson's disease. Therefore, the present work tested a protocol of prior differentiation of MSCs in dopaminergic neuron-like cells using CoCl2 – which activates the transcriptional factor hypoxia-inducible factor-1 (HIF-1) - and Y-27632, which inhibits the Rho kinase (ROCK) enzyme. For this purpose, we used bone marrow mesenchymal stem cells (bmMSCs) obtained from Wistar rats between the fourth and seventh passage.The bmMSCs were separated into three groups: G1, in which they were maintained in culture medium; G2, where they were treated with CoCl2 for 72 hours; and G3, in which the MSCs were incubated with CoCl2 and Y-27632 for 72 hours as well. Over the course of three days (72 hours) the cells were analyzed by light field microscopy. Then, these cells were labeled with immunocytofluorescence for the enzyme tyrosine hydroxylase (TH) and microtubule-associated protein 2 (MAP-2). Some cells were separated for assay with glyoxylic acid in order to detect intracytoplasmic cathecolamines. On the microscopic analyses after 72 hours, the G1 cells were unchanged; G2 presented neuroblast appearance and the G3 neuron-like characteristics, with several branches from the cell body. In immunocytofluorescence, G1 cells showed no labeling, G2 expressed positivity for MAP-2 and G3 for TH and MAP-2. The glyoxylic acid assay revealed that G3 cells had cathecolamines in their cytoplasm. The results indicate that rat bmMSCs are also susceptible to in vitro differentiation in neuron-like cells after treated with CoCl2 and Y-27632. In adition, considering these results together with what is described in the literature it is likely that the catecholamine present in the cytoplasm of neuron - like cells is dopamine.Fundação de Amparo à Pesquisa do Estado de Minas GeraisUniversidade Federal do Triângulo MineiroInstituto de Ciências da Saúde - ICS::Curso de MedicinaBrasilUFTMPrograma de Pós-Graduação em Ciências FisiológicasSILVA, Valdo José Dias da64003051653http://lattes.cnpq.br/4763314549493316OLIVEIRA, Lucas Felipe07127903654http://lattes.cnpq.br/7569159562428405MENDES FILHO, Daniel2019-09-18T16:30:05Z2017-10-23info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/masterThesisapplication/pdfapplication/pdfMENDES FILHO, Daniel. Diferenciação in vitro de células-tronco mesenquimais de ratos wistar em células neuron-like catecolaminérgicas. 2017. 52f . 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Mol Biol Cell, 2002 Dec; 13(12):4279-95.http://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessreponame:Biblioteca Digital de Teses e Dissertações da UFTMinstname:Universidade Federal do Triangulo Mineiro (UFTM)instacron:UFTM2022-08-10T14:20:31Zoai:bdtd.uftm.edu.br:tede/865Biblioteca Digital de Teses e Dissertaçõeshttp://bdtd.uftm.edu.br/PUBhttp://bdtd.uftm.edu.br/oai/requestbdtd@uftm.edu.br||bdtd@uftm.edu.bropendoar:2024-04-24T09:59:48.407346Biblioteca Digital de Teses e Dissertações da UFTM - Universidade Federal do Triangulo Mineiro (UFTM)false
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