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Doctoral Thesis
DOI
10.11606/T.41.2011.tde-12052011-141339
Document
Author
Full name
Natassia Moreira da Silva Vieira
E-mail
Institute/School/College
Knowledge Area
Date of Defense
Published
São Paulo, 2010
Supervisor
Committee
Zatz, Mayana (President)
Haddad, Luciana Amaral
Pranke, Patricia Helena Lucas
Vainzof, Mariz
Zago, Marco Antonio
Title in Portuguese
Avaliação do potencial terapêutico de células-tronco de tecido adiposo para doenças neuromusculares progressivas
Keywords in Portuguese
Células-tronco
Distrofia muscular
Tecido adiposo
Abstract in Portuguese
As Distrofias Musculares Progressivas (DMP) constituem um grupo de doenças genéticas caracterizadas por uma degeneração progressiva e irreversível da musculatura esquelética. A Distrofia Muscular de Duchenne (DMD) é a forma mais comum e grave de DMP. Obedece a herança recessiva ligada ao X e é caracterizada pela ausência de distrofina na membrana das fibras musculares. Atualmente não existe nenhum tratamento efetivo para este grupo de doenças. Deste modo, este trabalho tem como objetivo principal avaliar o potencial terapêutico das células-tronco mesenquimais de tecido adiposo humano (human Adipose-derived Stem Cells - hASCs) visando à regeneração ou diminuição da degeneração muscular. Para tanto, verificamos o potencial miogênico destas células in vitro, utilizando células musculares de pacientes DMD e in vivo utilizando como modelo camundongos distróficos e cães da raça Golden Retriever portadores de distrofia muscular (GRMD - Golden Retriever Muscular Dystrophy). Demonstramos neste estudo que hASCs são capazes de restaurar a expressão de distrofina in vitro, quando co-cultivadas com células musculares de pacientes DMD. Frente a estes resultados, continuamos nossos estudos em modelos animais, in vivo, e demonstramos que as hASCs são capazes de chegar à musculatura de camundongos distróficos e de cães GRMD, quando injetadas por via venosa, e de restaurar a expressão da proteína muscular defeituosa. Foi possível observar uma melhora funcional nos camundongos injetados. Nos cães GRMD encontramos distrofina humana seis meses após a última injeção entretanto é difícil julgar se houve melhora clínica. Todos esses experimentos de xenotransplantes foram feitos sem imunosupressão e não observamos rejeição. Concluímos que o tecido adiposo é uma fonte de células-tronco com potencial para regeneração muscular in vivo. Contudo é de extrema importância repetir os experimentos em um número maior de cães GRMD e ainda investigar novas estratégias visando melhorar os resultados obtidos neste trabalho, antes de começar qualquer teste clínico.
Title in English
Potential cell therapy for progressive muscular dystrophies using human adipose-derived stem cells
Keywords in English
Adipose tissue
Muscular dystrophies
Stem cells
Abstract in English
Progressive muscular dystrophies (PMD) are a clinically and genetically heterogeneous group of disorders caused by the deficiency or abnormal muscle proteins, resulting in progressive degeneration and loss of skeletal muscle function. As effective treatments for these diseases are still unavailable, they have been widely investigated as possible candidates for stem cell therapy. Duchenne Muscular Dystrophy (DMD), a lethal X-linked disorder, is the most common and severe form of muscular dystrophies, affecting 1 in 3000 male births. Mutations in the DMD gene lead to the absence of muscle dystrophin. The aim of this study is to evaluate the therapeutic potential of human Adipose-derived Stem Cells (hASCs) for muscle regeneration. First we verified the myogenic potential of these cells in vitro co-culturing them with muscle cells from DMD patients and verifying that hASCs are able to restore dystrophin expression in vitro. Subsequently we repeated this experiment in vivo using the dystrophic mice SJL and the dystrophic golden retriever dogs (GRMD - Golden Retriever Muscular Dystrophy) as animal models. We demonstrated that the hASCs are able to reach the muscles of the dystrophic mice and the GRMD dogs when injected systemically and restore expression of absent muscle protein, without any immunosupression. We observed a functional improvement in the injected mice. We found human dystrophin in injected dogs up to 6 months after the last injection. However it is difficult to evaluate if there was clinical improvement in the GRMD dogs due to their great phenotypic variability. We conclude that the adipose tissue is a source of stem cells with potential for muscle regeneration in vivo and that human cells are not rejected even in xenotransplants without immunosuppression. However it is important to repeat the experiments on a larger number of GRMD dogs and to investigate new strategies to improve our findings before starting any clinical trial.
 
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Publishing Date
2011-05-19
 
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