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Doctoral Thesis
DOI
10.11606/T.41.2009.tde-13092009-153027
Document
Author
Full name
Eder Zucconi
E-mail
Institute/School/College
Knowledge Area
Date of Defense
Published
São Paulo, 2009
Supervisor
Committee
Zatz, Mayana (President)
Haddad, Luciana Amaral
Krieger, Jose Eduardo
Vainzof, Mariz
Zago, Marco Antonio
Title in Portuguese
Isolamento e caracterização de células-tronco caninas do cordão umbilical para uso potencial em transplantes de cães distróficos
Keywords in Portuguese
Células-tronco
Cordão umbilical
Distrofia Muscular
Abstract in Portuguese
A Distrofia Muscular de Duchenne (DMD) é a forma mais comum e grave de Distrofia Muscular Progressiva. Esta doença possui herança recessiva ligada ao X e é caracterizada pela ausência de distrofina na membrana das fibras musculares. A DMD afeta 1/3.000 meninos nascidos vivos, e até os 12 anos de idade os pacientes são confinados à cadeira de rodas. Os afetados raramente sobrevivem após a terceira década de vida. Atualmente nenhum tratamento efetivo ainda foi desenvolvido para esta doença. Deste modo, nosso trabalho tem como objetivo principal contribuir para o entendimento do potencial terapêutico das células-tronco adultas do cordão umbilical visando a regeneração muscular. Para tanto, utilizamos como modelo cães da raça Golden Retriever portadores de distrofia muscular (GRMD Golden Retriever Muscular Dystrophy), uma vez que estes cães apresentam um quadro clínico muito semelhante com a patologia clínica humana. Demonstramos em nosso estudo que células hematopoiéticas provenientes do cordão umbilical canino não são capazes de restaurar a expressão de distrofina em níveis clinicamente relevantes em cães GRMDs. Frente a estes resultados, decidimos dar continuidade em nossos estudos com as células-tronco mesenquimais (CTMs) do cordão umbilical humano e canino as quais foram imunofenotipadas e caracterizadas, in vitro, quanto ao potencial de diferenciação. In vivo, demonstramos que as CTMs do cordão umbilical canino são capazes de chegar à musculatura de cães GRMDs, quando injetadas por via arterial, mas não de restaurar a expressão de distrofina em níveis clinicamente relevantes. Por fim, descrevemos um cão GRMD excepcional, Ringo, que apesar da completa ausência de distrofina nas fibras musculares, apresenta um fenótipo leve de distrofia muscular. Concluímos com nosso estudo que células-tronco do cordão umbilical parece não ser a fonte mais adequada para a regeneração muscular In vivo. Contudo é de extrema importância investigar novas estratégias visando melhorar o direcionamento destas células para o músculo esquelético.
Title in English
Isolation and characterization of canine umbilical cord stem cells for potential use in transplantation of dystrophic dogs
Keywords in English
Muscular dystrophy
Stem Cells
Umbilical cord
Abstract in English
Duchenne Muscular Dystrophy (DMD) is the most frequent and severe form of muscular dystrophy. It is an X-linked recessive disorder caused by complete absence of dystrophin in muscle fibers. DMD affects 1/3.000 living boys, with loss of independent ambulation occurring at approximately 12 years old. Without any special care, affected boys rarely survive beyond the third decade of life. Currently there is no treatment available for these patients, thus, the main purpose of these study is to understand the therapeutic contribution of umbilical cord stem cells aiming muscular regeneration. To perform our investigation we chose Golden Retriever Muscular Dystrophy (GRMD) dogs, since it is a large animal model of DMD with clinical signs closely mimicking those observed in humans. Here we showed that hematopoietic cells from umbilical cord blood failed to restore dystrophin expression at clinically relevant levels in GRMD dogs. Due to these results, we continued our studies with human and canine mesenchymal stem cells (MSCs) from umbilical cord, which were immunophenotyped and had their multipotent plasticity demonstrated in vitro. Using GRMD dogs we also showed that human and canine MSCs from umbilical cord were able to engraft in muscle fibers but were not sufficient to restore dystrophin expression at clinically relevant levels In vivo. Finally, we described an exceptional GRMD dog, Ringo, that besides the complete absence of dystrophin in his muscle fibers is showing a very mild phenotype. In conclusion, umbilical cord stem cells transplantation may not be a promising source for skeletal muscle regeneration In vivo, but further studies must take place in order to improve stem cell delivery to skeletal muscle.
 
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ederzucconi.pdf (32.83 Mbytes)
Publishing Date
2009-10-05
 
WARNING: The material described below relates to works resulting from this thesis or dissertation. The contents of these works are the author's responsibility.
  • AMBRóSIO, C.E., et al. Ringo, a Golden Retriever Muscular Dystrophy (GRMD) dog with absent dystrophin but normal strength [doi:10.1016/j.nmd.2008.06.385]. Neuromuscular Disorders [online], 2008, vol. 18, n. 11, p. 892-893.
  • SECCO, Mariane, et al. Mesenchymal stem cells from umbilical cord : Do not discard the cord! [doi:10.1016/j.nmd.2007.11.003]. Neuromuscular Disorders [online], 2008, vol. 18, n. 1, p. 17-18.
  • SECCO, Mariane, et al. Multipotent Stem Cells from Umbilical Cord : Cord Is Richer than Blood! [doi:10.1634/stemcells.2007-0381]. Stem Cells [online], 2008, vol. 26, n. 1, p. 146-150.
  • ZUCCONI, Eder, et al. Mesenchymal Stem Cells Derived From Canine Umbilical Cord Vein—A Novel Source for Cell Therapy Studies [doi:10.1089/scd.2008.0314]. Stem Cells and Development [online], 2010, vol. 19, n. 3, p. 395-402.
  • ZUCCONI, Eder, et al. Preclinical Studies with Umbilical Cord Mesenchymal Stromal Cells in Different Animal Models for Muscular Dystrophy [doi:10.1155/2011/715251]. Journal of Biomedicine and Biotechnology [online], 2011, vol. 2011, p. 1-9.
  • ZUCCONI, Eder, et al. Ringo : Discordance between the molecular and clinical manifestation in a Golden Retriever Muscular Dystrophy dog [doi:10.1016/j.nmd.2009.10.011]. Neuromuscular Disorders [online], 2010, vol. 20, n. 1, p. 64-70.
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