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Early transplantation of human immature dental pulp stem cells from baby teeth to golden retriever muscular dystrophy (GRMD) dogs: Local or systemic?

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Kerkis, Irina [1] ; Ambrosio, Carlos E. [2] ; Kerkis, Alexandre [3] ; Martins, Daniele S. [2] ; Zucconi, Eder [4] ; Fonseca, Simone A. S. [1] ; Cabral, Rosa M. [2] ; Maranduba, Carlos M. C. [1] ; Gaiad, Thais P. [2] ; Morini, Adriana C. [2] ; Vieira, Natassia M. [4] ; Brolio, Marina P. [2] ; Sant'Anna, Osvaldo A. [1] ; Miglino, Maria A. [2] ; Zatz, Mayana [4]
Número total de Autores: 15
Afiliação do(s) autor(es):
[1] Inst Butantan, Lab Genet & Imunoquim, Sao Paulo - Brazil
[2] Univ Sao Paulo, Fac Med Vet, Dept Cirurg, BR-05508 Sao Paulo - Brazil
[3] Atividades Vet LTD, Genet Aplicada, Sao Paulo - Brazil
[4] Univ Sao Paulo, Dept Genet & Biol Evolut, Ctr Estudos Genoma Humano, BR-05508 Sao Paulo - Brazil
Número total de Afiliações: 4
Tipo de documento: Artigo Científico
Citações Web of Science: 102

Background: The golden retriever muscular dystrophy (GRMD) dogs represent the best available animal model for therapeutic trials aiming at the future treatment of human Duchenne muscular dystrophy (DMD). We have obtained a rare litter of six GRMD dogs (3 males and 3 females) born from an affected male and a carrier female which were submitted to a therapeutic trial with adult human stem cells to investigate their capacity to engraft into dogs muscles by local as compared to systemic injection without any immunosuppression. Methods: Human Immature Dental Pulp Stem Cells (hIDPSC) were transplanted into 4 littermate dogs aged 28 to 40 days by either arterial or muscular injections. Two non-injected dogs were kept as controls. Clinical translation effects were analyzed since immune reactions by blood exams and physical scores capacity of each dog. Samples from biopsies were checked by immunohistochemistry (dystrophin markers) and FISH for human probes. Results and Discussion: We analyzed the cells' ability in respect to migrate, engraftment, and myogenic potential, and the expression of human dystrophin in affected muscles. Additionally, the efficiency of single and consecutive early transplantation was compared. Chimeric muscle fibers were detected by immunofluorescence and fluorescent in situ hybridisation (FISH) using human antibodies and X and Y DNA probes. No signs of immune rejection were observed and these results suggested that hIDPSC cell transplantation may be done without immunosuppression. We showed that hIDPSC presented significant engraftment in GRMD dog muscles, although human dystrophin expression was modest and limited to several muscle fibers. Better clinical condition was also observed in the dog, which received monthly arterial injections and is still clinically stable at 25 months of age. Conclusion: Our data suggested that systemic multiple deliveries seemed more effective than local injections. These findings open important avenues for further researches. (AU)

Processo FAPESP: 04/15370-9 - Potencial terapêutico de células tronco em cães GRMD (Golden Retriever Muscular Dystrophy)
Beneficiário:Carlos Eduardo Ambrósio
Linha de fomento: Bolsas no Brasil - Pós-Doutorado
Processo FAPESP: 05/50082-7 - Avaliação "in vivo" do potencial terapêutico de células tronco no modelo animal GRMD (Golden Retriever Muscular Dystrophy)
Beneficiário:Maria Angelica Miglino
Linha de fomento: Auxílio à Pesquisa - Regular
Processo FAPESP: 98/14254-2 - Centro de Estudos do Genoma Humano
Beneficiário:Mayana Zatz
Linha de fomento: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs