Mitomycin-treated undifferentiated embryonic stem cells as a safe and effective therapeutic strategy in a mouse model of Parkinson’s disease

Submitted by sandra infurna ([email protected]) on 2016-04-18T14:01:10Z No. of bitstreams: 1 gabriel_oliveira_etal_IOC_2015.pdf: 2045662 bytes, checksum: 8b60ebdede62c9d97710ca34971463a1 (MD5)Approved for entry into archive by sandra infurna ([email protected]) on 2016-04-18T14:20:55Z (GMT) No. of bitstreams: 1 gabriel_oliveira_etal_IOC_2015.pdf: 2045662 bytes, checksum: 8b60ebdede62c9d97710ca34971463a1 (MD5)Made available in DSpace on 2016-04-18T14:20:55Z (GMT). No. of bitstreams: 1 gabriel_oliveira_etal_IOC_2015.pdf: 2045662 bytes, checksum: 8b60ebdede62c9d97710ca34971463a1 (MD5) Previous issue date: 2015Universidade Federal do Rio de Janeiro. Centro de Ciências da Saúde. Instituto de Biociências. Rio de Janeiro, RJ, Brasil.Universidade Federal do Rio de Janeiro. Centro de Ciências da Saúde. Instituto de Biociências. Rio de Janeiro, RJ, Brasil.Instituto D`Or de Pesquisa e Educação. Rio de Janeiro, RJ, Brasil.Universidade Federal do Rio de Janeiro. Instituto de Bioquímica Leopoldo de Meis. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Rio de Janeiro, RJ, Brasil.Universidade Federal do Rio de Janeiro. Instituto de Bioquímica Leopoldo de Meis. Rio de Janeiro, RJ, Brasil.Universidade Federal do Rio de Janeiro. Centro de Ciências da Saúde. Instituto de Biociências. Rio de Janeiro, RJ, Brasil.Universidade Federal do Rio de Janeiro. Centro de Ciências da Saúde. Instituto de Biociências. Rio de Janeiro, RJ, Brasil / Instituto D`Or de Pesquisa e Educação. Rio de Janeiro, RJ, Brasil.Universidade Federal do Rio de Janeiro. Centro de Ciências da Saúde. Instituto de Biociências. Rio de Janeiro, RJ, Brasil.Universidade Federal do Rio de Janeiro. Centro de Ciências da Saúde. Instituto de Biociências. Rio de Janeiro, RJ, Brasil / Instituto D`Or de Pesquisa e Educação. Rio de Janeiro, RJ, Brasil.Parkinson’s disease (PD) is an incurable progressive neurodegenerative disorder. Clinical presentation of PD stems largely from the loss of dopaminergic neurons in the nigrostriatal dopaminergic pathway, motivating experimental strategies of replacement based on cell therapy. Transplantation of dopaminergic neurons derived from embryonic stem cells significantly improves motor functions in rodent and non-human primate models of PD. However, protocols to generate dopaminergic neurons from embryonic stem cells generally meet with low efficacy and high risk of teratoma formation upon transplantation. To address these issues, we have pre-treated undifferentiated mouse embryonic stem cells (mESCs) with the DNA alkylating agent mitomycin C (MMC) before transplantation. MMC treatment of cultures prevented tumorigenesis in a 12 week follow-up after mESCs were injected in nude mice. In 6-OH-dopamine-lesioned mice, intrastriatal injection of MMC-treated mESCs markedly improved motor function without tumor formation for as long as 15 months. Furthermore, we show that halting mitotic activity of undifferentiated mESCs induces a four-fold increase in dopamine release following in vitro differentiation. Our findings indicate that treating mESCs with MMC prior to intrastriatal transplant is an effective to strategy that could be further investigated as a novel alternative for treatment of PD