title: Mitomycin-treated undifferentiated embryonic stem cells as a safe and effective therapeutic strategy in a mouse model of Parkinson's disease.
abstract: 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.
authors.affiliation: Institute of Biomedical Sciences, Federal University of Rio de Janeiro Rio de Janeiro, Brazil.
authors.forename: Mariana
authors.initials: M
authors.lastname: Acquarone
authors.affiliation: Institute of Biomedical Sciences, Federal University of Rio de Janeiro Rio de Janeiro, Brazil.
authors.forename: Thiago M
authors.initials: TM
authors.lastname: de Melo
authors.affiliation: D'Or Institute for Research and Education (IDOR) Rio de Janeiro, Brazil.
authors.forename: Fernanda
authors.initials: F
authors.lastname: Meireles
authors.affiliation: Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro Rio de Janeiro, Brazil.
authors.forename: Jordano
authors.initials: J
authors.lastname: Brito-Moreira
authors.affiliation: Oswaldo Cruz Institute, Oswaldo Cruz Foundation Rio de Janeiro, Brazil.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Oliveira
authors.affiliation: Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro Rio de Janeiro, Brazil.
authors.forename: Sergio T
authors.initials: ST
authors.lastname: Ferreira
authors.affiliation: Institute of Biomedical Sciences, Federal University of Rio de Janeiro Rio de Janeiro, Brazil.
authors.forename: Newton G
authors.initials: NG
authors.lastname: Castro
authors.affiliation: Institute of Biomedical Sciences, Federal University of Rio de Janeiro Rio de Janeiro, Brazil ; D'Or Institute for Research and Education (IDOR) Rio de Janeiro, Brazil.
authors.forename: Fernanda
authors.initials: F
authors.lastname: Tovar-Moll
authors.affiliation: Institute of Biomedical Sciences, Federal University of Rio de Janeiro Rio de Janeiro, Brazil.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Houzel
authors.affiliation: Institute of Biomedical Sciences, Federal University of Rio de Janeiro Rio de Janeiro, Brazil ; D'Or Institute for Research and Education (IDOR) Rio de Janeiro, Brazil.
authors.forename: Stevens K
authors.initials: SK
authors.lastname: Rehen
keywords: Parkinson model; contrast-enhanced MRI; embryonic stem cell; mitomycin C; stem cell therapy