Direct generation of functional dopaminergic neurons from mouse and human fibroblasts

Massimiliano Caiazzo, Maria Teresa Dell'Anno, Elena Dvoretskova, Dejan Lazarevic, Stefano Taverna, Damiana Leo, Tatyana D. Sotnikova, Andrea Menegon, Paola Roncaglia, Giorgia Colciago, Giovanni Russo, Piero Carninci, Gianni Pezzoli, Raul R. Gainetdinov, Stefano Gustincich, Alexander Dityatev, Vania Broccoli

Research output: Contribution to journalArticle

Abstract

Transplantation of dopaminergic neurons can potentially improve the clinical outcome of Parkinson's disease, a neurological disorder resulting from degeneration of mesencephalic dopaminergic neurons. In particular, transplantation of embryonic-stem-cell-derived dopaminergic neurons has been shown to be efficient in restoring motor symptoms in conditions of dopamine deficiency. However, the use of pluripotent-derived cells might lead to the development of tumours if not properly controlled. Here we identified a minimal set of three transcription factors-Mash1 (also known as Ascl1), Nurr1 (also known as Nr4a2) and Lmx1a-that are able to generate directly functional dopaminergic neurons from mouse and human fibroblasts without reverting to a progenitor cell stage. Induced dopaminergic (iDA) cells release dopamine and show spontaneous electrical activity organized in regular spikes consistent with the pacemaker activity featured by brain dopaminergic neurons. The three factors were able to elicit dopaminergic neuronal conversion in prenatal and adult fibroblasts from healthy donors and Parkinson's disease patients. Direct generation of iDA cells from somatic cells might have significant implications for understanding critical processes for neuronal development, in vitro disease modelling and cell replacement therapies.

Original languageEnglish
Pages (from-to)224-227
Number of pages4
JournalNature
Volume476
Issue number7359
DOIs
Publication statusPublished - Aug 11 2011

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    Caiazzo, M., Dell'Anno, M. T., Dvoretskova, E., Lazarevic, D., Taverna, S., Leo, D., Sotnikova, T. D., Menegon, A., Roncaglia, P., Colciago, G., Russo, G., Carninci, P., Pezzoli, G., Gainetdinov, R. R., Gustincich, S., Dityatev, A., & Broccoli, V. (2011). Direct generation of functional dopaminergic neurons from mouse and human fibroblasts. Nature, 476(7359), 224-227. https://doi.org/10.1038/nature10284