Identification and Successful Negotiation of a Metabolic Checkpoint in Direct Neuronal Reprogramming

Despite the widespread interest in direct neuronal reprogramming, the mechanisms underpinning fate conversion remain largely unknown. Our study revealed a critical time point after which cells either successfully convert into neurons or succumb to cell death. Co-transduction with Bcl-2 greatly impro...

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Published in:Cell stem cell Vol. 18; no. 3; pp. 396 - 409
Main Authors: Gascón, Sergio, Murenu, Elisa, Masserdotti, Giacomo, Ortega, Felipe, Russo, Gianluca L, Petrik, David, Deshpande, Aditi, Heinrich, Christophe, Karow, Marisa, Robertson, Stephen P, Schroeder, Timm, Beckers, Johannes, Irmler, Martin, Berndt, Carsten, Angeli, José P Friedmann, Conrad, Marcus, Berninger, Benedikt, Götz, Magdalena
Format: Journal Article
Language:English
Published: United States 03.03.2016
Subjects:
Animals
Cellular Reprogramming
Cellular Reprogramming Techniques
Mice
Neuroglia - cytology
Neuroglia - metabolism
Neurons - cytology
Neurons - metabolism
Oxidative Stress
Proto-Oncogene Proteins c-bcl-2 - biosynthesis
Proto-Oncogene Proteins c-bcl-2 - genetics
Transduction, Genetic
ISSN:1875-9777
Online Access:Get more information
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Summary:Despite the widespread interest in direct neuronal reprogramming, the mechanisms underpinning fate conversion remain largely unknown. Our study revealed a critical time point after which cells either successfully convert into neurons or succumb to cell death. Co-transduction with Bcl-2 greatly improved negotiation of this critical point by faster neuronal differentiation. Surprisingly, mutants with reduced or no affinity for Bax demonstrated that Bcl-2 exerts this effect by an apoptosis-independent mechanism. Consistent with a caspase-independent role, ferroptosis inhibitors potently increased neuronal reprogramming by inhibiting lipid peroxidation occurring during fate conversion. Genome-wide expression analysis confirmed that treatments promoting neuronal reprogramming elicit an anti-oxidative stress response. Importantly, co-expression of Bcl-2 and anti-oxidative treatments leads to an unprecedented improvement in glial-to-neuron conversion after traumatic brain injury in vivo, underscoring the relevance of these pathways in cellular reprograming irrespective of cell type in vitro and in vivo.
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ISSN:1875-9777
DOI:10.1016/j.stem.2015.12.003