Identification and Successful Negotiation of a Metabolic Checkpoint in Direct Neuronal Reprogramming.
Cell Stem Cell
; 18(3): 396-409, 2016 Mar 03.
Article
em En
| MEDLINE
| ID: mdl-26748418
ABSTRACT
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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1
Base de dados:
MEDLINE
Assunto principal:
Transdução Genética
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Neuroglia
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Proteínas Proto-Oncogênicas c-bcl-2
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Reprogramação Celular
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Técnicas de Reprogramação Celular
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Neurônios
Idioma:
En
Ano de publicação:
2016
Tipo de documento:
Article