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Identification and successful negotiation of a metabolic checkpoint in direct neuronal repogramming.

Cell Stem Cell 18, 396-409 (2016)
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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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Publication type Article: Journal article
Document type Scientific Article
Keywords Nonapoptotic Cell-death; Oxidative Stress; In-vivo; Brain-injury; Vitamin-d; Mitochondrial Metabolism; Lipid-peroxidation; Functional-neurons; Direct Conversion; Progenitor Cells
Reviewing status