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

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 und Götz, Magdalena (2016): Identification and Successful Negotiation of a Metabolic Checkpoint in Direct Neuronal Reprogramming. In: Cell Stem Cell, Bd. 18, Nr. 3: S. 396-409

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.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 1934-5909
• Sprache: Englisch