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Cell Stem Cell. 2016 Mar 3;18(3):396-409. doi: 10.1016/j.stem.2015.12.003. Epub 2015 Dec 31.

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

Author information

1
Physiological Genomics, Biomedical Center Ludwig-Maximilians-University Munich, 80336 Munich, Germany; Institute for Stem Cell Research, Helmholtz Center Munich, 85764 Neuherberg, Germany. Electronic address: sergio.gascon@med.uni-muenchen.de.
2
Physiological Genomics, Biomedical Center Ludwig-Maximilians-University Munich, 80336 Munich, Germany; Institute for Stem Cell Research, Helmholtz Center Munich, 85764 Neuherberg, Germany.
3
Physiological Genomics, Biomedical Center Ludwig-Maximilians-University Munich, 80336 Munich, Germany; Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University Mainz, 55128 Mainz, Germany; Biochemistry and Molecular Biology Department, Faculty of Veterinary Medicine, Complutense University, Avenue Puerta de Hierro, 28040 Madrid, Spain.
4
Physiological Genomics, Biomedical Center Ludwig-Maximilians-University Munich, 80336 Munich, Germany.
5
Department of Women's and Children's Health, Dunedin School of Medicine, University of Otago, 9016 Dunedin, New Zealand.
6
Research Unit Stem Cell Dynamics, Helmholtz Center Munich, Neuherberg, 85764 Neuherberg, Germany.
7
German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany; Institute of Experimental Genetics, Helmholtz Center Munich GmbH, 85764 Neuherberg, Germany; Center of Life and Food Sciences Weihenstephan, Technical University Munich, 85354 Freising, Germany.
8
Institute of Experimental Genetics, Helmholtz Center Munich GmbH, 85764 Neuherberg, Germany.
9
Department of Neurology, Medical Faculty, Heinrich-Heine University Düsseldorf, Merowingerplatz 1a, 40225 Düsseldorf, Germany.
10
Institute of Developmental Genetics, Helmholtz Center Munich, 85764 Neuherberg, Germany.
11
Physiological Genomics, Biomedical Center Ludwig-Maximilians-University Munich, 80336 Munich, Germany; Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University Mainz, 55128 Mainz, Germany; Focus Program Translational Neuroscience, Johannes Gutenberg University Mainz, 55128 Mainz, Germany.
12
Physiological Genomics, Biomedical Center Ludwig-Maximilians-University Munich, 80336 Munich, Germany; Institute for Stem Cell Research, Helmholtz Center Munich, 85764 Neuherberg, Germany; Excellence Cluster of Systems Neurology (SYNERGY), 80336 Munich, Germany. Electronic address: magdalena.goetz@helmholtz-muenchen.de.

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.

PMID:
26748418
DOI:
10.1016/j.stem.2015.12.003
[Indexed for MEDLINE]
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