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
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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.
AbstractList	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.
Author	Gascón, Sergio Masserdotti, Giacomo Deshpande, Aditi Heinrich, Christophe Angeli, José P Friedmann Götz, Magdalena Conrad, Marcus Russo, Gianluca L Petrik, David Berninger, Benedikt Karow, Marisa Schroeder, Timm Murenu, Elisa Beckers, Johannes Irmler, Martin Berndt, Carsten Ortega, Felipe Robertson, Stephen P
Author_xml	– sequence: 1 givenname: Sergio surname: Gascón fullname: Gascón, Sergio email: sergio.gascon@med.uni-muenchen.de organization: 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 – sequence: 2 givenname: Elisa surname: Murenu fullname: Murenu, Elisa organization: Physiological Genomics, Biomedical Center Ludwig-Maximilians-University Munich, 80336 Munich, Germany; Institute for Stem Cell Research, Helmholtz Center Munich, 85764 Neuherberg, Germany – sequence: 3 givenname: Giacomo surname: Masserdotti fullname: Masserdotti, Giacomo organization: Physiological Genomics, Biomedical Center Ludwig-Maximilians-University Munich, 80336 Munich, Germany; Institute for Stem Cell Research, Helmholtz Center Munich, 85764 Neuherberg, Germany – sequence: 4 givenname: Felipe surname: Ortega fullname: Ortega, Felipe organization: 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 – sequence: 5 givenname: Gianluca L surname: Russo fullname: Russo, Gianluca L organization: Physiological Genomics, Biomedical Center Ludwig-Maximilians-University Munich, 80336 Munich, Germany; Institute for Stem Cell Research, Helmholtz Center Munich, 85764 Neuherberg, Germany – sequence: 6 givenname: David surname: Petrik fullname: Petrik, David organization: Physiological Genomics, Biomedical Center Ludwig-Maximilians-University Munich, 80336 Munich, Germany; Institute for Stem Cell Research, Helmholtz Center Munich, 85764 Neuherberg, Germany – sequence: 7 givenname: Aditi surname: Deshpande fullname: Deshpande, Aditi organization: Physiological Genomics, Biomedical Center Ludwig-Maximilians-University Munich, 80336 Munich, Germany – sequence: 8 givenname: Christophe surname: Heinrich fullname: Heinrich, Christophe organization: Physiological Genomics, Biomedical Center Ludwig-Maximilians-University Munich, 80336 Munich, Germany – sequence: 9 givenname: Marisa surname: Karow fullname: Karow, Marisa organization: Physiological Genomics, Biomedical Center Ludwig-Maximilians-University Munich, 80336 Munich, Germany – sequence: 10 givenname: Stephen P surname: Robertson fullname: Robertson, Stephen P organization: Department of Women's and Children's Health, Dunedin School of Medicine, University of Otago, 9016 Dunedin, New Zealand – sequence: 11 givenname: Timm surname: Schroeder fullname: Schroeder, Timm organization: Research Unit Stem Cell Dynamics, Helmholtz Center Munich, Neuherberg, 85764 Neuherberg, Germany – sequence: 12 givenname: Johannes surname: Beckers fullname: Beckers, Johannes organization: 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 – sequence: 13 givenname: Martin surname: Irmler fullname: Irmler, Martin organization: Institute of Experimental Genetics, Helmholtz Center Munich GmbH, 85764 Neuherberg, Germany – sequence: 14 givenname: Carsten surname: Berndt fullname: Berndt, Carsten organization: Department of Neurology, Medical Faculty, Heinrich-Heine University Düsseldorf, Merowingerplatz 1a, 40225 Düsseldorf, Germany – sequence: 15 givenname: José P Friedmann surname: Angeli fullname: Angeli, José P Friedmann organization: Institute of Developmental Genetics, Helmholtz Center Munich, 85764 Neuherberg, Germany – sequence: 16 givenname: Marcus surname: Conrad fullname: Conrad, Marcus organization: Institute of Developmental Genetics, Helmholtz Center Munich, 85764 Neuherberg, Germany – sequence: 17 givenname: Benedikt surname: Berninger fullname: Berninger, Benedikt organization: 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 – sequence: 18 givenname: Magdalena surname: Götz fullname: Götz, Magdalena email: magdalena.goetz@helmholtz-muenchen.de organization: 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
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References	26942845 - Cell Stem Cell. 2016 Mar 3;18(3):297-9 28217709 - Stem Cell Investig. 2017 Feb 09;4:7
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SubjectTerms	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
Title	Identification and Successful Negotiation of a Metabolic Checkpoint in Direct Neuronal Reprogramming
URI	https://www.ncbi.nlm.nih.gov/pubmed/26748418 https://www.proquest.com/docview/1770876547
Volume	18
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