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

被引：284

作者：

Gascon, Sergio ^{[1
,2
]}

Murenu, Elisa ^{[1
,2
]}

Masserdotti, Giacomo ^{[1
,2
]}

Ortega, Felipe ^{[1
,3
,4
]}

Russo, Gianluca L. ^{[1
,2
]}

Petrik, David ^{[1
,2
]}

Deshpande, Aditi ^{[1
,14
,15
]}

Heinrich, Christophe ^{[1
,16
]}

Karow, Marisa ^{[1
]}

Robertson, Stephen P. ^{[5
]}

Schroeder, Timm ^{[6
,17
]}

Beckers, Johannes ^{[7
,8
,9
]}

Irmler, Martin ^{[8
]}

Berndt, Carsten ^{[10
]}

Angeli, Jose P. Friedmann ^{[11
]}

Conrad, Marcus ^{[11
]}

Berninger, Benedikt ^{[1
,3
,12
]}

Goetz, Magdalena ^{[1
,2
,13
]}

机构：

[1] Univ Munich, Biomed Ctr, Physiol Genom, D-80336 Munich, Germany

[2] Helmholtz Ctr Munich, Inst Stem Cell Res, D-85764 Neuherberg, Germany

[3] Johannes Gutenberg Univ Mainz, Univ Med Ctr, Inst Physiol Chem, D-55128 Mainz, Germany

[4] Univ Complutense, Fac Vet Med, Dept Biochem & Mol Biol, E-28040 Madrid, Spain

[5] Univ Otago, Dunedin Sch Med, Dept Womens & Childrens Hlth, Dunedin 9016, New Zealand

[6] Helmholtz Ctr Munich, Res Unit Stem Cell Dynam, D-85764 Neuherberg, Germany

[7] German Ctr Diabet Res DZD, D-85764 Neuherberg, Germany

[8] Helmholtz Ctr Munich GmbH, Inst Expt Genet, D-85764 Neuherberg, Germany

[9] Tech Univ Munich, Ctr Life & Food Sci Weihenstephan, D-85354 Freising Weihenstephan, Germany

[10] Univ Dusseldorf, Fac Med, Dept Neurol, Merowingerpl 1a, D-40225 Dusseldorf, Germany

[11] Helmholtz Ctr Munich, Inst Dev Genet, D-85764 Neuherberg, Germany

[12] Johannes Gutenberg Univ Mainz, Focus Program Translat Neurosci, D-55128 Mainz, Germany

[13] Excellence Cluster Syst Neurol SYNERGY, D-80336 Munich, Germany

[14] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA

[15] Univ Calif San Francisco, Inst Human Genet, San Francisco, CA 94143 USA

[16] Univ Grenoble Alpes, INSERM, U1216, Grenoble Inst Neurosci, F-38000 Grenoble, France

[17] Swiss Fed Inst Technol, Dept Biosyst Sci & Engn, Mattenstr 26, CH-4058 Basel, Switzerland

来源：

CELL STEM CELL | 2016年 / 18卷 / 03期

关键词：

NONAPOPTOTIC CELL-DEATH; OXIDATIVE STRESS; IN-VIVO; BRAIN-INJURY; VITAMIN-D; MITOCHONDRIAL METABOLISM; LIPID-PEROXIDATION; FUNCTIONAL-NEURONS; DIRECT CONVERSION; PROGENITOR CELLS;

D O I：

10.1016/j.stem.2015.12.003

中图分类号：

Q813 [细胞工程];

学科分类号：

摘要：

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.

引用

页码：396 / 409

页数：14

共 58 条

[1] Interactions of Oxidative Stress and Neurovascular Inflammation in the Pathogenesis of Traumatic Brain Injury [J].