Cell Stem Cell
Volume 18, Issue 3, 3 March 2016, Pages 396-409
Journal home page for Cell Stem Cell

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

https://doi.org/10.1016/j.stem.2015.12.003Get rights and content
Under an Elsevier user license
open archive

Highlights

  • Oxidative stress is a major hurdle in converting different cell types into neurons

  • Ferroptosis inhibitors and antioxidants improve direct neuronal reprogramming

  • Bcl-2 reduces ROS and promotes direct neuronal reprogramming also in vivo

  • Antioxidants potently improve maturation of induced neurons in vitro and in vivo

Summary

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.

Cited by (0)

14

Co-first author

15

Present address: Department of Psychiatry and Institute for Human Genetics, University of California San Francisco, San Francisco, CA 94143, USA

16

Present address: INSERM, U1216, University Grenoble Alpes, Grenoble Institut des Neurosciences, GIN, F-38000 Grenoble, France

17

Present address: Department of Biosystems Science and Engineering, ETH Zurich, Mattenstrasse 26, 4058 Basel, Switzerland