Overcoming barriers in Direct Neuronal Reprogramming for disease modeling and brain repair

Seminar

  • Date: Jan 25, 2017
  • Time: 03:00 PM - 04:00 PM (Local Time Germany)
  • Speaker: Sergio Gascón
  • Department of Physiological Genomics, Ludwig-Maximilians-University, Planegg-Martinsried, Germany
  • Location: Max Planck Institute of Psychiatry
  • Room: Kraepelin Seminarroom
  • Host: Silvia Cappello
  • Contact: silvia_cappello@psych.mpg.de
Overcoming barriers in Direct Neuronal Reprogramming for disease modeling and brain repair
Direct reprogramming of somatic cells into different lineages allows generation of cell types that cannot otherwise be easily harnessed, such as human neurons from the central nervous system. This raises the exciting possibility of reprogramming-based therapies that may replenish cell populations using other cells surrounding an injured area in vivo. Moreover, direct reprogramming can be used as an alternative to iPSCs to model human diseases, with the advantages that lineage direct conversion is fast and does not imply cell rejuvenation. However, the efficiency of conversion mediated by transcription factors and/or small molecules is highly dependent of the cellular context.

Therefore we investigated the molecular processes underpinning cell fate re-specification. We have demonstrated that during reprogramming, the conversion of metabolic pathways from a glycolytic-metabotype typical of proliferative cells to a mitochondrial-dependent oxidative metabolism characteristic of postmitotic neurons is linked to an oxidative overshoot that induces cell death by ferroptosis. However, cells forced to remain in anaerobic glycolysis do not die but also do not convert, indicating that the metabolic conversion is up-stream of cell fate changes. Thus, expression of anti-oxidative proteins, such as Bcl-2 or its upstream regulator P-CREB, and/or treatments with anti-oxidant molecules lead to an unprecedented improvement in neuronal conversion of glial cells in vivo, reaching 90% transduced cells turning into neurons in the adult mouse cerebral cortex after stab wound injury, and also many cell types in vitro irrespectively of the transcription factor used for the conversion.

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