In vivo direct reprogramming of reactive glial cells into functional neurons after brain injury and in an Alzheimer's disease model

Cell Stem Cell. 2014 Feb 6;14(2):188-202. doi: 10.1016/j.stem.2013.12.001. Epub 2013 Dec 19.

Abstract

Loss of neurons after brain injury and in neurodegenerative disease is often accompanied by reactive gliosis and scarring, which are difficult to reverse with existing treatment approaches. Here, we show that reactive glial cells in the cortex of stab-injured or Alzheimer's disease (AD) model mice can be directly reprogrammed into functional neurons in vivo using retroviral expression of a single neural transcription factor, NeuroD1. Following expression of NeuroD1, astrocytes were reprogrammed into glutamatergic neurons, while NG2 cells were reprogrammed into glutamatergic and GABAergic neurons. Cortical slice recordings revealed both spontaneous and evoked synaptic responses in NeuroD1-converted neurons, suggesting that they integrated into local neural circuits. NeuroD1 expression was also able to reprogram cultured human cortical astrocytes into functional neurons. Our studies therefore suggest that direct reprogramming of reactive glial cells into functional neurons in vivo could provide an alternative approach for repair of injured or diseased brain.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / pathology*
  • Animals
  • Antigens / metabolism
  • Astrocytes / metabolism
  • Astrocytes / pathology
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Brain Injuries / pathology*
  • Cellular Reprogramming*
  • Disease Models, Animal
  • GABAergic Neurons / metabolism
  • GABAergic Neurons / pathology
  • Glutamates / metabolism
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Nerve Tissue Proteins / metabolism
  • Neuroglia / cytology*
  • Neuroglia / metabolism
  • Neuroglia / pathology
  • Neurons / cytology*
  • Neurons / metabolism*
  • Neurons / pathology
  • Proteoglycans / metabolism

Substances

  • Antigens
  • Basic Helix-Loop-Helix Transcription Factors
  • Glutamates
  • Nerve Tissue Proteins
  • Proteoglycans
  • chondroitin sulfate proteoglycan 4
  • NeuroD protein