Neurog2 directly converts astrocytes into functional neurons in midbrain and spinal cord

Cell Death Dis. 2021 Mar 1;12(3):225. doi: 10.1038/s41419-021-03498-x.

Abstract

Conversion of astrocytes into neurons in vivo offers an alternative therapeutic approach for neuronal loss after injury or disease. However, not only the efficiency of the conversion of astrocytes into functional neurons by single Neurog2, but also the conundrum that whether Neurog2-induced neuronal cells (Neurog2-iNs) are further functionally integrated into existing matured neural circuits remains unknown. Here, we adopted the AAV(2/8) delivery system to overexpress single factor Neurog2 into astrocytes and found that the majority of astrocytes were successfully converted into neuronal cells in multiple brain regions, including the midbrain and spinal cord. In the midbrain, Neurog2-induced neuronal cells (Neurog2-iNs) exhibit neuronal morphology, mature electrophysiological properties, glutamatergic identity (about 60%), and synapse-like configuration local circuits. In the spinal cord, astrocytes from both the intact and lesioned sources could be converted into functional neurons with ectopic expression of Neurog2 alone. Notably, further evidence from our study also proves that Neurog2-iNs in the intact spinal cord are capable of responding to diverse afferent inputs from dorsal root ganglion (DRG). Together, this study does not merely demonstrate the feasibility of Neurog2 for efficient in vivo reprogramming, it gives an indication for the Neurog2-iNs as a functional and potential factor in cell-replacement therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Astrocytes / metabolism*
  • Astrocytes / ultrastructure
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism*
  • Cell Transdifferentiation*
  • Cells, Cultured
  • Dependovirus / genetics
  • Gene Transfer Techniques
  • Genetic Vectors
  • Glutamate Decarboxylase / genetics
  • Glutamate Decarboxylase / metabolism
  • Mesencephalon / metabolism*
  • Mesencephalon / ultrastructure
  • Mice, Transgenic
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Neurogenesis*
  • Neurons / metabolism*
  • Neurons / ultrastructure
  • Oxidoreductases Acting on CH-NH Group Donors / genetics
  • Oxidoreductases Acting on CH-NH Group Donors / metabolism
  • Phenotype
  • Spinal Cord / metabolism*
  • Spinal Cord / ultrastructure
  • Vesicular Glutamate Transport Protein 2 / genetics
  • Vesicular Glutamate Transport Protein 2 / metabolism

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Nerve Tissue Proteins
  • Neurog2 protein, mouse
  • Slc17a6 protein, mouse
  • Vesicular Glutamate Transport Protein 2
  • Oxidoreductases Acting on CH-NH Group Donors
  • formyltetrahydrofolate dehydrogenase
  • Glutamate Decarboxylase
  • glutamate decarboxylase 1