Regeneration of Functional Neurons After Spinal Cord Injury via in situ NeuroD1-Mediated Astrocyte-to-Neuron Conversion

Frontiers in Cell and Developmental Biology, 2020 · DOI: 10.3389/fcell.2020.591883 · Published: December 16, 2020

Simple Explanation

Spinal cord injury often results in permanent motor and sensory function loss because the damaged neurons are not easily replaced. This study explores a new method, in vivo neuronal reprogramming, to regenerate neurons from existing glial cells. The researchers used AAV NeuroD1-based gene therapy to convert astrocytes, a type of glial cell, into neurons after spinal cord injury. They found that NeuroD1 effectively converted astrocytes into neurons in the dorsal horn of the injured spinal cord. These newly created neurons were able to mature, integrate into the spinal cord's network, and become active. This suggests a potential new approach to spinal cord repair by regenerating functional neurons directly within the spinal cord.

Study Duration

8 Weeks

Participants

GAD-GFP mice (Tg[Gad1-EGFP]94Agmo/J) and wild-type C57BL/6 mice of 2–4 months old

Evidence Level

Not specified

Key Findings

1
NeuroD1 can effectively convert reactive astrocytes into functional neurons in the dorsal horn of the injured spinal cord, with a conversion rate of approximately 95%.
2
The NeuroD1-converted neurons predominantly acquire a glutamatergic neuronal subtype, expressing spinal cord-specific markers like Tlx3, indicating the influence of local microenvironment and astrocytic lineage on cell fate.
3
Combining NeuroD1 with Dlx2 increases the proportion of GABAergic neurons generated in the spinal cord, suggesting a method to control the subtype of neurons produced through in vivo reprogramming.

Research Summary

This study investigates the potential of NeuroD1-mediated in vivo astrocyte-to-neuron conversion as a novel approach for spinal cord repair. The researchers used AAV NeuroD1-based gene therapy to regenerate neurons from reactive astrocytes after spinal cord injury (SCI). The results showed that NeuroD1 effectively converts reactive astrocytes into functional neurons in the dorsal horn of the injured spinal cord. These converted neurons were able to mature and integrate into local spinal cord circuitry. The study also found that the newly generated neurons primarily acquire a glutamatergic phenotype, and that combining NeuroD1 with Dlx2 can increase the generation of GABAergic neurons, suggesting a potential method to regenerate a diversity of neuronal subtypes for functional repair after SCI.

Practical Implications

Therapeutic Potential

AAV NeuroD1-based gene therapy may offer a new therapeutic avenue for spinal cord injury by regenerating functional neurons in situ.

Understanding Cell Fate

The study highlights the importance of local microenvironment and glial lineage in determining the fate of converted neurons, providing insights for targeted neuronal regeneration.

Combinatorial Approach

Combining different transcription factors, such as NeuroD1 and Dlx2, may allow for the generation of specific neuronal subtypes, enabling more precise and effective functional repair.

Study Limitations

1
The study primarily focuses on the dorsal horn of the spinal cord, and further research is needed to investigate motor neuron regeneration in the ventral horn.
2
The long-term effects and functional improvements of NeuroD1-mediated neuronal conversion in the contusive SCI model require further evaluation.
3
The exact mechanisms by which the local microenvironment influences the subtype of converted neurons need further investigation.

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