Transcription factors promote neural regeneration after spinal cord injury

NEURAL REGENERATION RESEARCH, 2022 · DOI: 10.4103/1673-5374.335805 · Published: April 1, 2022

Spinal Cord Injury Regenerative Medicine Neurology

Simple Explanation

Human spinal cord injury (SCI) results in locomotor and sensory disabilities, which severely affect the quality of life. To restore function after SCI, it is necessary to repair and reconstruct the damaged local circuitry. Promoting endogenous NSPCs to differentiate into functional neurons by transcription factors for regeneration and restoration of local neural circuitry is an emerging approach to develop therapeutics for traumatic CNS injury and neurodegenerative disorders. Our studies support that transcription factor-based gene therapy may be a viable treatment for SCI, as we have shown that Gsx1 or Nkx6.1 promote neural regeneration in the adult injured spinal cord.

Study Duration

Not specified

Participants

mouse model of lateral hemisection SCI

Evidence Level

Not specified

Key Findings

1
Virus-mediated Gsx1 expression leads to locomotor functional recovery while Nkx6.1 expression does not have a significant benefit in regaining locomotor function.
2
Gsx1 increases the number of glutamatergic and cholinergic neurons and reduces the number of GABAergic interneurons.
3
Gsx1 expression promotes 5-HT neuronal activity, which enhances locomotor functional recovery.

Research Summary

Major hurdles in neural regeneration include a limited level of neurogenesis in the adult spinal cord and an inflammatory microenvironment that inhibits neurogenesis and axon regeneration. Our studies show that lentivirus-mediated expression of Gsx1 or Nkx6.1 promotes NSPC signaling, activates NSPCs, increases cell proliferation and the number of specific interneurons and neuronal activities. It also reduces astrogliosis and glial scar formation at the lesion site As a heterogeneous mix of the NSPCs that contribute to neural regeneration after SCI in mammals, targeted approaches to modulate NSPC behavior are necessary for a better understanding of the cellular and molecular mechanism of the transcription factor-based gene therapies.

Practical Implications

Therapeutic Development

Reactivation of neurogenic transcription factors in adults may be key to treating traumatic CNS injuries and demyelinating conditions.

Targeted Gene Therapy

Designing targeted gene therapy for NSPCs with neurogenic transcription factors could improve outcomes.

Combination Therapy

Combining Gsx1 and Nkx6.1 may offer better results for SCI treatment than either alone.

Study Limitations

1
Low reprogramming efficiency when using Sox2 or NeuroD1.
2
Functional recovery may require generation of specific cell-types native to the spinal cord.
3
It is difficult to target NSPCs because they are not only heterogeneous but also resemble reactive astrocytes in their gene expression profiles

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